bluuebunny/crossref_metadata_2025 huggingface dataset:
De Novo Heterozygous Mutation in FGFR2 Causing Type II Pfeiffer Syndrome
Authors: Mosalli Rafat , Fatma Alfia , Almatrafi Mohammed A. , Mazroua Mayada , Paes Bosco
Published: June 2022

Pfeiffer syndrome (PS) is an autosomal dominant disorder with three subtypes stemming from heterozygous mutations in the fibroblast growth factors FGFR1 and FGFR2. The subtypes overlap with heterogeneous clinical manifestations and variable prognosis dependent on neurological and respiratory compromise that impact short- and long-term outcomes and survival. We present a male, term infant with type II PS that was diagnostically suspected antenatally based on three-dimensional ultrasonographic findings that were confirmed postnatally by craniofacial tomography and magnetic resonance imaging. A new generation sequencing panel identified a unique de novo FGFR2, c.335 A > G p. Tyr112Cys variant, the first of its kind, and features that closely aligned with subtype II PS. Initial molecular results categorized the mutation as nonpathogenic, but it was later reclassified as pathogenic. Antenatal, multidisciplinary parental counseling about the tentative diagnosis and prognosis facilitated postnatal decisions that culminated in an informed choice for palliative care and early demise.
Dynamic Analysis of a Rotating Cardan Shaft under the Influence of a Breathing Crack and Dense Fluid Force
Authors: Tchomeni Kouejou Bernard Xavier , Alugongo Alfayo Anyika
Published: June 2022

To extract any information from a complex data vibration, the time-frequency technique represents a suitable tool and a better indicator of the overall asset health of a rotating machine. Fluid influences on a cracked driveshaft and dynamic analysis of a rotating Cardan shaft are discussed in this paper. The study of the forced vibration signals of the rotating Cardan shaft focused uniquely on the impact of the hydrodynamic forces near the cracked driveshaft and its transmission of power to a driven shaft. By merging each subsystem consisting of the breathing crack mechanism in a rotating shaft, the perturbation function between misaligned shafts and transient hydrodynamic forces results in a strongly nonlinear system of partial differential equations, which becomes complicated when analyzing the dynamic response of the Cardan system. In view of the complexity of the Cardan system, the instantaneous frequency identification based on synchrosqueezing wavelet transform filters is numerically used to provide a reliable indication of the rotating system equipment’s health. A conclusive dynamic analysis through the wavelet synchrosqueezing demonstrated that the Cardan joint and the hydrodynamic resistance forces have a high impact on the system’s vibration characteristics and significantly influence the transmission motion with a continuous increase of the driven shaft vibration amplitudes.
Intelligent Deployment and Development Strategy of Agricultural Farmland Based on Improved Architecture of Internet of Things
Authors: Li Xiaofen
Published: June 2022

Agricultural modernization has gradually become the direction of future agricultural development. With the improvement of the technical capacity of the Internet of things, a new agricultural development model, namely, intelligent agriculture, has gradually emerged. It can not only improve the production efficiency of agriculture but also improve the efficiency of resource utilization. The main work of the software design of the terminal node is the IoT network connection, the sensor work acquisition, and the packaging of the collected data for transmission and acceptance control to fundamentally alleviate the pressure on food security and ensure the sustainable development of China's agriculture. The experiment demonstrates that the curve temperature cycle of the agricultural greenhouse monitored by the system in this paper is normal, and the maximum temperature has been constant under different time cycles. For example, the maximum values of 5, 15, and 20 are all 0.67.
Genistein: Therapeutic and Preventive Effects, Mechanisms, and Clinical Application in Digestive Tract Tumor
Authors: Hou Shenglin
Published: June 2022

Genistein is one of the numerous recognized isoflavones that may be found in a variety of soybeans and soy products, including tofu and tofu products. The chemical name for genistein is 4′, 5, 7-trihydroxyisoflavone, and it is found in plants. In recent years, the scientific world has become more interested in genistein because of its possible therapeutic effects on many forms of cancer. It has been widely investigated for its anticancer properties. The discovery of genistein’s mechanism of action indicates its potential for apoptosis induction and cell cycle arrest in gastrointestinal cancer, especially gastric and colorectal cancer. Genistein’s pharmacological activities as determined by the experimental studies presented in this review lend support to its use in the treatment of gastrointestinal cancer; however, additional research is needed in the future to determine its efficacy, safety, and the potential for using nanotechnology to increase bioavailability and therapeutic efficacy.
Ruscogenin Ameliorated Sjögren’s Syndrome by Inhibiting NLRP3 Inflammasome Activation
Authors: He Jing , Wang Yue , Xu Lei , Xu Changsong , Zhu Yamei , Xu Meimei , Chen Yueyue , Guo Liang , Hu Wei , Xu Dake , Jing Rongyue , Xu Bo
Published: June 2022

This article investigated the role and the specific mechanism of Ruscogenin in Sjögren's syndrome (SS). NOD/ShiLtJ mice were treated with Ruscogenin, and acinar cells isolated from submandibular glands were treated with TNF-α, Ruscogenin and transfected with NLRP3 overexpression plasmid. Salivary flow rate (SFR) was measured at weeks 11, 13, 15, 17, and 20. Histological analysis of the submandibular glands was conducted by hematoxylin-eosin staining assay. IL-6, IL-17, TNF-α, and IL-1β mRNA expression was detected through qRT-PCR. AQP 5, AQP 4, P2X7R, NLRP3, caspase 1, IL-1β, Bax, and Bcl-2 protein levels were tested by western blot. Cell apoptosis was assessed through acridine orange and propidium iodide (AO/PI) staining assay and flow cytometry assay. Ruscogenin ameliorated the SFR and submandibular gland inflammation of NOD/ShiLtJ mice. Ruscogenin promoted the preservation of acinar cells and suppressed inflammation-related factors (P2X7R, NLRP3, caspase 1, and IL-1β) in submandibular gland tissues of NOD/ShiLtJ mice. Ruscogenin inhibited acinar cell apoptosis in NOD/ShiLtJ mice and reversed TNF-α-induced apoptosis and inflammation of acinar cells. NLRP3 overexpression reversed the repressive effect of Ruscogenin on TNF-α-induced inflammation and apoptosis of acinar cells. Ruscogenin ameliorated SS by inhibiting NLRP3 inflammasome activation.
An Optimized PI Controller-Based SEPIC Converter for Microgrid-Interactive Hybrid Renewable Power Sources
Authors: Mohanta Harish Chandra , Geetha B. T. , Alzaidi Mohammed S. , Dhanoa Inderjit Singh , Bhambri Pankaj , Mamodiya Udit , Akwafo Reynah
Published: June 2022

With the use of hybrid renewable sources for example solar and wind turbines, an autonomous electric power generation system based on self-sufficient electric power generation is built in order to promote a smart and ecologically friendly environment. The three-phase inverter that links this scattered generating unit to the grid is in charge of ensuring that it is properly connected to the grid. While the energy produced by the hybrid unit is being utilized, it is also being stored in the batteries so that it may be used to transport power when other sources of power are not available, such as when the grid is down. This stand-alone power conversion and storage system is being built with the aid of power electronic converters and controllers, among other components, in order to ensure balanced power flow operation. To produce PWM pulses for the generator side converter, a PI controller is utilized. On the PV side, an improved PI controller is used to drive the SEPIC converter, which increases the transient responsiveness of the converter while it is being controlled by the controller. In order to communicate with the grid, the generated electricity is routed via a three-phase inverter that is controlled according to the DQ theory. The challenges connected with poor power quality are substantially resolved by the converters that have been presented. For simplicity of use, an automated control function has been introduced; in addition, an interactive MATLAB model of the system is being developed for minor and medium-scale microgrid applications; also, a prototype is being created to verify the simulation results.
The Impacts of Internet + Rural Financial Industry on County Economy and Industrial Growth Algorithm
Authors: Huang Yuanhui , Ye Yimao
Published: June 2022

In recent years, commercial banks and rural financial institutions in and below the county area have developed rapidly, and the number of outlets has increased rapidly. But for the vast rural areas of the country, the number of outlets is still limited. At present, there are still a large number of areas with zero financial coverage in rural the country. The development of the financial industry in a region not only affects the level of local economic growth but also has a good effect on improving the income level of local residents and changing the way of local economic development. To better develop rural finance and county economy, this paper constructs an artificial neural network model and FA model to predict the rural finance industry, and four indicators are selected to test the performance measurement of the model. The hit rates of the five models are 54.65%, 53.75%, 59.78%, 65.1%, and 73.08%, respectively. The model proposed in this paper has the highest hit rate and can predict rural finance more accurately as well, allowing for clearer changes in county economic and industrial growth.
Realization of Mental Health Counseling Service Platform Using Wireless Communication Network and Genetic Algorithm
Authors: Chen Zhiming , Duan Youtao , Chen Yan
Published: June 2022

Healthy life has always been the goal pursued by human beings. Physical health is not just about physical health but also mental health. Although mental health has become more and more important in people’s minds, there are still a large number of people who do not understand psychological counseling or do not enjoy psychological counseling. Based on this, this paper was aimed at designing a mental health counseling service platform, so that most people can solve their own psychological problems through the modern high-speed developed network. For the design of the platform, this paper focuses on the design of three functions: instant messaging, psychological testing, and expert consultation. The optimization of the platform uses the genetic algorithm to optimize the wireless communication technology, so that the communication efficiency of the platform is higher and the energy consumption is less. The experimental results of this paper show that compared with the other three algorithms, the algorithm in this paper is in the leading position, and the overall power consumption is reduced by 10%. And after testing, the platform of this paper can operate effectively and can provide a solution platform for mental health counseling users.
An Extremely Rare Presentation of Four Coronary Anomaly Patterns Originating from the Right Coronary Sinus
Authors: Braiteh Nabil , Rehman Wajeeh , Ali Wajiha , Ahmed Owais
Published: June 2022

Background. “Coronary anomaly” is defined as the coronary feature or pattern seen in <1% of the population. The most common CAAs are anomalies of origin, specifically having a separate LCX and LAD origin with an incidence of 0.41%. The second most common anomaly is the LCX arising from the RCA (0.37%). Treatment options include CABG, coronary unroofing, reimplantation, or medical therapy. Case Presentation. We present the case of an 85-year-old male who presents with an acute coronary syndrome who was found to have an extremely rare combination of different coronary anomaly patterns including left main coronary artery (LMCA) atresia, small LAD arising posteriorly from the right coronary cusp, anomalous left circumflex artery arising from the RCA, and an anomalous LAD arising from the left circumflex artery which is originating from the RCA. Conclusions. To the best of our knowledge, this is the first case report to describe four coronary anomalies in a single patient. When CAAs are diagnosed, it is of utmost importance for cardiologists to do further imaging and workup that might include a stress test to be able to offer patients the best management options.
An Optimized Hyperparameter of Convolutional Neural Network Algorithm for Bug Severity Prediction in Alzheimer’s-Based IoT System
Authors: Yousaf Iqra , Anwar Fareeha , Imtiaz Salma , Almadhor Ahmad S. , Ishmanov Farruh , Kim Sung Won
Published: June 2022

Softwares are involved in all aspects of healthcare, such as booking appointments to software systems that are used for treatment and care of patients. Many vendors and consultants develop high quality software healthcare systems such as hospital management systems, medical electronic systems, and middle-ware softwares in medical devices. Internet of Things (IoT) medical devices are gaining attention and facilitate the people with new technology. The health condition of the patients are monitored by the IoT devices using sensors, specifically brain diseases such as Alzheimer, Parkinson’s, and Traumatic brain injury. Embedded software is present in IoT medical devices and the complexity of software increases day-by-day with the increase in the number and complexity of bugs in the devices. Bugs present in IoT medical devices can have severe consequences such as inaccurate records, circulatory suffering, and death in some cases along with delay in handling patients. There is a need to predict the impact of bugs (severe or nonsevere), especially in case of IoT medical devices due to their critical nature. This research proposes a hybrid bug severity prediction model using convolution neural network (CNN) and Harris Hawk optimization (HHO) based on an optimized hyperparameter of CNN with HHO. The dataset is created, that consists of the bugs present in healthcare systems and IoT medical devices, which is used for evaluation of the proposed model. A preprocessing technique on textual dataset is applied along with a feature extraction technique for CNN embedding layer. In HHO, we define the hyperparameter values of “Batch Size, Learning Rate, Activation Function, Optimizer Parameters, and Kernel Initializers,” before training the model. Hybrid model CNN-HHO is applied, and a 10-fold cross validation is performed for evaluation. Results indicate an accuracy of 96.21% with the proposed model.
Research on Human Pose Capture Based on the Deep Learning Algorithm
Authors: Xie Wenbin , Gu Xueyun , Li Xiuming , Zheng Luqi , Li Guodong , Lu Haisheng , Li Huakang
Published: June 2022

A method based on the deep learning algorithm is proposed to accurately capture the posture of the human body. It is one of the important means to improve athletes’ competitive level in modern sports to accurately analyze the posture of sports training by technical means. Aiming at the application demand of using artificial intelligence technology to accurately analyze and predict the motion training posture, a motion posture analysis and prediction system based on deep learning is designed in this paper. Based on the Arduino embedded development board and equipped with multiple IMU sensors, the scheme established a system to collect accurate human movement data such as speed and acceleration by using stepper motors and obtained accurate human movement data. The experimental results show that these models have been trained with H3.6 m data sets. The sampling frequency was reduced to 25 Hz, and the joint angles were converted into exponential graphs. When the time window covers approximately 1 660 ms, the loop network will be initialized to 40 frames, equivalent to 1 600 ms. For each action, a separate pretrained recursive model is used. It is proved that the method based on deep learning can reduce the prediction error of fine-tuning specific movements and effectively classify and predict the movements not included in the original training data.
Pharmacological Mechanism of Ganlu Powder in the Treatment of NASH Based on Network Pharmacology and Molecular Docking
Authors: Gao Rui , Zhang Xiaobo , Zhou Zhen , Sun Jiayi , Tang Xuehua , Li Jialiang , Zhou Xin , Shen Tao
Published: June 2022

Nonalcoholic steatohepatitis (NASH), a progression of nonalcoholic fatty liver disease (NAFLD), is a clinical syndrome characterized by liver steatosis, inflammation, and hepatocellular damage. Ganlu powder (GLP) is a classic traditional Chinese medicine prescription that has shown favorable treatment effects on NASH. However, the underlying therapeutic mechanisms are still poorly understood. This study is aimed at exploring the potential mechanism of GLP in the treatment of NASH via network pharmacology and molecular docking. PubMed and CNKI databases were used to identify the components of GLP. Swiss and STITCH databases were employed to obtain corresponding drug targets. NASH targets were adopted from the Therapeutic Target Database (TTD), DisGeNET, DrugBank, GeneCards, and MalaCards databases. Cytoscape software was utilized to construct “drug-ingredient-target-disease” networks and the protein-protein interaction (PPI) network of GLP in NASH. AKT1 was identified as the key target. The GO functional enrichment analysis revealed that GLP might treat NASH by modulating the inflammatory response and regulating phosphatidylinositol 3-kinase signaling. The KEGG analysis showed that GLP might treat NASH by regulating the tumor necrosis factor (TNF) signal pathway by affecting the role of AKT1. According to the network pharmacology results, a virtual docking of active compounds with AKT1 was carried out, and the results indicated that the 7 components, berberine, epiberberine, jatrorrhizine, coptisine, palmatine, evodiamine, and rutecarpine, can bind stably with AKT1 and have higher binding energy than AKT1 inhibitors. The overall study findings suggest that GLP may treat NASH by regulating AKT1.
Signal Analysis of Characteristics Using Passive Acoustic Emission Technique in Gas‐Solid Pipeline Flows
Authors: Qin Weigang
Published: June 2022

This paper investigates a case study of the use of a passive acoustic sensor for online measurement of the dilute phase gas‐solid pipeline flows. The acoustic emission sensor is mounted externally on a stainless steel line conveying silica powders. For different experimental conditions, including the solid to air mass ratios from 0.6 to 1.4 and the gas volume flows from 160 to 240 m3/h, the sound signals in the pipeline are discussed using the wavelet transform technique. The measured values of transmission mechanism of two different lengths, 25 mm and 35 mm, are analyzed. The results show that the variation tendency of standard deviations is consistent and that the noninvasive, online acoustic detect technique can be regarded as a satisfactory tool in gas‐solid flows.
The Effect of Inhalation Aromatherapy and Music Therapy on Anxiety in Patients Undergoing Shockwave Lithotripsy: A Randomized Controlled Clinical Trial
Authors: Rohi Ganji Mohammad , Jafari Faranak , Rezaeian Shahab , Abdi Hossein , Farzaei Mohammad Hussein , Khatony Alireza
Published: June 2022

Patients undergoing shock wave lithotripsy (SWL) have a high level of anxiety. This study was aimed to compare the effect of music therapy and aromatherapy on patients’ anxiety levels during SWL. In this clinical trial, 176 patients undergoing SWL were randomly assigned to four groups: music therapy, aromatherapy, combined music therapy and aromatherapy, and control. The state-trait anxiety inventory (STAI) was used to collect data. In the aromatherapy group, three drops of rosemary essential oil were used during SWL. For the music therapy group, soft music was played during SWL. In the music therapy and aromatherapy group, soft music and three drops of rosemary essential oil were used simultaneously. In the control group, three drops of aromatic distilled water were used. The results showed that all patients had moderate anxiety before the intervention. The analysis of variance test did not show a statistically significant difference between the groups, but this difference was significant after the intervention. The levels of anxiety after the intervention were higher in the music therapy, aromatherapy, and combined music therapy and aromatherapy groups than in the control group. The results of the paired t-test showed the level of anxiety after the intervention was significantly increased in the intervention group (

P
<
001

). In conclusion, the results indicated that music therapy, aromatherapy, and combined music therapy and aromatherapy had no effect on reducing patients’ anxiety during SWL.
Effects of Graphene Oxide and Reduced Graphene Oxide on the Mechanical and Dielectric Properties of Acrylonitrile-Butadiene Rubber and Ethylene-Propylene-Diene-Monomer Blend
Authors: Mensah Bismark , Konadu David Sasu , Agyei-Tuffour Benjamin
Published: June 2022

The composites of properties of ethylene-propylene-diene-monomer (E) and acrylonitrile butadiene-rubber (N) composites of graphene oxide (GO) and reduced graphene oxide (G) were prepared by a combination of solution and open-roll method. They include single matrices (EGO and EG) and blends N/E, 20 part of hundreds of rubber (phr)/80 phr (A), 80 phr/20 phr (B), and 50 phr/50 phr(C) blend containing GO and G. The physico-mechanical properties including vulcanization, tensile, glass transition temperature (

T

g

), and dielectric spectroscopic properties were evaluated. The N-rich systems reinforced with GO, cured faster than the E-rich systems. Also, N-rich systems obtained the highest dielectric constant

ɛ

′

, especially when GO and G were incorporated, for example, NG and N-GO obtained 317 and 283% increment in

ɛ

′

than EG and EGO, respectively. In terms of tensile properties, AGO exhibited the highest strength and elongation at break properties (%). Therefore, solution mixing technique of rubber blends filled with nanoinclusion can be achieved with the tendency of reducing cost without the use of compatibilizer and still maintain the integrity of the physical properties of the final product. The result obtained therefore shows that the current compositions can find various applications in oil/gas sealants, heat-resistant applications, and energy storage materials with minimal losses.
Modeling the Temperature Field of the Microwave Heating Asphalt Mixture with the Utilization of a Mathematical Model
Authors: Zhang Yifei , Wang Qingxian , Guo Bofu
Published: June 2022

Microwave heating asphalt mixture is an auspicious method since it requires a minimum level of outside intervention. It has been a recent method with some certain advantages over conventional ones. To obtain the temperature field of microwave heating asphalt mixture utilizing an oblique horn antenna, the aperture field of the oblique horn antenna was deduced based on the Maxwell equations. The three-dimensional mathematical model of a microwave heating asphalt mixture was established by introducing a position relation of the horn caliber called an oblique horn antenna, and the calculation results were simplified and verified by experiments. The results showed that the calculated values of the mathematical model tally with the experimental outcomes. The model is found to be accurate and reliable.
A Novel Hybrid Model Based on Spatiotemporal Correlation for Air Quality Prediction
Authors: Dun Ao , Yang Yuning , Lei Fei
Published: June 2022

With the rapid development of urbanization, environmental pollution has drawn worldwide attention. Accurate air quality prediction is very significant for alleviating severe pollution conditions and human healthy life. A novel hybrid model that combines a spatiotemporal correlation analysis method and an effectively simple network is proposed to forecast the concentrations of air pollutants. Firstly, a new calculation method considering distance and

PM

2.5

concentrations among stations is proposed to select stations strongly correlated with the target station on the basis of grey relation analysis. Secondly, a fully convolutional network is proposed to extract spatiotemporal features efficiently based on a temporal convolutional network. In addition, meteorological factors and other pollutants are selected as auxiliary factors to further improve the prediction accuracy. To verify the validity of the proposed model, the air quality and meteorological data collected from 40 monitoring stations in Fushun, which is an important industrial city in China, are applied for air quality prediction. The performance of models is evaluated by a series of metrics. The RMSE, MAE, and

R

2

values of the proposed model are 12.505, 8.214, and 0.884 for forecasting the next hour

PM

2.5

concentration. Compared with other conventional models and hybrid models, the proposed model verified that it outperforms the other models with air quality prediction.
Squalene Epoxidase Metabolic Dependency Is a Targetable Vulnerability in Castration-Resistant Prostate Cancer
Authors: Shangguan Xun , Ma Zehua , Yu Minghao , Ding Jie , Xue Wei , Qi Jun
Published: June 2022

Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC.

Significance:

This study reveals PTEN and p53 deficiency confers a dependence on SQLE-mediated cholesterol metabolism, providing insights for new therapeutic strategies for treating castration-resistant prostate cancer.
Phase I Trial of a Novel Anti-HER2 Antibody–Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer
Authors: Zhang Jian , Ji Dongmei , Shen Weina , Xiao Qin , Gu Yajia , O'Shaughnessy Joyce , Hu Xichun
Published: June 2022

Purpose:

ARX788 is a novel antibody–drug conjugate (ADC) comprised of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269 that is site-specifically conjugated to the antibody via a nonnatural amino acid incorporated into the antibody. Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in patients with HER2-positive metastatic breast cancer (MBC).

Patients and Methods:

Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, or 1.5 mg/kg every 3 weeks, or 0.88, 1.1, or 1.3 mg/kg every 4 weeks. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities.

Results:

In total, 69 patients were enrolled. No DLT or drug-related deaths occurred. Most patients (67/69; 97.1%) experienced at least one treatment-related adverse event (TRAE). Common (≥ 30%) TRAEs included an increase in aspartate aminotransferase, an increase in alanine aminotransferase, corneal epitheliopathy, alopecia, hypokalemia, interstitial lung disease (ILD)/pneumonitis, and an increase in aldosterone. While 34.8% of participants experienced ILD/pneumonitis, only 2 had a severity of grade 3. At 1.5 mg/kg every 3 weeks, the recommended phase II dose, the objective response rate was 65.5% [19/29, 95% confidence interval (CI), 45.7–82.1], the disease control rate was 100% (95% CI, 81.2–100), and the median progression-free survival was 17.02 months (95% CI, 10.09–not reached).

Conclusions:

ARX788 demonstrated a manageable safety profile with promising preliminary signs of activity in patients with HER2-positive MBC who progressed on prior anti-HER2 therapies.
Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer
Authors: Schoenfeld Adam J. , Rizvi Hira A. , Memon Danish , Shaverdian Narek , Bott Matthew J. , Sauter Jennifer L. , Tsai C. Jillian , Lihm Jayon , Hoyos David , Plodkowski Andrew J. , Perez-Johnston Rocio , Sawan Peter , Egger Jacklynn V. , Greenbaum Benjamin D. , Rimner Andreas , Riely Gregory J. , Rudin Charles M. , Rusch Valerie W. , Gomez Daniel R. , Hellmann Matthew D.
Published: June 2022

Purpose:

Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.

Experimental Design:

All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions.

Results:

Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g., radiation, surgery; HR, 0.41; P = 0.039). Fifty-eight percent of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than 2 years after local therapy.

Conclusions:

OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.
Phase II Study of TQB2450, a Novel PD-L1 Antibody, in Combination with Anlotinib in Patients with Locally Advanced or Metastatic Soft Tissue Sarcoma
Authors: Liu Jiayong , Gao Tian , Tan Zhichao , Li Shu , Xu Jie , Bai Chujie , Xue Ruifeng , Xie Lu , Zhang Lu , Fan Zhengfu , Guo Wei
Published: June 2022

Purpose:

To explore the efficacy and safety of TQB2450 combined with anlotinib in patients with locally advanced or metastatic soft-tissue sarcoma (LA/M STS).

Patients and Methods:

This was a single arm phase II study (TQB2450-Ib-02 study) performed at two hospitals in China to assess the potency of TQB2450 combined with anlotinib in patients with LA/M STS. Patients were previously unresponsive to at least one chemotherapy regimen. Anlotinib (12 mg every day) was administered orally from day 1 to day 14 every 3 weeks. TQB2450 was administered by intravenous infusion at 1,200 mg on day 1 every 3 weeks. The primary endpoint was the objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety.

Results:

Between January 2019 and June 2020, 30 patients were enrolled. The ORR was 36.67% and the DCR was 76.67%. The median PFS was 7.85 months [95% confidence interval (CI), 2.89–23.06] and the median OS was not reached [95% CI, 10.58–not estimable (NE)]. Among the patients with alveolar soft part sarcoma (ASPS; 12/30, 40%), the ORR was 75% and the median PFS was 23.06 months (95% CI, 8.97–NE). The most common treatment related adverse events were hypothyroidism (76.67%), hypertriglyceridemia (63.33%), hypercholesterolemia (60.00%), and elevated blood lactate dehydrogenase (53.33%).

Conclusions:

The study showed the promising activity in patients with ASPS, also indicating the trend of treatment efficacy in other sarcomas. The toxicity was tolerable. More studies with larger sample size and controlled arm were warranted.
Quantifying the Benefits of Digital Biomarkers and Technology-Based Study Endpoints in Clinical Trials: Project Moneyball
Authors: Mori Hiromasa , Wiklund Stig Johan , Zhang Jason Yuren
Published: June 2022

Introduction: Digital biomarkers have significant potential to transform drug development, but only a few have contributed meaningfully to bring new treatments to market. There are uncertainties in how they will generate quantifiable benefits in clinical trial performance and ultimately to the chances of phase 3 success. Here we have proposed a statistical framework and ran a proof-of-concept model with hypothetical digital biomarkers and visualized them in a familiar manner to study power calculation. Methods: A Monte Carlo simulation for Parkinson’s disease (PD) was performed using the Captario SUM® platform and illustrative study technology impact calculations were generated. We took inspiration from the EMA-qualified wearable-derived digital endpoint stride velocity 95th centile (SV95C) for Duchenne muscular dystrophy, and we imagined a similar measurement for PD would be available in the future. DaTscan enrichment and “SV95C-like” endpoint biomarkers were assumed on a hypothetical disease-modifying drug pivotal trial aiming for an 80% probability of achieving a study p value of less than 0.05. Results: Four scenarios with different combinations of technologies were illustrated. The model illustrated a way to quantify the magnitude of the contributions that enrichment and endpoint technologies could make to drug development studies. Discussion/Conclusion: Quantitative models could be valuable not only for the study sponsors but also as an interactive and collaborative engagement tool for technology players and multi-stakeholder consortia. Establishing values of digital biomarkers could also facilitate business cases and financial investments.
Heart Rate Variability in Huntington Disease: A Long-Term Longitudinal Study
Authors: Kobal Jan , Cankar Ksenija , Melik Ziva
Published: June 2022

Introduction: The aim of the study was to follow tonic and phasic autonomic nervous activity in Huntington disease (HD) mutation carriers and patients. Methods: Evaluation of motor functions and total functional capacity was performed in 30 HD mutation carriers or patients at the beginning and in 22 subjects after 8–10 years. Continuous arterial blood pressure, heart rate (HR), and ECG at rest were measured, and HR variability analysis was performed in four different ways. A group of matched controls was also evaluated. Results: Eighteen subjects were assorted in 3 groups: 6 HD mutation carriers without motor symptoms (PHD) who remained so (PHD-PHD); 6 early symptomatic patients (EHD) who remained so (EHD-EHD); and 6 early symptomatic patients who deteriorated to a late symptomatic (LHD) (EHD-LHD). At the beginning, sympathetic tonic activity in PHD was elevated, according to mean arterial pressure (99 ± 10.6 mm Hg) higher than in controls (85 ± 8.7 mm Hg) and EHD (82 ± 9.9 mm Hg) (Dunnett’s test, p < 0.05) and higher HR (78 ± 16 beats/min) than after 8–10 years (64 ± 11.3 beats/min) (paired t test, p < 0.05). There was also a decreased phasic sympathetic activity in EHD patients compared controls at the beginning (219 ± 106 vs. 664 ± 466 s2/Hz) and after 8–10 years (182 ± 136 vs. 1,012 ± 1,369 s2/Hz) (Dunnett’s test, p < 0.05). In patients who deteriorated from EHD to LHD, there was a drop in phasic parasympathetic activity from 887 ± 433 to 230 ± 235 s2/Hz (paired t test, p < 0.05). Conclusions: Our long-term observational study provides important information on the timeline of ANS activity in HD progress. There was a temporary increase in cardiac and vascular sympathetic activity in PHD subjects. The normalization of HR in PHD subjects might indicate the approach of an outbreak of clinical disease phase.
Penalized Logistic Regression Analysis for Genetic Association Studies of Binary Phenotypes
Authors: Yu Ying , Chen Siyuan , Jones Samantha Jean , Hoque Rawnak , Vishnyakova Olga , Brooks-Wilson Angela , McNeney Brad
Published: June 2022

Introduction: Increasingly, logistic regression methods for genetic association studies of binary phenotypes must be able to accommodate data sparsity, which arises from unbalanced case-control ratios and/or rare genetic variants. Sparseness leads to maximum likelihood estimators (MLEs) of log-OR parameters that are biased away from their null value of zero and tests with inflated type I errors. Different penalized likelihood methods have been developed to mitigate sparse data bias. We study penalized logistic regression using a class of log-F priors indexed by a shrinkage parameter m to shrink the biased MLE toward zero. Methods: We proposed a two-step approach to the analysis of a genetic association study: first, a set of variants that show evidence of association with the trait is used to estimate m; second, the estimated m is used for log-F-penalized logistic regression analyses of all variants using data augmentation with standard software. Our estimate of m is the maximizer of a marginal likelihood obtained by integrating the latent log-ORs out of the joint distribution of the parameters and observed data. We consider two approximate approaches to maximizing the marginal likelihood: (i) a Monte Carlo EM algorithm and (ii) a Laplace approximation to each integral, followed by derivative-free optimization of the approximation. Results: We evaluated the statistical properties of our proposed two-step method and compared its performance to other shrinkage methods by a simulation study. Our simulation studies suggest that the proposed log-F-penalized approach has lower bias and mean squared error than other methods considered. We also illustrated the approach on data from a study of genetic associations with “Super Senior” cases and middle-aged controls. Discussion/Conclusion: We have proposed a method for single rare variant analysis with binary phenotypes by logistic regression penalized by log-F priors. Our method has the advantage of being easily extended to correct for confounding due to population structure and genetic relatedness through a data augmentation approach.
Reversal of Diabesity: Normalization of Insulin Release Curve in Association with Reversal of Non-Alcoholic Fatty Liver Disease
Authors: Gong Junmei , Chen Bo , Fan Meiqiu , Tian Hui , Liu Haiming , Xiao Yi , Chen Wanhong , Zhang Xiaoyu , Xu Gugen
Published: June 2022

Objective: Type 2 diabetes with obesity is regarded as an incurable, progressive disease with many complications. The hypothesis was tested that glycated haemoglobin (HbA1c) and the insulin release curve can be restored by traceable systematic methods. Methods: 122 people with diabesity were investigated before and after three and 6 months of traceable systematic management methods. Basal body mass index (BMI), fatty liver, HbA1c, and insulin release curve were measured. Results: After 3 months of traceable systematic management, BMI decreased from 30.76 ± 0.48 to 21.86 ± 0.09 kg/m2 (p < 0.001) and remained stable during the last 3 months (21.82 ± 0.09 kg/m2 at 6 months). Colour Doppler ultrasound showed non-alcoholic fatty liver disease (NAFLD) in all diabesity participants at baseline. At 3 months, only one participant had low-grade fatty liver, and fatty liver was reversed in other participants (p < 0.001). The number and grade of fatty liver at 6 months were the same as at 3 months. Fasting plasma glucose decreased and continued to decrease thereafter (p < 0.001). Two-hour postprandial plasma glucose decreased and continued to decline until 6 months (p < 0.001). HbA1c also decreased and maintained this level at 6 months. At baseline, the peak value of insulin release was 1,141.09 ± 43.02 pmol/L at 2 h after meals, and the early phase of insulin secretion was lost. After 3 months of management, the insulin concentration was 621.62 ± 19.32 pmol/L at 2 h after meals. After 6 months, the value decreased, and the early phase of insulin secretion recovered. Conclusions: Normalization of the insulin release curve in type 2 diabetes was achieved by traceable systematic methods. This was associated with recovery from NAFLD. Diabesity is reversible by traceable systematic management.
Comparison of Echocardiographic Changes Between Surgery and Medication Treatment in Patients With Primary Aldosteronism
Authors: Ueda Tomomi , Tsurutani Yuya , Osada Jun , Inoue Kosuke , Hoshino Yoshitomo , Ono Masato , Nakai Kazuki , Saito Jun , Yumoto Kazuhiko , Nishikawa Tetsuo
Published: June 2022

Background

Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information.

Methods and Results

We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group (
P
=0.047). However, this relationship was not noted after multivariable regression analysis (standard β=−0.08,
P
=0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score‐matched analysis.

Conclusions

This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.
B‐Type Natriuretic Peptide and Long‐Term Cardiovascular Mortality in Patients With Coronary Heart Disease
Authors: Stewart Ralph A. H. , Kirby Adrienne , White Harvey D. , Marschner Simone L. , West Malcolm , Thompson Peter L. , Sullivan David , Janus Edward , Hunt David , Kritharides Leonard , Keech Anthony , Simes John , Tonkin Andrew M.
Published: June 2022

Background

The plasma concentration of B‐type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured.

Methods and Results

Six thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient‐years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1‐year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1‐year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44–1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44–1.60]), and years 10–16 (HR, 1.43 [95% CI, 1.36–1.50]),
P
<0.0001 for all.

Conclusions

BNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long‐term risk prediction.
Bidirectional Longitudinal Relationships Between Arterial Stiffness and Hypertension Are Independent of Those Between Arterial Stiffness and Diabetes: A Large‐Scale Prospective Observational Study in Employees of a Japanese Company
Authors: Nakano Hiroki , Shiina Kazuki , Takahashi Takamichi , Fujii Masatsune , Iwasaki Yoichi , Matsumoto Chisa , Yamashina Akira , Chikamori Taishiro , Tomiyama Hirofumi
Published: June 2022

Background

Hypertension and diabetes frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes.

Methods and Results

In this 16‐year prospective observational study, 3960 middle‐aged employees of a Japanese company without hypertension/diabetes at the study baseline underwent annual repeated measurements of blood pressure, serum glycosylated hemoglobin A
1c
levels, and brachial‐ankle pulse wave velocity. By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes, and prediabetes, respectively. Increased brachial‐ankle pulse wave velocity at the baseline was associated with a significant odds ratio (per 1 SD increase) for new onset of prehypertension/hypertension with (2.45/3.28;
P
<0.001) or without (2.49/2.76;
P
<0.001) coexisting prediabetes/diabetes, but not for new onset of prediabetes/diabetes without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between brachial‐ankle pulse wave velocity and hypertension, but no such relationship was observed between brachial‐ankle pulse wave velocity and abnormal glucose metabolism.

Conclusions

In middle‐aged employees of a Japanese company, while bidirectional relationships were found to exist between increased arterial stiffness and hypertension, such a relationship was not found between increased arterial stiffness and diabetes. Therefore, it appears that increased arterial stiffness may be associated with the development of hypertension but not with that of diabetes.