bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage
Authors: Schlosser Pascal , Zhang Jingning , Liu Hongbo , Surapaneni Aditya L. , Rhee Eugene P. , Arking Dan E. , Yu Bing , Boerwinkle Eric , Welling Paul A. , Chatterjee Nilanjan , Susztak Katalin , Coresh Josef , Grams Morgan E.
Published: June 2023

Background

The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.

Results

Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are supported as putatively causal. We then prioritize 153 of these genomic regions using additional colocalization analyses. Our genome-wide findings are supported by existing knowledge (animal models forMANBA,DACH1,SH3YL1, INHBB), exceed the underlying GWAS signals (28 region-trait combinations without significant GWAS hit), identify independent gene/protein-trait associations within the same genomic region (INHBC,SPRYD4), nominate tissues underlying the associations (tubule expression ofNRBP1), and distinguish markers of kidney filtration from those with a role in creatinine and cystatin C metabolism.Furthermore, we follow up on members of the TGF-beta superfamily of proteins and find a prognostic value of INHBC for kidney disease progression even after adjustment for measured glomerular filtration rate (GFR).

Conclusion

In summary, this study combines multimodal, genome-wide association studies to generate a catalog of putatively causal target genes and proteins relevant to kidney function and damage which can guide follow-up studies in physiology, basic science, and clinical medicine.
Synthesis, α-Glucosidase inhibitory activity and docking studies of Novel Ethyl 1,2,3-triazol-4-ylmethylthio-5,6-diphenylpyridazine-4-carboxylate derivatives
Authors: Firoozpour Loghman , Moghimi Setareh , Salarinejad Somayeh , Toolabi Mahsa , Rafsanjani Mahdi , Pakrad Roya , Salmani Farzaneh , Shokrolahi Seyed Mohammad , Sadat Ebrahimi Seyed Esmail , Karima Saeed , Foroumadi Alireza
Published: June 2023

In this work, a novel series of pyridazine-triazole hybrid molecules were prepared and evaluated as inhibitors of rat intestinalα-glucosidase enzyme. Amongst all newly synthesized compounds,10kshowed good inhibition in the series with IC50value of 1.7 µM which is 100 folds stronger than positive control, acarbose. The cytotoxicity revealed that this compound is not toxic against normal cell line, HDF. The docking studies showed that triazole ring plays an important role in the binding interactions with the active site. The insertion of compound10kinto the active pocket ofα-glucosidase and formation of hydrogen bonds with Leu677 was observed from docking studies. The kinetic studies revealed that this compound has uncompetitive mode of inhibition againstα-glucosidase enzyme.
Comparison of fasting and random lipid profiles among subjects with type 2 diabetes mellitus: an outpatient-based cross-sectional study in Bangladesh
Authors: Kamrul-Hasan A. B. M. , Talukder Samir Kumar , Kabir Md Ahamedul , Mustari Marufa , Un Nabi Md Masud , Gaffar Abu Jar , Hossain Md Firoj , Alam Muhammad Shah , Islam Md Rashedul , Hannan Mohammad Abdul , Zarin Nusrat , Paul Ajit Kumar , Akter Farhana , Ahammed Afsar , Kabir Md Lutful , Rahman Mohammad Motiur , Asaduzzaman Md , Saifuddin Mohammad , Chanda Palash Kumar , Rafi Md Abdur , Hasan Mohammad Jahid , Selim Shahjada
Published: June 2023

Background

Despite the wide acceptability of fasting lipid profiles in practice, emerging evidence suggests that random lipid profiles might be a convenient alternative for lipid measurement. The objective of the present study was to compare the fasting and random lipid profile among subjects with type 2 diabetes mellitus (T2DM).

Methods

The present cross-sectional study included 1543 subjects with T2DM visiting several endocrinology outpatient clinics throughout Bangladesh from January to December 2021. The fasting lipid profile was measured in the morning following 8–10 h of overnight fasting, and the random lipid profile was measured at any time of the day, irrespective of the last meal. The values of fasting and random lipids were compared using the Wilcoxon signed-rank test and Spearman rank correlation coefficients.

Results

In this study, a good level of correlation was observed between fasting and random lipid levels [r = 0.793, p < 0.001 for triglyceride (TG); r = 0.873, p < 0.001 for low-density lipoprotein cholesterol (LDL-C); r = 0.609, p < 0.001 for high-density lipoprotein cholesterol (HDL-C); and r = 0.780, p < 0.001 for total cholesterol (TC)]. In addition, TG and TC levels increased by 14% and 0.51%, respectively, in the random state compared to the fasting state (p- <0.05), while LDL-C levels decreased by 0.71% (p-value 0.42). No change was noticed in the HDL-C level. The difference between fasting and random lipid profiles was similar irrespective of patients’ age, sex, BMI, glucose-lowering drug(s), and lipid-lowering therapy.

Conclusions

Random lipid profile correlates significantly with fasting lipid profile with little difference. Hence, it might be a reliable alternative for fasting lipid profile in patients with T2DM.
Dynamic programming network for point target detection
Authors: Fu Jingneng , Wei Hongyan
Published: June 2023

To improve the efficiency of the dim point target detection based on dynamic programming (DP), this paper proposes a multi-frame target detection method based on a DP ring network (DPRN). In the proposed method, first, the target trajectory is approximated using the piecewise linear function. The velocity space partition DP (VSP-DP) is used to accumulate the merit functions of a target on each piecewise linear trajectory segment to avoid the merit function diffusion in different velocity spaces. In addition, the velocity space matching DP (VSM-DP) is employed to realize the state transition of a target between adjacent piecewise linear trajectory segments. Then, the VSP-DP and VSM-DP are used to construct a DP network (DPN). Second, to suppress the merit function diffusion further, the sequential and reverse DPNs are connected in a head-to-tail manner to form a DPRN, and the merit function of the DPRN is obtained by averaging the merit functions of the sequential and reverse DPNs. Finally, the target trajectory is obtained by tracking the extreme points of the merit functions of the DPRN. The simulation and analysis results show that the proposed DPRN combines the advantages of high detection probability of the high-order DP and high execution efficiency of the first-order DP. The proposed DPRN is suitable for radars and infrared searching and tracking systems.
Brain metabolism in Alzheimer’s disease: biological mechanisms of exercise
Authors: Xu Longfei , Liu Ran , Qin Yingkai , Wang Tianhui
Published: June 2023

Alzheimer’s disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aβ metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.
Perfectionism and binge eating association: a systematic review and meta-analysis
Authors: Vicent María , Gonzálvez Carolina , Quiles María José , Sánchez-Meca Julio
Published: June 2023

Background

Perfectionism is considered a vulnerability factor for eating disorders. However, the role of perfectionism in binge eating needs clarification due to notably inconsistencies between studies. The purpose to this study was to conduct a systematic review and meta-analysis to estimate the perfectionism-binge eating association.

Method

Systematic review was performed according to the PRISMA 2020 statement. Four databases (Web of Science, Scopus, PsycINFO and Psicodoc) were searched to identify studies published until September 2022. The literature search yielded 30 published articles (N = 9392) that provided 33 independent estimations of the correlation between the two variables.

Results

Random-effects meta-analysis revealed a small-to-moderate positive average effect size between general perfectionism and binge eating (r+ = .17) with a large heterogeneity. Perfectionistic Concerns showed a significant small-to-moderate relationship with binge eating (r+ = .27), whereas Perfectionistic Strivings presented a negligible relationship with binge eating (r+ = .07). Moderator analyses showed that the age, the type of the sample, the study design, and the tools for assessing both variables were statistically associated with the perfectionism-binge eating effect sizes.

Conclusions

Our findings suggest that Perfectionism Concerns are closely associated with binge eating symptomatology. This relationship might be moderated by certain variables, especially by the clinical or non-clinical nature of the sample and the instrument employed to assess binge eating.
Performance comparison between multi-center histopathology datasets of a weakly-supervised deep learning model for pancreatic ductal adenocarcinoma detection
Authors: Carrillo-Perez Francisco , Ortuno Francisco M. , Börjesson Alejandro , Rojas Ignacio , Herrera Luis Javier
Published: June 2023

Background

Pancreatic ductal carcinoma patients have a really poor prognosis given its difficult early detection and the lack of early symptoms. Digital pathology is routinely used by pathologists to diagnose the disease. However, visually inspecting the tissue is a time-consuming task, which slows down the diagnostic procedure. With the advances occurred in the area of artificial intelligence, specifically with deep learning models, and the growing availability of public histology data, clinical decision support systems are being created. However, the generalization capabilities of these systems are not always tested, nor the integration of publicly available datasets for pancreatic ductal carcinoma detection (PDAC).

Methods

In this work, we explored the performace of two weakly-supervised deep learning models using the two more widely available datasets with pancreatic ductal carcinoma histology images, The Cancer Genome Atlas Project (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). In order to have sufficient training data, the TCGA dataset was integrated with the Genotype-Tissue Expression (GTEx) project dataset, which contains healthy pancreatic samples.

Results

We showed how the model trained on CPTAC generalizes better than the one trained on the integrated dataset, obtaining an inter-dataset accuracy of 90.62% ± 2.32 and an outer-dataset accuracy of 92.17% when evaluated on TCGA + GTEx. Furthermore, we tested the performance on another dataset formed by tissue micro-arrays, obtaining an accuracy of 98.59%. We showed how the features learned in an integrated dataset do not differentiate between the classes, but between the datasets, noticing that a stronger normalization might be needed when creating clinical decision support systems with datasets obtained from different sources. To mitigate this effect, we proposed to train on the three available datasets, improving the detection performance and generalization capabilities of a model trained only on TCGA + GTEx and achieving a similar performance to the model trained only on CPTAC.

Conclusions

The integration of datasets where both classes are present can mitigate the batch effect present when integrating datasets, improving the classification performance, and accurately detecting PDAC across different datasets.
Tessaratoma javanica and Coridius singhalanus in the practice of entomophagy in Nagaland: an assessment of their nutritional quality
Authors: Pongener Anungla , Ao Bendang , Yenisetti Sarat Chandra , Soren Amar Deep
Published: June 2023

Background

A survey was executed to estimate the extent of entomophagy practiced by the tribal population in Nagaland. From the survey, two consumed stink bugs, namely Tessaratoma javanica and Coridius singhalanus, were assessed. Nutrient contents were assessed following the AOAC guidelines and elements were quantised using ICP-OES.

Results

About 55% of the people surveyed consumed T. javanica, and 49% were consumers of C. singhalanus. The survey also indicated that the non-consumer respondents did not have any aversion towards the consumption of these insects. Biochemical analysis revealed that except for carbohydrate and moisture contents, all the other evaluated parameters (ash, crude fats, crude protein, and fibre content) were found to be comparatively higher in C. singhalanus, although the difference was significant (p ≤ 0.05) only for crude fat, carbohydrate, and fibre content. Trace elements analysis revealed that calcium (107.74 ± 0.213 mg/100 g), iron (22.17 ± 0.080 mg/100 g), and sodium (120.34 ± 0.214 mg/100 g) contents were significantly higher in T. javanica, whereas magnesium (76.06 ± 0.166 mg/100 g) content was significantly higher in C. singhalanus.

Conclusions

Both the bugs show good nutritive contents and are liked for their distinctive smell and flavour.
An effectiveness-implementation hybrid trial of phone-based tobacco cessation interventions in the Lebanese primary healthcare system: protocol for project PHOENICS
Authors: Salloum Ramzi G. , Romani Maya , Bteddini Dima S. , El-Jardali Fadi , Lee Ji-Hyun , Theis Ryan , LeLaurin Jennifer H. , Hamadeh Randa , Osman Mona , Abla Ruba , Khaywa Jihan , Ward Kenneth D. , Shelley Donna , Nakkash Rima
Published: June 2023

Background

Tobacco use remains the leading cause of preventable disease, disability, and death in the world. Lebanon has an exceptionally high tobacco use burden. The World Health Organization endorses smoking cessation advice integrated into primary care settings as well as easily accessible and free phone-based counseling and low-cost pharmacotherapy as standard of practice for population-level tobacco dependence treatment. Although these interventions can increase access to tobacco treatment and are highly cost-effective compared with other interventions, their evidence base comes primarily from high-income countries, and they have rarely been evaluated in low- and middle-income countries. Recommended interventions are not integrated as a routine part of primary care in Lebanon, as in other low-resource settings. Addressing this evidence-to-practice gap requires research on multi-level interventions and contextual factors for implementing integrated, scalable, and sustainable cessation treatment within low-resource settings.

Methods

The objective of this study is to evaluate the comparative effectiveness of promising multi-component interventions for implementing evidence-based tobacco treatment in primary healthcare centers within the Lebanese National Primary Healthcare Network. We will adapt and tailor an existing in-person smoking cessation program to deliver phone-based counseling to smokers in Lebanon. We will then conduct a three-arm group-randomized trial of 1500 patients across 24 clinics comparing (1) ask about tobacco use; advise to quit; assist with brief counseling (AAA) as standard care; (2) ask; advise; connect to phone-based counseling (AAC); and (3) AAC + nicotine replacement therapy (NRT). We will also evaluate the implementation process to measure factors that influence implementation. Our central hypothesis is that connecting patients to phone-based counseling with NRT is the most effective alternative. This study will be guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework, supported by Proctor’s framework for implementation outcomes.

Discussion

The project addresses the evidence-to-practice gap in the provision of tobacco dependence treatment within low-resource settings by developing and testing contextually tailored multi-level interventions while optimizing implementation success and sustainability. This research is significant for its potential to guide the large-scale adoption of cost-effective strategies for implementing tobacco dependence treatment in low-resource settings, thereby reducing tobacco-related morbidity and mortality.

Trial registration

ClinicalTrials.gov, NCT05628389, Registered 16 November 2022.
Study the impact of transient state on the doubly fed induction generator for various wind speeds
Authors: Alsati Batoul Amen , Ibrahim Ghassan Issa , Moussa Rami Ramadan
Published: June 2023

Recently, renewable resources such as wind, hydro, and tidal have experienced a rapid development. Electricity production, based on wind, has been concentrated on a large scale. Additionally, a doubly fed induction generator has been used in wind farms on a large scale. This machine is influenced by the multiple transient states that are happening in the grid. Many researchers studied the effect of voltage-dip on DFIG performance; none of them studied the effect of voltage-dip sharing with wind-speed changing for both sub- and hyper-synchronous modes. In this paper, DFIG behavior is investigated under a transient state which is represented by 3-phase voltage-dip, in both operation modes (sub-synchronous & hyper-synchronous) with various values of the wind speed. Based on MATLAB Simulink, the various DFIG parameters are extracted to determine the relation between voltage-dip, variable wind speed, and DFIG performance. Results show that the parameters that are affected were rotor-current, rotor-voltage, and DC-Link voltage, while stator-current and stator-flux are not affected. It is also shown that DC-Link voltage values are smaller in the hyper-synchronous mode compared with sub-synchronous one.
Bilateral transversus abdominis plane (TAP) block reduces pain and the need for additional analgesics after elective cesarean section under opioid-free spinal anesthesia: findings from a randomized clinical trial
Authors: Innamorato Massimo Antonio , Vittori Alessandro , Natoli Silvia , Perna Paolo , Farinelli Ilaria , Petrucci Emiliano , Baciarello Marco , Francia Elisa , Marinangeli Franco , Bignami Elena Giovanna , Cascella Marco
Published: June 2023

Background

Cesarean section (CS) is the most frequently performed obstetric procedure globally, and postoperative pain remains a prominent concern. This study aimed to evaluate the effectiveness of the bilateral transversus abdominis plane (TAP) block in addressing this issue.

Methods

We performed a randomized trial in women with term pregnancies who underwent elective CS with spinal anesthesia. The women were randomized (1:1) to receive bilateral TAP or postoperative systemic analgesics (control group). The primary outcome was the effect on postoperative pain assessed using the numeric rating score (NRS) at 2, 6, 12, and 24 h in the postoperative period.

Results

At 2 and 6 h after the surgical procedure, there was a significant reduction in both resting (rNRS p = 0.004) and movement-related pain (dNRS p = 0.0001, p = 0.001 respectively). However, at 12 h, a reduction of dNRS was demonstrated (p = 0.0001), while no benefit was observed at rest. The percentage of women with NRS ≤ 4 was higher after the block at 2 h for both resting and movement-related pain (rNRS p = 0.010; dNRS p = 0.0001); at 6 and 12 h, it was only significant for dNRS (p = 0.002). Rescue doses of analgesics were significantly higher in the control group at 2, 6, and 12 h (p = 0.01, p = 0.0383, p = 0.0003 respectively). No complications with the procedure were recorded.

Conclusion

Bilateral TAP block has the potential to alleviate postoperative pain and reduce the need for additional analgesics after CS.

Trial registration

This study is registered with ClinicalTrials.gov, number (NCT02801968), registered 28 May 2016, https://clinicaltrials.gov/ct2/show/NCT02801968?term=NCT02801968&draw=2&rank=1
Exploring geothermal resources using electromagnetic methods in coastal areas of volcanic islands: Challenges of nearshore and land 3D controlled-source electromagnetic data
Authors: Védrine Simon , Bretaudeau François , Darnet Mathieu , Hautot Sophie , Tarits Pascal
Published: June 2023

Three-dimensional geophysical exploration is essential in identifying favorable areas and derisking high-temperature geothermal projects. In particular, electrical resistivity imaging plays a key role in this exploration due to its sensitivity to the presence of alteration products, geothermal fluid circulation, and temperature. As 3D seismic exploration is rarely effective in volcanic environments, resistivity methods such as magnetotellurics (MTs) are often used to extract deep structural information. However, deep electromagnetic (EM) imaging in coastal areas of volcanic islands with MT can be challenging due to anthropogenic noise induced by urbanized areas concentrated around the coast. The use of active EM sources, such as airborne EM (AEM) and controlled-source EM (CSEM), as a complement to MT is a solution for overcoming anthropogenic noise. However, applying these methods in this context is still challenging due to the proximity to the sea/land interface, large variations in topography and nearshore bathymetry, and the heterogeneity of the near surface. Our approach outlines the challenges of acquiring, processing, and inverting nearshore and land 3D CSEM data in such complex environments. The CSEM data are part of a multimethod geothermal exploration on the island of Martinique in the French West Indies, and its 3D inversion result is compared with the previous regional 3D MT and AEM inversion results. In addition to MT, CSEM may highlight the location of a potential high-temperature paleo-reservoir at shallow depths under the urbanized area of Petite-Anse covered by a paleo-clay cap ranging from a few meters to several hundred meters in thickness. We conclude by proposing possible improvements for CSEM and multimethod methodologies to obtain more reliable exploratory models.
Effects of collar eccentricity on azimuthal response characteristics for acoustic reflection measurement while drilling
Authors: Rao Bo , Su Yuanda , Li Shengqing , Tang Xiaoming
Published: June 2023

Acoustic reflection imaging has been successfully applied in postdrilling wireline logging, and the technique is potentially more valuable in acoustic logging while drilling (ALWD), particularly in geosteering while drilling. Because of the common occurrence of tool eccentering in drilling, the impact of drill collar eccentricity on the acoustic wavefield inside and outside the borehole must be considered. Therefore, we analyze the effect of an eccentric drill collar on acoustic reflection imaging while drilling using analytical solutions in a dual-cylindrical coordinate system. The virtual source analogy and the translational addition theorem for cylindrical Bessel functions are used to calculate the response of the fluid-filled borehole with an eccentric collar to the incident wavefield from a formation reflector. The analysis results are validated with those from 3D finite-difference simulations. We also have studied the azimuthal variation of the received wavefield and compared the results with their centralized counterparts, for which the effects of collar eccentricity, frequency of the source, and formation elastic property are analyzed. The results indicate that the asymmetric feature of the wavefield due to the eccentric collar allows for determining the azimuth of the reflector, providing a solution to the azimuth ambiguity problem of borehole acoustic reflection imaging. Our results, besides developing an effective method for eccentric collar ALWD modeling, can be used to provide a theoretical foundation for ALWD tool development and data interpretation.
Operational Challenges of an Asia-Pacific Academic Oncology Clinical Trial
Authors: Day Daphne , Toh Han Chong , Ali Raghib , Foo Estelle Mei Jye , Simes John , Chia John Whay Kuang , Segelov Eva ,   on behalf of the ASCOLT Investigators
Published: June 2023

PURPOSE

The Asia-Pacific (APAC) region is a major focus for multinational clinical trials, although its cultural, linguistic, economic, and regulatory diversity pose significant challenges for trial conduct, particularly for academic clinical trials.

METHODS

We describe our experience running the investigator-initiated phase III randomized, fully accrued, Aspirin for Dukes C and high-risk Dukes B Colorectal cancer trial (ASCOLT, ClinicalTrials.gov identifier:
NCT00565708
, N = 1,587), studying the benefit of aspirin in resected high-risk colorectal cancer. ASCOLT opened in 2008 and is the first large academic adjuvant trial fully conducted in the APAC region. Centrally coordinated by the Trial Management Team at the National Cancer Centre Singapore, it has involved 74 sites across 12 APAC countries/regions, including five middle-income countries.

RESULTS

Challenges encountered included regulatory complexity, communication and logistical barriers, limited funding and resources, disparate experience and infrastructure across sites, recruitment holds because of changes in local laws, patient attrition, and disruptions caused by the COVID-19 pandemic. Over 100 contracts and 49 ethics board reviews were required, contributing to a lengthy prestudy preparation time of 2 years and start-up times of approximately 6 months per site. Some of the mitigating actions included engaging local cooperative groups (eg, the Australasian Gastro-Intestinal Trials Group in Australia and New Zealand) and seven contract research organizations to manage sites, regular communication with the central team, transition to electronic data management, and a centralized drug-dispensing system.

CONCLUSION

To ensure an efficient and patient-centered clinical trials environment in the APAC region and sustained growth, we suggest coordinated approaches to harmonize regulatory processes, APAC academic oncology trials consortia to streamline processes and provide governance, and ongoing commitment from governments, funding agents, and industry.
Relacorilant + Nab-Paclitaxel in Patients With Recurrent, Platinum-Resistant Ovarian Cancer: A Three-Arm, Randomized, Controlled, Open-Label Phase II Study
Authors: Colombo Nicoletta , Van Gorp Toon , Matulonis Ursula A. , Oaknin Ana , Grisham Rachel N. , Fleming Gini F. , Olawaiye Alexander B. , Nguyen Dorothy D. , Greenstein Andrew E. , Custodio Joseph M. , Pashova Hristina I. , Tudor Iulia C. , Lorusso Domenica
Published: June 2023

PURPOSE

Despite therapeutic advances, outcomes for patients with platinum-resistant/refractory ovarian cancer remain poor. Selective glucocorticoid receptor modulation with relacorilant may restore chemosensitivity and enhance chemotherapy efficacy.

METHODS

This three-arm, randomized, controlled, open-label phase II study (ClinicalTrials.gov identifier: NCT03776812 ) enrolled women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer, or ovarian carcinosarcoma treated with ≤4 prior chemotherapeutic regimens. Patients were randomly assigned 1:1:1 to (1) nab-paclitaxel (80 mg/m2) + intermittent relacorilant (150 mg the day before, of, and after nab-paclitaxel); (2) nab-paclitaxel (80 mg/m2) + continuous relacorilant (100 mg once daily); or (3) nab-paclitaxel monotherapy (100 mg/m2). Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. The primary end point was progression-free survival (PFS) by investigator assessment; objective response rate (ORR), duration of response (DOR), overall survival (OS), and safety were secondary end points.

RESULTS

A total of 178 women were randomly assigned. Intermittent relacorilant + nab-paclitaxel improved PFS (hazard ratio [HR], 0.66; log-rank test P = .038; median follow-up, 11.1 months) and DOR (HR, 0.36; P = .006) versus nab-paclitaxel monotherapy, while ORR was similar across arms. At the preplanned OS analysis (median follow-up, 22.5 months), the OS HR was 0.67 ( P = .066) for the intermittent arm versus nab-paclitaxel monotherapy. Continuous relacorilant + nab-paclitaxel showed numerically improved median PFS but did not result in significant improvement over nab-paclitaxel monotherapy. Adverse events were comparable across study arms, with neutropenia, anemia, peripheral neuropathy, and fatigue/asthenia being the most common grade ≥3 adverse events.

CONCLUSION

Intermittent relacorilant + nab-paclitaxel improved PFS, DOR, and OS compared with nab-paclitaxel monotherapy. On the basis of protocol-prespecified Hochberg step-up multiplicity adjustment, the primary end point did not reach statistical significance ( P < .025). A phase III evaluation of this regimen is underway (ClinicalTrials.gov identifier: NCT05257408 ).
Outcome of Children and Adolescents With Relapsed/Refractory/Progressive Malignancies Treated With Molecularly Informed Targeted Drugs in the Pediatric Precision Oncology Registry INFORM
Authors: Heipertz Anna-Elisa , Pajtler Kristian W. , Pfaff Elke , Schramm Kathrin , Blattner-Johnson Mirjam , Milde Till , Jones Barbara C. , Zuliani Cecilia , Hutter Caroline , Lohi Olli , Kattamis Antonis , Dachowska-Kalwak Iwona , Nilsson Anna , Gerber Nicolas U. , Langenberg Karin P.S. , Goemans Bianca F. , Zwaan C. Michel , Molenaar Jan J. , Jäger Natalie , Dirksen Uta , Witt Ruth , Pfister Stefan M. , Jones David T.W. , Kopp-Schneider Annette , Witt Olaf , van Tilburg Cornelis M.
Published: June 2023

PURPOSE

INFORM is an international pediatric precision oncology registry, prospectively collecting molecular and clinical data of children with recurrent, progressive, or very high-risk malignancies. We have previously identified a subgroup of patients with improved outcomes on the basis of molecular profiling. The present analysis systematically investigates progression-free survival (PFS) and overall survival (OS) of patients receiving matching targeted treatment (MTT) with the most frequently applied drug classes and its correlation with underlying molecular alterations.

METHODS

A cohort of 519 patients with relapsed or refractory high-risk malignancies who had completed a follow-up of at least 2 years or shorter in the case of death or loss to follow-up was analyzed. Survival times were compared using the log-rank test.

RESULTS

MTT with anaplastic lymphoma kinase (ALK), neurotrophic tyrosine receptor kinase (NTRK), and B-RAF kinase (BRAF) inhibitors showed significantly improved PFS ( P = .012) and OS ( P = .036) in comparison with conventional treatment or no treatment. However, analysis of the four most commonly applied MTT groups, mitogen-activated protein kinase (MEK- n = 19), cyclin-dependent kinase (CDK- n = 23), other kinase (n = 62), and mammalian-target of rapamycin (mTOR- n = 20) inhibitors, did not reveal differences in PFS or OS compared with conventional treatment or no treatment in patients with similar molecular pathway alterations. We did not observe differences in the type of pathway alterations (eg, copy number alterations, single-nucleotide variants, InDels, gene fusions) addressed by MTT.

CONCLUSION

Patients with respective molecular alterations benefit from treatment with ALK, NTRK, and BRAF inhibitors as previously described. No survival benefit was observed with MTT for mutations in the MEK, CDK, other kinase, or mTOR signaling pathways. The noninterventional character of a registry has to be taken into account when interpreting these data and underlines the need for innovative interventional biomarker–driven clinical trials in pediatric oncology.
Physical Activity, Sedentary Behavior, and Type 2 Diabetes: Mendelian Randomization Analysis
Authors: Yuan Shuai , Li Xue , Liu Qianwen , Wang Zhe , Jiang Xia , Burgess Stephen , Larsson Susanna C
Published: June 2023

Context

The causality and pathways of the associations between physical activity and inactivity and the risk of type 2 diabetes remain inconclusive.

Objective

We conducted an updated mendelian randomization (MR) study to explore the associations of moderate-to-vigorous physical activity (MVPA) and leisure screen time (LST) with type 2 diabetes mellitus (T2DM).

Methods

Genetic variants strongly associated with MVPA or LST with low linkage disequilibrium were selected as instrumental variables from a genome-wide meta-analysis including more than 600 000 individuals. Summary-level data on T2DM were obtained from the DIAbetes Genetics Replication And Meta-analysis consortium including 898 130 individuals. Data on possible intermediates (adiposity indicators, lean mass, glycemic traits, and inflammatory biomarkers) were extracted from large-scale genome-wide association studies (n = 21 758-681 275). Univariable and multivariable MR analyses were performed to estimate the total and direct effects of MVPA and LST on T2DM. Methylation MR analysis was performed for MVPA in relation to diabetes.

Results

The odds ratio of T2DM was 0.70 (95% CI, 0.55-0.88; P = .002) per unit increase in the log-odds ratio of having MVPA and 1.45 (95% CI, 1.30-1.62; P = 7.62 × 10−11) per SD increase in genetically predicted LST. These associations attenuated in multivariable MR analyses adjusted for genetically predicted waist-to-hip ratio, body mass index, lean mass, and circulating C-reactive protein. The association between genetically predicted MVPA and T2DM attenuated after adjusting for genetically predicted fasting insulin levels. Two physical activity-related methylation biomarkers (cg17332422 in ADAMTS2 and cg09531019) were associated with the risk of T2DM (P < .05).

Conclusion

The study suggests causal associations of MVPA and LST with T2DM that appear to be mediated by obesity, lean mass, and chronic low-grade inflammation.
The role of thyroid hormones in the development of coloration of two species of Neotropical cichlids
Authors: Prazdnikov Denis V. , Shkil Fedor N.
Published: June 2023

Neotropical cichlids demonstrate an enormous diversity of pigment patterns, a morphological trait that plays an important role in adaptation and speciation. It has been suggested that alterations of the activity of the thyroid axis, one of the main endocrine axes regulating fish ontogeny, are involved in the development and diversification of pigment patterns in Neotropical cichlids. To test this hypothesis, we assessed thyroid hormone developmental dynamics and pigment patterning, and experimentally induced hyperthyroidism and hypothyroidism at different developmental stages in the convict cichlid, Amatitlania nigrofasciata, and blue-eye cichlid, Cryptoheros spilurus. We found that the two species display a similar type of coloration development and similar reactions to changes of thyroid hormone level, but species-specific differences in hormonal dynamics and thyroid hormone responsiveness. These findings indicate that thyroid hormone is a necessary but not sufficient signal to induce the transition from larval to juvenile coloration, and is a component of a complex, concerted endocrine cascade that drives skin development.
Enhancing Multiphase Reactions by Boosting Local Gas Concentration with Ultrafine Bubbles
Authors: Kozuka Tomoki , Iio Takuya , Suzuki Soma , Kakiuchi Kenta , Tadano Genta , Sato Kohei , Narumi Tetsuo , Mase Nobuyuki
Published: June 2023

Gas–liquid phase reactions have proven invaluable for molecular transformations in laboratory and industrial applications. However, despite their advantages, the high pressure and vigorous agitation that are required to increase the dissolved gas concentration hinder their possible applications. Application of fine bubbles (FBs), which have a diameter smaller than 100 µm, enables gas-involved reactions under mild conditions. In this study, we quantified and evaluated the reactivities of FBs and dissolved gases under various FB conditions. The photooxidation of sulfide using O2-FB-generated sulfoxide depends on the dissolved O2; meanwhile, H2-FB-mediated hydrogenation of alkenes with a Pd catalyst produced higher yields than expected from the dissolved H2. In a gas–liquid–solid phase reaction, FBs on the metal catalyst may form a gas tunnel between neighboring FBs and increase the local gas concentration, providing higher yields. The applicability of this effect was evaluated via hydrogenation using a deactivated metal catalyst in the presence of H2-FBs, which led to recovery from catalyst poisoning. The research findings demonstrated that surface FBs play a crucial role in enhancing reactivity that involves solid phases. In addition, we executed FB-mediated hydrogenation with a poisoned catalyst to demonstrate the ability of bubbles to suppress the catalyst poisoning.
Investigation of the diagnostic importance and accuracy of CT in the chest compared to the RT-PCR test for suspected COVID-19 patients in Jordan
Authors: Alewaidat Haytham , Bataineh Ziad , Bani-Ahmad Mohammad , Alali Manar , Almakhadmeh Ali
Published: June 2023

Background: COVID-19 affects different people in different ways. The illness varies from mild to acute. Mild illness is treated even without hospitalization. RT-PCR is one of the main techniques, which are used to diagnose COVID-19, but in this paper, we have investigated that Chest CT is a more efficient alternative option to RT-Polymerase Chain Reaction. The purpose of our study is to diagnose the importance of chest CT in comparison to the RT-PCR test method for the patients who might have COVID-19 virus. The study will aid in contrasting the performance of chest CT method and RT-PCR method.

Methods: This retrospective study included 1276 patients of the Jordanian hospitals' medical database that reception and following of suspected Covid-19 patients receiving high-resolution chest CT and real-time RT-PCR. Patients chosen underwent both chest CT and RT-PCR examinations, and the performance of chest CT in the diagnosis of COVID-19 evaluated, with maintaining the RT-PCR test as the reference standard.

Results: The sensitivity and accuracy of chest CT in identifying COVID-19 were all higher in patients over 60 than in those under 60, with no difference in positive predictive values and negative predictive values. The accuracy in-patient under 60 is higher than over 60 patients. Males had a higher specificity of chest CT in the diagnosis of the COVID-19 virus than females, but there was no difference in sensitivity, negative predictive value, positive predictive value, or accuracy.

Conclusions: RT-PCR is considered as the great standard for the diagnosis of Covid-19. According to the findings of our study, the best alternative option to RT-PCR is chest CT scan. CT scan is the less sensitive method but faster than RT-PCR. In a clinical setting, a radiologist with adequate training can distinguish the virus COVID-19 from other viral-induced pneumonias.
Seroepidemiology of Hepatitis E virus among the voluntary blood donors in the coastal region of Karnataka, India
Authors: S Sangthang , Shastry Shamee , N Sudheesh , Chawla Kiran , Madiyal Mridula , Kandasamy Dhivya
Published: June 2023

Background: Hepatitis E is a fecal orally transmitted disease and an emerging transfusion transmissible infection with potential transfusion safety implications. Hepatitis E Virus screening among blood donors is not routinely done despite the fact that it is endemic in India. As there are very few reports and evidence, the justification for mandating HEV screening among blood donors is still only marginally convincing. Therefore, the present study was carried out to determine the incidence and prevalence of HEV infection among blood donors in Coastal Karnataka, India.

Methods: This cross-sectional study was conducted in a tertiary care hospital in Udupi district of Karnataka, India. A total of 1939 blood donors were randomly selected between June 2020 to June 2022 to participate in the study, where anti-HEV IgM antibody screening was performed using HEV IgM ELISA test kit (DiaPro, Italy). Further, a randomly selected 588 and 1620 pooled donor samples were screened for anti-HEV IgG antibodies and HEV RNA, respectively.

Results: The overall prevalence of HEV IgM antibodies among study population is found to be 1.39%, with a statistically significant difference between males and females (n=20, 1.18% vs. n=7, 3.07 %; p=0.027). The prevalence of HEV IgG antibodies was 11.39%. Exposure to agriculture, animal husbandry, and poor hand hygiene were significant risk factors for HEV IgG reactivity.

Conclusions: Given the high prevalence of HEV viral markers in the study population, routine screening of blood donors for risk factors and implementation of serologic testing in endemic areas may be considered.
On the limits of inferring biophysical parameters of RBP-RNA interactions from in vitro RNA Bind’n Seq data
Authors: Schlusser Niels , Zavolan Mihaela
Published: June 2023

We develop a thermodynamic model describing the binding of RNA binding proteins (RBP) to oligomers in vitro. We apply expectation-maximization to infer the specificity of RBPs, represented as position-specific weight matrices (PWMs), by maximizing the likelihood of RNA Bind’n Seq data from the ENCODE project. We demonstrate that the model can reproduce known specificities for well-studied proteins and that in some cases we predict

novel, longer binding motifs. However, the model does not recover all the motifs that are in principle known, indicating that the data is not well explained by a single underlying biophysical model. Our code is publicly available.
Use of the opioid receptor antagonist – naltrexone in the treatment of non-suicidal self-injury
Authors: Karakuła-Juchnowicz Hanna , Banaszek Agnieszka , Juchnowicz Dariusz
Published: June 2023

Cel

Celem pracy jest przegląd dotychczasowych badań poświęconych możliwościom zastosowania niskich dawek naltreksonu (LDN) w terapii NSSI przeprowadzonych na modelach zwierzęcych oraz ludzkich.

Metoda

Dokonano przeglądu dostępnej literatury w języku polskim oraz angielskim poświęconej NSSI, używając słów kluczy: niesamobójcze samouszkodzenia, NSSI, naltrekson, LDN, samouszkodzenia, autoagresja oraz deskryptorów czasowych 1982-2022, przeszukując bazy PubMed/MEDLINE oraz Google Scholar. Przegląd oparto na informacjach zawartych w pracach oryginalnych, przeglądowych oraz opisach przypadków. W celu weryfikacji jakości artykułu, posłużono się sześciopunktową skalą SANRA (Scale for the Assesment of Narrative Review Articles).

Wyniki

Badania przeprowadzone na modelach zwierzęcych potwierdzają zasadność stosowania LDN w zapobieganiu nawykowym samouszkodzeniom. W odniesieniu do możliwości zastosowania klinicznego wyniki stosunkowo nielicznych przeprowadzonych badań potwierdzają skuteczność naltreksonu w dawce 25-50 mg/dobę w NSSI w postaci istotnej redukcji lub zaprzestania dokonywania samookaleczeń.

Wnioski

Zastosowanie LDN w terapii NSSI wydaje się obiecującą opcją kliniczną, wymagającą jednak potwierdzenia swej skuteczności w większej liczbie randomizowanych kontrolowanych placebo badań klinicznych.
Logical Constants and Arithmetical Forms
Authors: Speitel Sebastian G. W.
Published: June 2023

This paper reflects on the limits of logical form set by a novel criterion of logicality proposed in (Bonnay and Speitel, 2021). The interest stems from the fact that the delineation of logical terms according to the criterion exceeds the boundaries of standard first-order logic. Among ‘novel’ logical terms is the quantifier “there are infinitely many”. Since the structure of the natural numbers is categorically characterisable in a language including this quantifier we ask: does this imply that arithmetical forms have been reduced to logical forms? And, in general, what other conditions need to be satisfied for a form to qualify as “fully logical”? We survey answers to these questions.
Optimization Formulations for Storage Devices with Disjoint Operating Modes
Authors: Baldick Ross , Chen Yonghong , Huang Bing
Published: June 2023

Optimizing State of Charge for Storage Resources

Storage of generated energy has existed as a contributing resource within the power sector for more than a century in the case of pumped hydro storage. Even though most regional transmission organizations/independent system operators do not currently optimize state of charge (SOC) for storage, the SOC is an essential aspect of the operating characteristics of storage. This paper investigates the impact on computational performance of optimizing storage with explicit representation of SOC. To investigate the model, the paper considers two contexts, stand-alone and large-scale. Analysis of the stand-alone context helps to explain why the combination of features in the storage model results in a difficult problem. Numerical results for large-scale test cases verify that new tighter valid inequalities can improve the computation compared with the standard model in the literature.
Angina pectoris as a manifestation of ALCAPA syndrome in a 20-year-old female: a case report and review of literature
Authors: Bigdelu Leila , Maadarani Ossama , Azari Ali , Heidari-Bakavoli Ali , Bitar Zouheir
Published: June 2023

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is considered a rare congenital heart disease where the take-off of the left coronary artery abnormally originates from the pulmonary artery instead of left aortic sinus. It is associated with a high mortality rate in the first year of life and sudden death in adults if left untreated. We report an adult form of ALCAPA syndrome in a 20-year-old female who presented with anginal pain for the previous few months. Unfortunately, the patient was hesitant to have surgery at the time.
Acute musculoskeletal infection in children: assessment and management
Authors: Sykes Mark C , Ahluwalia Aashish K , Hay Daniel , Dalrymple James , Firth Gregory B
Published: June 2023

Musculoskeletal infection in children is challenging to treat, and includes septic arthritis, deep tissue infection, osteomyelitis, discitis and pyomyositis. Delays to diagnosis and management, and under-treatment can be life-threatening and result in chronic disability. The British Orthopaedic Association Standards for Trauma include critical steps in the timely diagnosis and management of acute musculoskeletal infection in children, the principles of acute clinical care and the service delivery requirements to appropriately manage this cohort of patients. Orthopaedic and paediatric services are likely to encounter cases of acute musculoskeletal infection in children and thus an awareness and thorough understanding of the British Orthopaedic Association Standards for Trauma guidelines is essential. This article reviews these guidelines and associated published evidence for the management of children with acute musculoskeletal infection.