bluuebunny/crossref_metadata_2025_split huggingface dataset:
Backfilling cohorts in phase I dose-escalation studies
Authors: Barnett Helen , Boix Oliver , Kontos Dimitris , Jaki Thomas 
Published: March 2023

Background: The use of ‘backfilling’, assigning additional patients to doses deemed safe, in phase I dose-escalation studies has been used in practice to collect additional information on the safety profile, pharmacokinetics and activity of a drug. These additional patients help ensure that the maximum tolerated dose is reliably estimated and give additional information to determine the recommended phase II dose. Methods: In this article, we study the effect of employing backfilling in a phase I trial on the estimation of the maximum tolerated dose and the duration of the study. We consider the situation where only one cycle of follow-up is used for escalation as well as the case where there may be delayed onset toxicities. Results: We find that, over a range of scenarios, the use of backfilling gives an increase in the percentage of correct selections by up to 9%. On average, for a treatment with a cycle length of 6 weeks, each additional backfilling patient reduces the trial duration by half a week. Conclusions: Backfilling in phase I dose-escalation studies can substantially increase the accuracy of estimation of the maximum tolerated dose, with a larger impact in the setting with a dose-limiting toxicity event assessment period of only one cycle. This increased accuracy and reduction in the trial duration are at the cost of increased sample size.
Evolution hesitancy: challenges and a way forward for teachers and teacher educators
Authors: Newall Emma , Reiss Michael J. 
Published: March 2023

Abstract
Background
It has long been acknowledged that evolution is a difficult topic for many students, partly because of the conceptual demands it makes, and partly because for some students an acceptance of evolution conflicts with their religious beliefs. The study we report on here was designed to see if there were additional reasons why evolution might be a difficult topic for certain students.

Results
Using in-depth, semi-structured interviews with seventeen adults studying for education qualifications, we show that evolution is a difficult topic for certain people because it can give rise to existential concerns. Thematic content analysis of interview transcripts revealed six themes associated with existential concerns: time, identity, death, responsibility/freedom, meaninglessness, and isolation. Analysis revealed that the topic of evolution frequently gave rise to feelings of disquiet.

Conclusions
Because it concerns issues to do with death, extinction and change, evolution can be deeply unsettling for many people, even if they may have difficulty articulating why this is so. Teachers when they teach evolution therefore need to consider at least three overlapping constituencies who may find evolution difficult: those for whom it is cognitively challenging; those who reject aspects of evolution on religious grounds; and those who are uncomfortable with evolution for existential reasons. Teacher educators need to decide how best to prepare new teachers for these challenges. We argue that a pedagogy based on two approaches—treating evolution as a conceptually demanding topic and treating it as a sensitive issue—may provide a way forward.
Detection of anomalies in cycling behavior with convolutional neural network and deep learning
Authors: Yaqoob Shumayla , Cafiso Salvatore , Morabito Giacomo , Pappalardo Giuseppina 
Published: March 2023

Abstract
Background
Cycling has always been considered a sustainable and healthy mode of transport. With the increasing concerns of greenhouse gases and pollution, policy makers are intended to support cycling as commuter mode of transport. Moreover, during Covid-19 period, cycling was further appreciated by citizens as an individual opportunity of mobility. Unfortunately, bicyclist safety has become a challenge with growing number of bicyclists in the 21st century. When compared to the traditional road safety network screening, availability of suitable data for bicycle based crashes is more difficult. In such framework, new technologies based smart cities may require new opportunities of data collection and analysis.

Methods
This research presents bicycle data requirements and treatment to get suitable information by using GPS device. Mainly, this paper proposed a deep learning-based approach “BeST-DAD” to detect anomalies and spot dangerous points on map for bicyclist to avoid a critical safety event (CSE). BeST-DAD follows Convolutional Neural Network and Autoencoder (AE) for anomaly detection. Proposed model optimization is carried out by testing different data features and BeST-DAD parameter settings, while another comparison performance is carried out between BeST-DAD and Principal Component Analysis (PCA).

Result
BeST-DAD over perform than traditional PCA statistical approaches for anomaly detection by achieving 77% of the F-score. When the trained model is tested with data from different users, 100% recall is recorded for individual user’s trained models.

Conclusion
The research results support the notion that proper GPS trajectory data and deep learning classification can be applied to identify anomalies in cycling behavior.
Genome-wide mapping of signatures of selection using a high-density array identified candidate genes for growth traits and local adaptation in chickens
Authors: Mastrangelo Salvatore , Ben-Jemaa Slim , Perini Francesco , Cendron Filippo , Biscarini Filippo , Lasagna Emiliano , Penasa Mauro , Cassandro Martino 
Published: March 2023

AbstractBackgroundAvailability of single nucleotide polymorphism (SNP) genotyping arrays and progress in statistical analyses have allowed the identification of genomic regions and genes under selection in chicken. In this study, SNP data from the 600 K Affymetrix chicken array were used to detect signatures of selection in 23 local Italian chicken populations. The populations were categorized into four groups for comparative analysis based on live weight (heavy vs light) and geographical area (Northern vs Southern Italy). Putative signatures of selection were investigated by combining three extended haplotype homozygosity (EHH) statistical approaches to quantify excess of haplotype homozygosity within (iHS) and between (RsbandXP-EHH) groups. Presence of runs of homozygosity (ROH) islands was also analysed for each group.ResultsAfter editing, 541 animals and 313,508 SNPs were available for statistical analyses. In total, 15 candidate genomic regions that are potentially under selection were detected among the four groups: eight within a group byiHSand seven by combining the results ofRsbandXP-EHH, which revealed divergent selection between the groups. The largest overlap between genomic regions identified to be under selection by the three approaches was on chicken chromosome 8. Twenty-one genomic regions were identified with the ROH approach but none of these overlapped with regions identified with the three EHH-derived statistics. Some of the identified regions under selection contained candidate genes with biological functions related to environmental stress, immune responses, and disease resistance, which indicate local adaptation of these chicken populations.ConclusionsCompared to commercial lines, local populations are predominantly reared as backyard chickens, and thus, may have developed stronger resistance to environmental challenges. Our results indicate that selection can play an important role in shaping signatures of selection in local chicken populations and can be a starting point to identify gene mutations that could have a useful role with respect to climate change.
Determining the survival benefit of postoperative radiotherapy in patients with pT1-3N1M0 rectal cancer undergoing total mesorectal excision: a retrospective analysis
Authors: Chen Jin-hu , Ye Qing , Huang Feng 
Published: March 2023

Abstract
Background
The National Comprehensive Cancer Network guidelines recommend routine postoperative adjuvant radiotherapy and chemotherapy for patients with stage III rectal cancer who do not receive neoadjuvant therapy before surgery. The present study aimed to evaluate the value of postoperative radiotherapy in patients with low-risk disease (pT1-3N1M0) who did not receive neoadjuvant therapy prior to total mesorectal excision.

Methods
We used the Surveillance, Epidemiology, and End Results database (2004–2016) to retrospectively recruit patients with pT1-3N1M0 rectal cancer whose initial treatment was radical surgery with postoperative adjuvant chemotherapy. A propensity score model was used to balance the baseline covariates.

Results
Of the 2012 patients included in the present study, 1384 received adjuvant chemoradiotherapy (radio group), whereas the remaining 718 received chemotherapy alone (no-radio group). There was no significant difference in cancer-specific survival rate between the two groups (log-rank test χ2 = 2.372, P = 0.124) in the overall sample. Additionally, in the propensity score−matched cohort, adjuvant radiotherapy did not improve cancer-specific survival. Subgroup analysis showed that having three positive lymph nodes and a tumor > 50 mm, combined with postoperative adjuvant chemotherapy, could lead to an improved tumor-specific survival rate, while other cases did not benefit from postoperative radiotherapy.

Conclusions
For patients with pT1-3N1M0 rectal cancer who did not receive neoadjuvant therapy before surgery, postoperative radiotherapy in addition to adjuvant chemotherapy did not significantly improve survival rates. The number of positive nodes (n = 3) and tumor size (> 50 mm) were found to be potential screening indicators for postoperative adjuvant radiotherapy.
The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial
Authors: Kant-Smits Kim , Bartels Bart , Asselman Fay-Lynn , Veldhoen Esther S. , van Eijk Ruben P. A. , van der Pol W. Ludo , Hulzebos Erik H. J. 
Published: March 2023

Abstract
Background
Spinal Muscular Atrophy (SMA) is characterized by progressive and predominantly proximal and axial muscle atrophy and weakness. Respiratory muscle weakness results in impaired cough with recurrent respiratory tract infections, nocturnal hypoventilation, and may ultimately lead to fatal respiratory failure in the most severely affected patients. Treatment strategies to either slow down the decline or improve respiratory muscle function are wanting.

Objective
The aim of this study is to assess the feasibility and efficacy of respiratory muscle training (RMT) in patients with SMA and respiratory muscle weakness.

Methods
The effect of RMT in patients with SMA, aged ≥ 8 years with respiratory muscle weakness (maximum inspiratory mouth pressure [PImax] ≤ 80 Centimeters of Water Column [cmH2O]), will be investigated with a single blinded randomized sham-controlled trial consisting of a 4-month training period followed by an 8-month open label extension phase.

Intervention
The RMT program will consist of a home-based, individualized training program involving 30-breathing cycles through an inspiratory and expiratory muscle training device. Patients will be instructed to perform 10 training sessions over 5–7 days per week. In the active training group, the inspiratory and expiratory threshold will be adjusted to perceived exertion (measured on a Borg scale). The sham-control group will initially receive RMT at the same frequency but against a constant, non-therapeutic resistance. After four months the sham-control group will undergo the same intervention as the active training group (i.e., delayed intervention). Individual adherence to the RMT protocol will be reviewed every two weeks by telephone/video call with a physiotherapist.

Main study parameters/endpoints
We hypothesize that the RMT program will be feasible (good adherence and good acceptability) and improve inspiratory muscle strength (primary outcome measure) and expiratory muscle strength (key secondary outcome measure) as well as lung function, patient reported breathing difficulties, respiratory infections, and health related quality of life (additional secondary outcome measures, respectively) in patients with SMA.

Discussion
RMT is expected to have positive effects on respiratory muscle strength in patients with SMA. Integrating RMT with recently introduced genetic therapies for SMA may improve respiratory muscle strength in this patient population.

Trial registration
Retrospectively registered at clinicaltrial.gov: NCT05632666.
Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype
Authors: Almobarak Bilal , Amlani Vishal , Inge Linda , Hofving Tobias , Muth Andreas , Nilsson Ola , Johansson Martin , Arvidsson Yvonne , Elias Erik 
Published: March 2023

Abstract
Background
Small intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location.

Methods
Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.

Results
Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.

Conclusion
Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
Exposure to interparental violence and justification of intimate partner violence among women in Papua New Guinea
Authors: Aboagye Richard Gyan , Asare Bernard Yeboah-Asiamah , Adu Collins , Cadri Abdul , Seidu Abdul-Aziz , Ahinkorah Bright Opoku , Yaya Sanni 
Published: March 2023

Abstract
Background
Previous studies have demonstrated that exposure to interparental violence is associated with intimate partner violence justification in a variety of contexts. In this study, we examined the association between exposure to interparental violence and justification of intimate partner violence among women in Papua New Guinea.

Methods
We used data from the 2016–18 Papua New Guinea Demographic and Health Survey. We included 2839 women of reproductive age (15–49 years) in a sexual union (married and cohabiting) in the study. We used a multivariable binary multilevel regression analysis to examine the association between interparental violence and justification of intimate partner violence. We presented the results of the regression analysis using crude odds ratio (cOR) and adjusted odds ratios (aORs), with their 95% confidence intervals (CIs).

Results
Women exposed to interparental violence were 1.26 (95%CI = 1.05, 1.53) times more likely to justify intimate partner violence than those who were not exposed. Women who resided in the Highlands (aOR = 2.50, 95%CI = 1.78, 3.51), Momase (aOR = 1.96, 95%CI = 1.40, 2.75), and Islands (aOR = 1.42, 95%CI = 1.01, 1.99) were more likely to justify intimate partner violence compared to those in the Southern region. Women who were exposed to one (aOR = 1.38, 95%CI = 1.06, 1.82) mass media were more likely to justify intimate partner violence compared to those who had no exposure to mass media. On the other hand, women aged 25–34 years (aOR = 0.66, 95%CI = 0.48, 0.91) and 35–49 years (aOR = 0.66, 95%CI = 0.44, 0.97) were less likely to justify intimate partner violence compared to those aged 15–24 years.

Conclusions
Our study has shown that exposure to interparental violence is a predictor of intimate partner violence justification. This study suggests the need for conscious and continuous efforts to identify and assist women who have been exposed to interparental violence to help prevent its transition to later life. Policies and interventions should be developed and implemented to curtail children’s exposure to domestic violence in their households. Also, laws and policies need to condemn any violence and demystify community justification and acceptance of intimate partner violence, taking into consideration the significant sociodemographic characteristics of the women highlighted in the study.
Metabolically healthy obesity is associated with higher risk of both hyperfiltration and mildly reduced estimated glomerular filtration rate: the role of serum uric acid in a cross-sectional study
Authors: Zhang Hong , Chen Rui , Xu Xiaohong , Yang Minxing , Xu Wenrong , Xiang Shoukui , Wang Long , Jiang Xiaohong , Hua Fei , Huang Xiaolin 
Published: March 2023

AbstractBackgroundThe impact of metabolically healthy obesity (MHO) on kidney dysfunction remains debatable. Moreover, few studies have focused on the early stages of kidney dysfunction indicated by hyperfiltration and mildly reduced eGFR. Thus, we aimed to investigate the association between the MHO and early kidney dysfunction, which is represented by hyperfiltration and mildly reduced estimated glomerular filtration rate (eGFR), and to further explore whether serum uric acid affects this association.MethodsThis cross-sectional study enrolled 1188 residents aged ≥ 40 years old from Yonghong Communities. Metabolically healthy phenotypes were categorized based on Adult Treatment Panel III criteria. Obesity was defined as body mass index (BMI) ≥ 25 kg/m2. Mildly reduced eGFR was defined as being in the range 60 < eGFR ≤ 90 ml/min/1.73m2. Hyperfiltration was defined as eGFR > 95th percentile after adjusting for sex, age, weight, and height.ResultsOverall, MHO accounted for 12.8% of total participants and 24.6% of obese participants. Compared to metabolically healthy non-obesity (MHNO), MHO was significantly associated with an increased risk of mildly reduced eGFR (odds ratio [OR] = 1.85, 95% confidence interval [CI]  1.13–3.01) and hyperfiltration (OR = 2.28, 95% CI 1.03–5.09). However, upon further adjusting for uric acid, the association between the MHO phenotype and mildly reduced eGFR was reduced to null. Compared with MHNO/non-hyperuricemia, MHO/non-hyperuricemia was associated with an increased risk of mildly reduced eGFR (OR = 2.04, 95% CI  1.17–3.58), whereas MHO/hyperuricemia was associated with an observably increased risk (OR = 3.07, 95% CI  1.34–7.01).ConclusionsMHO was associated with an increased risk of early kidney dysfunction, and the serum uric acid partially mediated this association. Further prospective studies are warranted to clarify the causality.
DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight
Authors: Cameron Vicky A. , Jones Gregory T. , Horwood L. John , Pilbrow Anna P. , Martin Julia , Frampton Chris , Ip Wendy T. , Troughton Richard W. , Greer Charlotte , Yang Jun , Epton Michael J. , Harris Sarah L. , Darlow Brian A. 
Published: March 2023

Abstract
Background
Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented.

Results
Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults.

Conclusions
These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.