bluuebunny/crossref_metadata_2025 huggingface dataset:
Lifting scheme-based wavelet transform method for improved genomic classification and sequence analysis of Coronavirus
Authors: Kar Subhajit , Ganguly Madhabi , Sen Supratik
Published: June 2023

The paper proposes a lifting scheme-based wavelet transform clustering method as a better alternative to traditional alignment-based virus genome classification and grouping techniques. The efficiency of the proposed alignment-free algorithm have been tested using Coronavirus datasets obtained from NCBI database, against established results from proven techniques. In the proposed approach, the nucleotide sequences are converted into numerical ones leveraging purine–pyrimidine mapping and a DNA walk is calculated to visually interpret them. Second-generation wavelet transform employing Cohen–Daubechies–Feauveau wavelet is applied to the numerical sequences of Coronavirus to determine the approximate coefficients. Approximate coefficients are used to cluster Coronavirus sequences using UPGMA phylogenetic tree for three different datasets of Coronaviruses comprising Coronavirus groups, Human Coronaviruses (HCoVs) and [Formula: see text]–[Formula: see text]–[Formula: see text]–[Formula: see text] Coronavirus genre. The proposed algorithm has successfully classified all the datasets with more than 97% of average accuracy compared in terms of complexity and accuracy against FFT, first-generation DWT, MEGA, and CLUSTAL-W. The obtained accuracy for Corona group is 100%, HCoV dataset is 100%, and for [Formula: see text]–[Formula: see text]–[Formula: see text]–[Formula: see text] CoV is 92%. The runtimes of the algorithm are 0.70, 1.22, and 0.63 sec for the respective Coronavirus datasets.
Passages
Authors: Groce Alex
Published: June 2023

John Sladek's The Complete Roderick [1] collects both of Sladek's novels about the eponymous (though almost everyone gets his name wrong throughout the books) robot: Roderick, or The Education of a Young Machine and sequel, Roderick at Random, or Further Education of a Young Machine. Presumably named for the hero of Tobias Smollet's picaresque 18th century novel The Adventures of Roderick Random, Roderick has his own series of random and absurd adventures.
Analog In-memory Circuit Design of Polynomial Multiplication for Lattice Cipher Acceleration Application
Authors: Du Sichun , Li Jun , Sun Chen , Xiao Pingdan , Hong Qinghui , Zhang Jiliang
Published: June 2023

As the core operation of lattice cipher, large-scale polynomial multiplication is the biggest computational bottleneck in its realization process. How to quickly calculate polynomial multiplication under resource constraints has become an urgent problem to be solved in the hardware implementation of lattice ciphers. Therefore, an analog in-memory circuit for fast polynomial multiplication calculation is proposed. First, an in-memory computing circuit for Discrete Fourier Transform and Inverse Discrete Fourier Transform based on memristor array is designed. On this basis, a fully analog circuit that can realize polynomial multiplication in one step is designed. Compared with traditional hardware implementation, the in-memory calculation method used in this article decreases the calculation time of polynomial multiplication to the microsecond level, which greatly improves the speed of lattice cipher encryption and decryption. For the specific examples in this article, PSPICE simulation shows that the average accuracy of the calculation result is above 99.90%.
S3Mix: Same Category Same Semantics Mixing for Augmenting Fine-grained Images
Authors: Zhang Zi-Chao , Chen Zhen-Duo , Xie Zhen-Yu , Luo Xin , Xu Xin-Shun
Published: June 2023

Data augmentation is a common technique to improve the generalization performance of models for image classification. Although methods such as Mixup and CutMix that mix images randomly are indeed instrumental in general image classification, randomly swapping or masking regions is not friendly to fine-grained images, since the key to fine-grained image classification precisely lies in discriminative and informative regions, and it is unreasonable to generate labels solely consistent with the proportion of synthesis. Some erasing methods like Cutout even endanger fine-grained image classification because of erasing the discriminative regions by chance. In this article, we propose the Same Category Same Semantics Mixing method (S3Mix) corresponding to the characteristics of fine-grained images. Specifically, we limit the mixture to regions of the same category and semantics. The core of the method is two constraints. The exchange with the semantic region ensures the discrimination and semantics integrity of the generated image, and the exchange in the same class avoids the problem of unreasonable label generation. At the same time, we propose a homology loss to promote the semantic relationship between the generated positive image pairs. Experiments have been conducted on four fine-grained datasets, and the results show the proposed method is superior to the traditional image augmentation methods as well as some fine-grained data augmentation methods.
Multi-objective ω-Regular Reinforcement Learning
Authors: Hahn Ernst Moritz , Perez Mateo , Schewe Sven , Somenzi Fabio , Trivedi Ashutosh , Wojtczak Dominik
Published: June 2023

The expanding role of reinforcement learning (RL) in safety-critical system design has promoted ω-automata as a way to express learning requirements—often non-Markovian—with greater ease of expression and interpretation than scalar reward signals. However, real-world sequential decision making situations often involve multiple, potentially conflicting, objectives. Two dominant approaches to express relative preferences over multiple objectives are: (1)
weighted preference
, where the decision maker provides scalar weights for various objectives, and (2)
lexicographic preference
, where the decision maker provides an order over the objectives such that any amount of satisfaction of a higher-ordered objective is preferable to any amount of a lower-ordered one. In this article, we study and develop RL algorithms to compute optimal strategies in Markov decision processes against multiple ω-regular objectives under weighted and lexicographic preferences. We provide a translation from multiple ω-regular objectives to a scalar reward signal that is both
faithful
(maximising reward means maximising probability of achieving the objectives under the corresponding preference) and
effective
(RL quickly converges to optimal strategies). We have implemented the translations in a formal reinforcement learning tool,
Mungojerrie
, and we present an experimental evaluation of our technique on benchmark learning problems.
Improving the Electrocatalytic Performance for the Hydrogen Evolution Reaction in the Electrodeposited Ni-Based Matrix by Incorporating WS2 Nanoparticles
Authors: Laszczyńska A. , Tylus W.
Published: June 2023

Ni based alloys and composites may constitute an alternative to noble metal as a catalyst for the hydrogen evolution reaction (HER) during the water electrolysis. The aim of the present study was to evaluate the electrocatalytic activity of the electrodeposited Ni-WS2 and Ni–Mo–WS2 composites. The effect of the addition of WS2 nanoparticles on the structure, surface morphology and surface composition of Ni and Ni–Mo metallic matrix was thoroughly examined. The obtained results were used to explain the catalytic performance and the HER mechanism of the studied composites. It was found that the incorporation of the WS2 nanoparticles increased the electrocatalytic activity of the Ni and Ni–Mo matrix. The highest electrocatalytic activity was found for the Ni–Mo–WS2 electrode. This was, firstly, a consequence of the quasi-amorphous structure of the composite, which increased the real surface area of the electrode. On the other hand, the intrinsic catalytic activity was enhanced by the outer oxide layer rich in Mo oxides formed on the surface of the composite electrode. The presented research is an important contribution to the design of the non-precious composite electrodes for the HER.
Electrochemical-Mechanical Parameterization and Modeling of Expansion, Pressure, and Porosity Evolution in NMC811∣SiOx-Graphite Lithium-Ion Cells
Authors: von Kessel Otto , Hoehl Tobias , Heugel Philipp , Brauchle Felix , Vrankovic Dragoljub , Birke Kai Peter
Published: June 2023

The mechanical changes in active materials with large volume expansion such as silicon and nickel not only affect the electrochemical performance of modern batteries but also pose a great challenge to their mechanical design due to the pressure increase during operation. In this study, we show that the large expansion and consequently changing mechanical properties of silicon and nickel strongly affect the electrochemical and mechanical performance. A multi-scale electrochemical model is developed, parameterized, and validated for a pouch cell with a SiO
x
-graphite anode (22 wt% SiO
x
) and an NMC∣811 cathode. Mechanical parameters such as expansion and compressive properties are determined experimentally using an in-house-developed high-precision cell press and electrode dilatometer, thus parameterizing a semi-empirical mechanical model. We employ a new characterization technique to measure mechanical changes in the cell in-operando and propose a phenomenological parameterization where physical modeling is not yet sufficient. Through electrode porosity, we show that mechanical and electrochemical performance are interdependent, as the latter is reduced upon expansion and pressure development. On the one hand, the active material of the anode seems to expand into the pores at increased pressure, and on the other hand, the mechanical deformation of the cell components can no longer be neglected.
HTTP Cookie Covert Channel Detection Based on Session Flow Interaction Features
Authors: Yuan Wenxin , Chen Xingshu , Zhu Yi , Zeng Xuemei , Yue Yawei
Published: June 2023

HTTP cookie covert channel is a covert communication method that encodes malicious information in cookie fields to escape regulatory audits. It is difficult to detect this kind of covert channel according to the cookie content because cookie fields are mainly encoded in custom modes. To effectively identify the HTTP cookie covert channel, this paper proposes a detection method based on the interaction features of the session flow. First, we split the HTTP session flow into fine-grained “interaction process” subflows to comprehensively describe the communication process of the cookie. Then, we compare and analyze the differences between HTTP cookie covert channels and normal cookie communications based on the interaction process, design three types of 7-dimensional features, and build the detection model combined with the machine learning algorithm. Experimental results show that our method can effectively detect HTTP cookie covert channels, and the detection rate can reach 99%. We also prove that our method has advantages in stability and time performance compared with the existing detection methods through experiment and analysis. In addition, our method has certain practicability in the simulation environment with imbalanced data.
Water-Based Exercises on Peak Oxygen Consumption, Exercise Time, and Muscle Strength in Patients with Coronary Artery Disease: A Systematic Review with Meta-Analysis
Authors: Guimarães Alana Lalucha Andrade , Gomes-Neto Mansueto , Conceição Lino Sérgio Rocha , Saquetto Micheli Bernardone , Gois Caroline Oliveira , Carvalho Vitor Oliveira
Published: June 2023

Background. There is a growing use of water-based exercises in cardiac rehabilitation programs. However, there is little data concerning the effects of water-based exercise on the exercise capacity of coronary artery disease (CAD) patients. Objective. To perform a systematic review to investigate the effects of water-based exercise on peak oxygen consumption, exercise time, and muscle strength in patients with CAD. Methods. Five databases were searched to find randomized controlled trials that evaluated the effects of water-based exercise for coronary artery disease patients. Mean differences (MD) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the

I

2

test. Results. Eight studies were included. Water-based exercise resulted in an improvement in peak VO2 of 3.4 mL/kg/min (95% CI, 2.3 to 4.5;

I

2

=
0

%; 5 studies,

N
=
167

), exercise time of 0.6 (95% CI, 0.1 to 1.1;

I

2

=
0

%; 3 studies,

N
=
69

), and total body strength of 32.2 kg (95% CI, 23.9 to 40.7;

I

2

=
3

%; 3 studies,

N
=
69

) when compared to no exercising controls. Water-based exercise resulted in an improvement in peak VO2 of 3.1 mL/kg/min (95% CI, 1.4 to 4.7;

I

2

=
13

%; 2 studies,

N
=
74

), when compared to the plus land exercise group. No significant difference in peak VO2 was found for participants in the water-based exercise plus land exercise group compared with the land exercise group. Conclusions. Water-based exercise may improve exercise capacity and should be considered as an alternative method in the rehabilitation of patients with CAD.
The Impact of Origanum vulgare Supplementation on Human Asthenozoospermic Sperm Parameter Quality
Authors: Zarhouti Ahlam , Mbaye Moudou M. , Addoum Boutaina , Louanjli Noureddine , El Khalfi Bouchra , Soukri Abdelaziz
Published: June 2023

Male infertility is a complex multifactorial disease and a real health problem; 50% of infertile men have identifiable causes detectable by fundamental sperm analysis. Numerous research studies have shown the possibility of treating abnormal semen samples with some drugs before artificial insemination, yet evidence of the drug’s effectiveness remains minimal. In our previous work, we tested the effectiveness of some essential oils, such as eucalyptus (Eucalyptus globulus Labill.), oregano (Origanum vulgare L.), and sage (Salvia officinalis L.) on sperm parameters. The essential oil of oregano showed the best ameliorative effect. In present, we examined the effect of the essential oil of O. vulgare on the physiological parameters and the specific activity of certain antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), lipid peroxidation rate (MDA), and GAPDH and antioxidant and metabolic biomarkers, characterizing the quality of human sperm. The results showed that in vitro supplementation of oregano significantly improves the mobility and antioxidant activities, without harmful effects on the integrity of the sperm’s DNA, and that the selected concentration of oregano EO is nontoxic and may be considered a therapeutic alternative to heal sperm motility problems in asthenozoospermic patients.
Hyperinsulinemic Hypoglycemia and Growth Hormone Deficiency Secondary to 20p11 Deletion
Authors: Wee Erica , Herriges John , Dileepan Kavitha , Tsai Sarah L. , Alaimo Joseph T. , Paprocki Emily
Published: June 2023

Hypoglycemia is concerning for neurological complications in infants and children. Determining the cause of hypoglycemia is essential in providing appropriate treatment. Hyperinsulinism and growth hormone deficiency are known causes of hypoglycemia but are not commonly found together. We report a 4-month-old boy who presented with severe hypoglycemia and was found to have both hyperinsulinism and growth hormone deficiency. Treatment with both recombinant human growth hormone and diazoxide led to blood glucose normalization. Subsequently, he was found to have a genetic diagnosis of 20p11.22p11.21 deletion. 20p11 deletions have been associated with hypopituitarism, most commonly seen in growth hormone deficiency causing hypoglycemia. This case is one of a few to report hyperinsulinism as a manifestation of this deletion.
Accuracy of Microimplant Placement Using a 3D Guide Plate for Orthodontic Anchorage
Authors: Zhu Fangyong , Ji Lian , Zhou Chen , Cao Yannan , Chen Zhifei , Wu Xiangbing , Zou Jianming , Gao Yufeng
Published: June 2023

This study aimed to design a three-dimensional (3D) guide plate using computer-aided design and a 3D printing system for precise implantation of microimplants for orthodontic treatment and investigate the accuracy and feasibility of a 3D guide plate in clinical practice. A total of 30 microimplants were placed in 15 patients in the Department of Stomatology, Affiliated Hospital of Jiangnan University. Before surgery, DICOM data from cone-beam computed tomography (CBCT) scans and STereoLithography data from the 3D model scan were imported to 3Shape Dental System. Data fitting and matching were performed, and 3D guide plates were designed primarily focusing on the thickness of guide plates, amount of concave compensation, and dimensions of the ring. Assist implantation method was used to place the microimplants, and postoperative CBCT images were used to evaluate the position and implantation angle. The feasibility of placing microimplants and precise implantation guided by the 3D guide plate. CBCT data before and after the placement of microimplants were compared. Regarding the secure positioning of microimplants based on CBCT data, 26 implants were categorized as Grade i, four as Grade ii, and none as Grade iii. No loosening of microimplants 1 and 3 months after surgery was reported. The implantation of microimplants is more accurate under the guidance of a 3D guide plate. This technology can achieve accurate implant positioning, thus ensuring safety, stability, and improved success rates after implantation.
Diabetes Detection Models in Mexican Patients by Combining Machine Learning Algorithms and Feature Selection Techniques for Clinical and Paraclinical Attributes: A Comparative Evaluation
Authors: García-Domínguez Antonio , Galván-Tejada Carlos E. , Magallanes-Quintanar Rafael , Gamboa-Rosales Hamurabi , Curiel Irma González , Peralta-Romero Jesús , Cruz Miguel
Published: June 2023

The development of medical diagnostic models to support healthcare professionals has witnessed remarkable growth in recent years. Among the prevalent health conditions affecting the global population, diabetes stands out as a significant concern. In the domain of diabetes diagnosis, machine learning algorithms have been widely explored for generating disease detection models, leveraging diverse datasets primarily derived from clinical studies. The performance of these models heavily relies on the selection of the classifier algorithm and the quality of the dataset. Therefore, optimizing the input data by selecting relevant features becomes essential for accurate classification. This research presents a comprehensive investigation into diabetes detection models by integrating two feature selection techniques: the Akaike information criterion and genetic algorithms. These techniques are combined with six prominent classifier algorithms, including support vector machine, random forest, k-nearest neighbor, gradient boosting, extra trees, and naive Bayes. By leveraging clinical and paraclinical features, the generated models are evaluated and compared to existing approaches. The results demonstrate superior performance, surpassing accuracies of 94%. Furthermore, the use of feature selection techniques allows for working with a reduced dataset. The significance of feature selection is underscored in this study, showcasing its pivotal role in enhancing the performance of diabetes detection models. By judiciously selecting relevant features, this approach contributes to the advancement of medical diagnostic capabilities and empowers healthcare professionals in making informed decisions regarding diabetes diagnosis and treatment.
Intake of Proton-Pump Inhibitors and Gastric Cancer within the Stomach Cancer Pooling (StoP) Project
Authors: Sassano Michele , Mariani Marco , Pelucchi Claudio , Lunet Nuno , Morais Samantha , Martín Vicente , Moreno Victor , Curado Maria Paula , Dias-Neto Emmanuel , Leja Marcis , Gašenko Evita , La Vecchia Carlo , Boccia Stefania , Pastorino Roberta
Published: June 2023

Background:

A potential association between proton-pump inhibitors (PPI) and gastric cancer remains undefined. Thus, we aimed to evaluate such association within the Stomach cancer Pooling (StoP) Project.

Methods:

Data from five case–control studies of the StoP Project were included (1,889 cases and 6,517 controls). We assessed the impact of different exposure definitions, specifically any reported use of PPIs and exposure definitions based on the duration of PPI intake. Additionally, we modeled the dose–response relationship between the cumulative duration of PPI intake and gastric cancer.

Results:

Significant associations between PPI intake and gastric cancer, both overall and in the stratified analyses, were limited to exposure definitions based on short durations of intake. The overall odds ratio (OR) for any reported PPI intake was 1.78 [95% confidence interval (CI): 0.76–4.14]. In the dose–response analysis, the ORs of gastric cancer were found to be higher for short durations of PPI intake (6 months: OR 3.26; 95% CI: 2.40–4.42; one year: OR 2.14; 95% CI: 1.69–2.70; 2 years: OR 1.50; 95% CI: 1.22–1.85; 3 years: OR 1.27; 95% CI: 1.03–1.56), with the association becoming not significant for durations longer than 3 years.

Conclusions:

Our findings suggest that the observed association between PPIs and gastric cancer might be mainly due to reverse causality.

Impact:

The results of this study suggest that PPIs are a safe therapeutic choice regarding their effect on the occurrence of gastric cancer.

See related commentary by Richman and Leiman, p. 1127
Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment
Authors: Roschewski Mark , Patel Manish R. , Reagan Patrick M. , Saba Nakhle S. , Collins Graham P. , Arkenau Hendrik-Tobias , de Vos Sven , Nuttall Barrett , Acar Melih , Burke Kathleen , White Rafael D. , Udriste Maria , Sharma Shringi , Dougherty Brian , Stetson Daniel , Jenkins David , Mortlock Andrew , Forcina Alessandra , Munugalavadla Veerendra , Flinn Ian
Published: June 2023

Purpose:

Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL.

Patients and Methods:

Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.

Results:

Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders.

Conclusions:

Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.
Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study
Authors: Oaknin Ana , Pothuri Bhavana , Gilbert Lucy , Sabatier Renaud , Brown Jubilee , Ghamande Sharad , Mathews Cara , O'Malley David M. , Kristeleit Rebecca , Boni Valentina , Gravina Adriano , Banerjee Susana , Miller Rowan , Pikiel Joanna , Mirza Mansoor R. , Dewal Ninad , Antony Grace , Dong Yuping , Zografos Eleftherios , Veneris Jennifer , Tinker Anna V.
Published: June 2023

Purpose:

This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators.

Patients and Methods:

A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR).

Results:

A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports.

Conclusions:

Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab.

See related commentary by Jangra and Dhani, p. 4521
Efficacy and Quality-of-Life Following Involved Nodal Radiotherapy for Head and Neck Squamous Cell Carcinoma: The INRT-AIR Phase II Clinical Trial
Authors: Sher David J. , Moon Dominic H. , Vo Dat , Wang Jing , Chen Liyuan , Dohopolski Michael , Hughes Randall , Sumer Baran D. , Ahn Chul , Avkshtol Vladimir
Published: June 2023

Purpose:

Elective neck irradiation (ENI) has long been considered mandatory when treating head and neck squamous cell carcinoma (HNSCC) with definitive radiotherapy, but it is associated with significant dose to normal organs-at-risk (OAR). In this prospective phase II study, we investigated the efficacy and tolerability of eliminating ENI and strictly treating involved and suspicious lymph nodes (LN) with intensity-modulated radiotherapy.

Patients and Methods:

Patients with newly diagnosed HNSCC of the oropharynx, larynx, and hypopharynx were eligible for enrollment. Each LN was characterized as involved or suspicious based on radiologic criteria and an in-house artificial intelligence (AI)–based classification model. Gross disease received 70 Gray (Gy) in 35 fractions and suspicious LNs were treated with 66.5 Gy, without ENI. The primary endpoint was solitary elective volume recurrence, with secondary endpoints including patterns-of-failure and patient-reported outcomes.

Results:

Sixty-seven patients were enrolled, with 18 larynx/hypopharynx and 49 oropharynx cancer. With a median follow-up of 33.4 months, the 2-year risk of solitary elective nodal recurrence was 0%. Gastrostomy tubes were placed in 14 (21%), with median removal after 2.9 months for disease-free patients; no disease-free patient is chronically dependent. Grade I/II dermatitis was seen in 90%/10%. There was no significant decline in composite MD Anderson Dysphagia Index scores after treatment, with means of 89.1 and 92.6 at 12 and 24 months, respectively.

Conclusions:

These results suggest that eliminating ENI is oncologically sound for HNSCC, with highly favorable quality-of-life outcomes. Additional prospective studies are needed to support this promising paradigm before implementation in any nontrial setting.
Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer
Authors: Williams Christopher J.M. , Elliott Faye , Sapanara Nancy , Aghaei Faranak , Zhang Liping , Muranyi Andrea , Yan Dongyao , Bai Isaac , Zhao Zuo , Shires Michael , Wood Henry M. , Richman Susan D. , Hemmings Gemma , Hale Michael , Bottomley Daniel , Galvin Leanne , Cartlidge Caroline , Dance Sarah , Bacon Chris M. , Mansfield Laura , Young-Zvandasara Kathe , Sudan Ajay , Lambert Katy , Bibby Irena , Coupland Sarah E. , Montazeri Amir , Kipling Natalie , Hughes Kathryn , Cross Simon S. , Dewdney Alice , Pheasey Leanne , Leng Cathryn , Gochera Tatenda , Mangham D. Chas , Saunders Mark , Pritchard Martin , Stott Helen , Mukherjee Abhik , Ilyas Mohammad , Silverman Rafael , Hyland Georgina , Sculthorpe Declan , Thornton Kirsty , Gould Imogen , O'Callaghan Ann , Brown Nicholas , Turnbull Samantha , Shaw Lisa , Seymour Matthew T. , West Nicholas P. , Seligmann Jenny F. , Singh Shalini , Shanmugam Kandavel , Quirke Philip
Published: June 2023

Purpose:

High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.

Experimental Design:

Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).

Results:

A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56–0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50–0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.

Conclusions:

High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice.

See related commentary by Randon and Pietrantonio, p. 4021
Simultaneous Targeting of DNA Polymerase Theta and PARP1 or RAD52 Triggers Dual Synthetic Lethality in Homologous Recombination–Deficient Leukemia Cells
Authors: Sullivan-Reed Katherine , Toma Monika M. , Drzewiecka Malgorzata , Nieborowska-Skorska Margaret , Nejati Reza , Karami Adam , Wasik Mariusz A. , Sliwinski Tomasz , Skorski Tomasz
Published: June 2023

DNA polymerase theta (Polθ, encoded by POLQ gene) plays an essential role in Polθ-mediated end-joining (TMEJ) of DNA double-strand breaks (DSB). Inhibition of Polθ is synthetic lethal in homologous recombination (HR)-deficient tumor cells. However, DSBs can be also repaired by PARP1 and RAD52-mediated mechanisms. Because leukemia cells accumulate spontaneous DSBs, we tested if simultaneous targeting of Polθ and PARP1 or RAD52 enhance the synthetic lethal effect in HR-deficient leukemia cells. Transformation potential of the oncogenes inducing BRCA1/2-deficiency (BCR-ABL1 and AML1-ETO) was severely limited in Polq−/−;Parp1−/− and Polq−/−;Rad52−/− cells when compared with single knockouts, which was associated with accumulation of DSBs. Small-molecule inhibitor of Polθ (Polθi) when combined with PARP or RAD52 inhibitors (PARPi, RAD52i) caused accumulation of DSBs and exerted increased effect against HR-deficient leukemia and myeloproliferative neoplasm cells.

Implications:

In conclusion, we show that PARPi or RAD52i might improve therapeutic effect of Polθi against HR-deficient leukemias.
Evaluation of Gas 6 as a Prognostic Marker in Papillary Renal Cell Carcinoma
Authors: Mikuteit Marie , Zschäbitz Stefanie , Stöhr Christine , Herrmann Edwin , Polifka Iris , Agaimy Abbas , Trojan Lutz , Ströbel Philipp , Becker Frank , Wülfing Christian , Barth Peter , Stöckle Michael , Staehler Michael , Stief Christian , Haferkamp Axel , Hohenfellner Markus , Duensing Stefan , Macher-Göppinger Stephan , Wullich Bernd , Noldus Joachim , Brenner Walburgis , Roos Frederik , Walter Bernhard , Otto Wolfgang , Burger Maximilian , Erlmeier Maximillian , Schrader Andres Jan , Hartmann Arndt , Erlmeier Franziska , Steffens Sandra ,   German Network Of Kidney Cancer
Published: June 2023

Introduction: Growth arrest-specific protein 6 (Gas 6) is a ligand that plays a role in proliferation and migration of cells. For several tumor entities, high levels of Gas 6 are associated with poorer survival. We examined the prognostic role of Gas 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), which is still unclear. Methods: The patients’ sample collection is a joint collaboration of the PANZAR consortium. Patients’ medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Gas 6 was determined by immunohistochemistry. Results: In total, Gas 6 staining was evaluable in 180 of 240 type 1 and 110 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed no significant difference in 5-year overall survival for all pRCC nor either subtype. Also, Gas+ and Gas– groups did not significantly differ in any tumor or patient characteristics. Conclusion: Gas 6 was not found to be an independent prognostic marker in pRCC. Future studies are warranted to determine if Gas 6 plays a role as prognostic marker or therapeutic target in pRCC.
Medication Formulation Preference of Mild and Moderate Ulcerative Colitis Patients: a European Survey
Authors: Hébuterne Xavier , Vavricka Stephan R , Thorne Helen C , MacKenzie-Smith Lara , Laoun Raphaël , Burisch Johan
Published: June 2023

Introduction: Patient adherence is a major challenge for the successful management of any chronic disease, and ulcerative colitis (UC) is no exception. Patient adherence is closely related to patient preference of medication and formulation used. Aim: The aim of this study was to investigate patient and physician perspectives around UC treatment preference. Methods: This study was conducted in France, Germany, Spain, and the UK. Physicians and UK inflammatory bowel disease (IBD) nurses answered an online questionnaire. In addition, adult mild-to-moderate UC patients, treated with oral mesalazine, were invited to answer a 30-min online survey which included a conjoint exercise. Results: 400 patients, 160 physicians, and 20 IBD nurses participated in the survey. 68% of patients were taking tablets and 32% granules. Physicians stated that from their perspective patients are more adherent to tablets than granules (76% vs. 24%), patients tended to have better relief of symptoms with tablets (69% vs. 31%), and patients found tablets to be the most convenient formulation (61% vs. 39%). From the patients’ perspective, when questioned which formulation they prefer, 58% answered tablets, 37% granules, and 5% none of these. When patients were asked about some negative attributes of tablets, the highest agreement was for “I would like to take fewer each day” (6.1/10) and “I wish I could take fewer at a time” (5.4/10). Conclusions: The majority of UC patients in this survey prefer the tablet formulation. A high strength tablet overcoming the high pill burden could be a good solution to address patient expectations.
Reanalysis of Chromosomal Microarray Data Using a Smaller Copy Number Variant Call Threshold Identifies Four Cases with Heterozygous Multiexon Deletions of ARID1B, EHMT1, and FOXP1 Genes
Authors: Kubota Noriko , Takeda Ryojun , Kobayashi Jun , Hidaka Eiko , Nishi Eriko , Takano Kyoko , Wakui Keiko
Published: June 2023

Introduction: Chromosomal microarray (CMA) is a highly accurate and established method for detecting copy number variations (CNVs) in clinical genetic testing. CNVs are important etiological factors for disorders such as intellectual disability, developmental delay, and multiple congenital anomalies. Recently developed analytical methods have facilitated the identification of smaller CNVs. Therefore, reanalyzing CMA data using a smaller CNV calling threshold may yield useful information. However, this method was left to the discretion of each institution. Methods: We reanalyzed the CMA data of 131 patients using a smaller CNV call threshold: 50 kb 50 probes for gain and 25 kb 25 probes for loss. We interpreted the reanalyzed CNVs based on the most recently available information. In the reanalysis, we filtered the data using the Clinical Genome Resource dosage sensitivity gene list as an index to quickly and efficiently check morbid genes. Results: The number of copy number loss was approximately 20 times greater, and copy number gain was approximately three times greater compared to those in the previous analysis. We detected new likely pathogenic CNVs in four participants: a 236.5 kb loss within ARID1B, a 50.6 kb loss including EHMT1, a 46.5 kb loss including EHMT1, and an 89.1 kb loss within the FOXP1 gene. Conclusion: The method employed in this study is simple and effective for CMA data reanalysis using a smaller CNV call threshold. Thus, this method is efficient for both ongoing and repeated analyses. This study may stimulate further discussion of reanalysis methodology in clinical laboratories.
The Ratio of Intraoperative Red Blood Cell Transfusion to Blood Loss Associated with Early Postoperative Complications in Pediatric Liver Transplantation Patients
Authors: Ma Yiming , Li Cheng , Sun Liying , Li Xiaofei
Published: June 2023

Introduction: Liver transplantation (LT) is an operation purposed to save the lives of children with acute or chronic liver diseases, hepatic tumors, and some genetic and metabolic diseases. However, patients who underwent LT have a significant risk of intraoperative blood loss and red blood cell (RBC) transfusion, especially in pediatric patients. Methods: In this study, 569 pediatric patients (<18 years old) who underwent LT at a tertiary university hospital between 2013 and 2020 were included. Multiple logistic regression was used to analyze the association between the ratio of intraoperative RBC transfusion to blood loss (IRTBL) and the complications after LT in pediatric patients. IRTBL was divided into quartiles in the adjusted model. Odds ratios, 95% confidence intervals, and p values for trends were calculated. Restricted cubic spline (RCS) regression was used to evaluate the nonlinear association between IRTBL and complications. Results: Compared with the lowest level and the highest level of IRTBL, Q2 and Q3 quartiles of IRTBL showed significantly positive association with early complications. A significantly nonlinear association was observed between the IRTBL and early complications in the RCS model with the multiple adjustments of potential covariates (P overall<0.01, P nonlinear<0.01). However, no significant association was observed between late complications and IRTBL. Conclusion: In this study, we found there was a nonlinear relationship between the ratio of IRTBL and early postoperative complications in pediatric LT patients, which provides a theoretical basis for RBC transfusion in pediatric LT patients.
The Single-Matrix Digit Cancellation Test, a Screener for Selective Attention Deficits: Standardization in an Italian Population Sample and Clinical Usability in Acute Stroke Patients
Authors: Pasotti Fabrizio , Aiello Edoardo Nicolò , Bollani Alessandra , Querzola Matteo , Cozzi Sara , Manfrin Francesca , Bruno Stefania , Poletti Barbara , Ticozzi Nicola , Silani Vincenzo , Bottini Gabriella
Published: June 2023

Introduction: This study aimed at validating and providing Italian norms for the Single-Matrix Digit Cancellation Test (SMDCT), a cancellation task to screen for selective attention deficits, as well as providing clinical usability evidence for it in acute stroke patients. Methods: The SMDCT stimulus is a specular, 4-quadrant, horizontally oriented matrix, across which target distribution is homogeneous. Both accuracy (-A) and time (-T) outcomes were computed. N = 263 healthy participants (HPs) and N = 76 acute stroke patients were recruited. N = 108 HPs also underwent the Mini-Mental State Examination, Frontal Assessment Battery (FAB), and Trail-Making Test (TMT), while patients were further assessed by the Mental Performance in Acute Stroke (MEPS). Regression-based norms were derived (equivalent scores). Construct and factorial validity, as well as case-control discrimination, were tested. Results: The matrix was underpinned by a two-component structure reflecting left and right hits. The SMDCT-T and -A were associated with TMT and FAB scores, respectively. Education predicted the SMDCT-A/-T, whereas age predicted the SMDCT-T only. In patients, the SMDCT converged with the MEPS, also accurately discriminating them from HPs. An index of right-left difference differentiated right- from left-damaged patients. Conclusions: The SMDCT is a valid and normed screener for selective attention deficits, encompassing measures of both accuracy and time, whose adoption is encouraged in acute stroke patients. Relatedly, the horizontal disposition of its matrix does allow for the qualitative report of either leftward of rightward biases due to underlying visual or attentional-representational deficits in this population.
Copper, Lysyl Oxidase Activity, and Collagen in Aqueous Humour of Primary Glaucoma: An Association with Clinical Parameters
Authors: NikhalaShree Sampath , George Ronnie Jacob , Shantha Balekudaru , Vijaya Lingam , Sulochana Konerirajapuram Natarajan , Coral Karunakaran
Published: June 2023

Introduction: To measure copper (Cu), lysyl oxidase (LOX) activity, and collagen levels in aqueous humour (AH) of primary glaucoma patients and correlate with clinical parameters. Methods: 120 patients with 40 each of primary open angle glaucoma (POAG), primary angle closure glaucoma (PACG), and cataract controls were recruited in this case-control study. AH samples were collected during the trabeculectomy and cataract surgeries. Cu levels were measured using an atomic absorption spectrophotometer. LOX unit activity was determined by Amplex Red assay and collagen concentration by Sirius red assay. Results: Significantly higher levels of Cu expressed as median (IQR) µmol/L were observed in POAG (p = 0.008) and PACG (p = 0.005) compared to controls. The LOX activity was increased in POAG and PACG (p = 0.04) compared to controls represented as median (IQR) µmol/min. The collagen levels given as median (IQR) mg/ml showed an insignificant increase in POAG and PACG compared to controls (p = 0.78). The LOX unit activity was correlated with visual field index (VFI), which showed a significant increase with the progression of the diseases (p < 0.05), whereas Cu levels were negatively correlated with LOX activity in AH. Cu and LOX activity showed weak correlation with YAG peripheral iridotomy (YAGPI), duration of anti-glaucoma medications, and highest preoperative intraocular pressure. Conclusion: Elevated Cu and LOX activity was observed in both POAG and PACG groups compared to controls. LOX activity showed notable increase with VFI as the severity of the disease. Although Cu levels are increased in glaucoma, it’s insufficient to significantly increase the activity of LOX.
Comparison of Urinary Protein/Creatinine Ratio as an Alternative to 24-h Proteinuria in Lupus Nephritis: TUNARI Study
Authors: Gutiérrez-Peredo Gabriel Brayan , Montaño-Castellón Iris , Gutiérrez-Peredo Andrea Jimena , Aguilar Ticona Juan P , Montaño-Castellón Fabio , Batista Oliveira Filho José César , Almeida Antonio Raimundo Pinto
Published: June 2023

Background: Lupus nephritis (LN) occurs in approximately 50% of people with systemic lupus erythematosus (SLE). The 24-h proteinuria (gold standard) is measured among other tests for the control and monitoring of LN activity. This study investigates the use of the protein/creatinine ratio (PCR) as an alternative for the detection of proteinuria and its accuracy compared to the gold standard in a predominantly non-white population. Methods: This was a prospective study conducted in Salvador, Brazil, between December 2021 and May 2022. We invited adult patients diagnosed with SLE and LN, regardless of their disease activity. The estimation of the PCR and 24-h proteinuria was performed using conventional methods. The analysis used was Spearman’s r correlation coefficient (rs), coefficient of determination (r2), and concordance by the Bland-Altman method. A specific sensitivity was measured by the ROC curve with its respective cut-off by the Youden Index. Results: We compared 112 samples of 75 patients with LN, with a mean age of 34.5 ± 11.8 years. Of these patients, 85% were women, 87.9% were non-white. A high degree of correlation was observed between PCR with 24-h proteinuria (rs = 0.77 and r2 = 0.59). The ROC analysis shows an area under the curve of 0.92 and the cut-off point calculated by the Youden Index was 0.78 with a sensitivity of 90.0% and specificity of 82%. However, the Bland-Altman graph indicated decreasing concordance as the degree of proteinuria increased, despite showing concordance at high levels of proteinuria. Conclusion: The PCR shows high sensitivity to follow-up patients with LN when compared with 24-h proteinuria. Our findings suggest that PCR is a useful parameter for the evaluating and monitoring patients in complete remission. However, in cases of partial remission, the utility of PCR is limited.
Persistent Hiccups after Subthalamic Nucleus Deep Brain Stimulator Implantation for Parkinson’s Disease: Case Report and Literature Review
Authors: Waack Andrew , Maddens Michael E. , Maddens Nicholas J. , Kuhlman Adam , Staudt Michael D.
Published: June 2023

Hiccups are mediated by a reflex arc that consists of afferent, central, and efferent components. The structures involved in the central component have not been fully elucidated, although several brainstem structures have been implicated, including the subthalamic nucleus (STN). Accordingly, Parkinson’s disease (PD), a disease defined by the loss of dopaminergic neurons in the STN, has an interesting, although unspecified, relationship to hiccups. Hiccups have been described in association with PD and the use of dopaminergic medications. Interestingly, deep brain stimulation (DBS) of the STN appears to be implicated in the pathogenesis of hiccups as well. There have been sporadic reports of hiccups occurring in conjunction with STN-DBS. We present a case of hiccups occurring after STN-DBS for PD in a 65-year-old man. STN-DBS significantly improved his PD symptoms; however, he developed persistent and daily hiccups. As of writing, 24 months after surgery, the patient experiences hiccups several times per day with no associated gastrointestinal complaints and with significant improvement in his PD symptoms. This report describes the case details and summarizes the existing literature describing hiccups in patients undergoing surgical treatment for PD.