bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating behavioral phenotypes related to autism spectrum disorder in a gene-environment interaction model of Cntnap2 deficiency and Poly I:C maternal immune activation
Authors: Haddad Faraj L. , De Oliveira Cleusa , Schmid Susanne 
Published: March 2023

IntroductionAutism Spectrum Disorder (ASD) has been associated with a wide variety of genetic and environmental risk factors in both human and preclinical studies. Together, findings support a gene-environment interaction hypothesis whereby different risk factors independently and synergistically impair neurodevelopment and lead to the core symptoms of ASD. To date, this hypothesis has not been commonly investigated in preclinical ASD models. Mutations in the Contactin-associated protein-like 2 (Cntnap2) gene and exposure to maternal immune activation (MIA) during pregnancy have both been linked to ASD in humans, and preclinical rodent models have shown that both MIA and Cntnap2 deficiency lead to similar behavioral deficits.MethodsIn this study, we tested the interaction between these two risk factors by exposing Wildtype, Cntnap2+/–, and Cntnap2–/– rats to Polyinosinic: Polycytidylic acid (Poly I:C) MIA at gestation day 9.5.ResultsOur findings showed that Cntnap2 deficiency and Poly I:C MIA independently and synergistically altered ASD-related behaviors like open field exploration, social behavior, and sensory processing as measured through reactivity, sensitization, and pre-pulse inhibition (PPI) of the acoustic startle response. In support of the double-hit hypothesis, Poly I:C MIA acted synergistically with the Cntnap2–/– genotype to decrease PPI in adolescent offspring. In addition, Poly I:C MIA also interacted with the Cntnap2+/– genotype to produce subtle changes in locomotor hyperactivity and social behavior. On the other hand, Cntnap2 knockout and Poly I:C MIA showed independent effects on acoustic startle reactivity and sensitization.DiscussionTogether, our findings support the gene-environment interaction hypothesis of ASD by showing that different genetic and environmental risk factors could act synergistically to exacerbate behavioral changes. In addition, by showing the independent effects of each risk factor, our findings suggest that ASD phenotypes could be caused by different underlying mechanisms.
Latency of breast cancer stigma during survivorship and its influencing factors: A qualitative study
Authors: Melhem Samar J. , Nabhani-Gebara Shereen , Kayyali Reem 
Published: March 2023

IntroductionBreast cancer diagnosis and treatment have been shown in studies to have a negative impact on patients’ physical, psychological, and social well-being, as well as overall quality of life. Psychologically, it’s linked to sadness, anxiety, and demoralisation. Stigma contributes to the hidden burden of breast cancer as a chronic illness. Research on the elements that breast cancer survivors encounter as influences on stigma associated to the disease is lacking. Based on the lived experiences of breast cancer survivors, this study sought to investigate the factors that lead to the manifestations of both self- and public breast cancer stigma.MethodsIndividual semi-structured interviews with 24 patients diagnosed with breast cancer were performed, followed by five focus groups with 25 patients diagnosed with breast cancer. Interviews were verbatim transcribed and analysed using thematic framework analysis.ResultsTwo major themes have emerged from the data: a) Breast cancer stigma among breast cancer survivors, highlighting the various manifestations of stigma and the variables that influence them; including disease-related factors, patients’ views of cancer, public perceptions of breast cancer, family and interpersonal dynamics, and b) Stigma resilience and empowerment, emphasising the necessity of sociocultural transformation and coping strategies to preserve resilience.ConclusionsTo improve the well-being of breast cancer survivors, practitioners and health policymakers should be aware of the breast cancer stigma that underpins patients’ emotional and behavioural outlooks and its potential consequences on patients’ quality of life. They need to develop interventions to address the different stages of cancer stigma taking into consideration sociocultural influences, norms, and beliefs.
Cost-effectiveness evaluation based on two models of first-line atezolizumab monotherapy and chemotherapy for advanced non-small cell lung cancer with high-PDL1 expression
Authors: Zhang Chuan , Liu Yue , Tan Jing , Tian Panwen , Li Weimin 
Published: March 2023

BackgroundAtezolizumab may provide clinical benefits to patients with advanced non-small cell lung cancer (NSCLC). However, the price of atezolizumab is relatively high, and its economic outcomes have remained unclear. In this study, we used two models to examine the cost-effectiveness of initial atezolizumab monotherapy versus chemotherapy for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC in the context of the Chinese healthcare system.MethodsPartitioned Survival model and Markov model were performed to evaluate the cost-effectiveness of first-line single-agent atezolizumab versus platinum-based chemotherapy for patients with advanced NSCLC with PD-L1 high-expressing EGFR and ALK wild-type disease. Clinical outcomes and safety information were obtained from the most recent data from the IMpower110 trial, while cost and utility values were obtained from Chinese hospitals and relevant literature. Total costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated. One-way and probabilistic sensitivity analyses were performed to explore model uncertainty. Scenario analyses were also conducted for the Patient Assistance Program (PAP) and various provinces in China.ResultsIn the Partitioned Survival model, the total cost of atezolizumab was $145,038, providing 2.92 LYs and 2.39 QALYs, while the total cost of chemotherapy was $69,803, providing 2.12 LYs and 1.65 QALYs. The ICER for atezolizumab versus chemotherapy was $102,424.83/QALY; in the Markov model, the ICER was $104,806.71/QALY. Atezolizumab was not cost-effective at the WTP threshold of three times China’s per capita gross domestic product (GDP). Sensitivity analysis showed that the cost of atezolizumab, the utility of PFS, and the discount rate had a significant impact on ICER; PAP significantly reduced ICER, but atezolizumab was still not cost-effective in China.ConclusionFirst-line monotherapy with atezolizumab for patients with PD-L1 high-expressing EGFR and ALK wild-type advanced NSCLC was estimated to be less cost-effective than chemotherapy in terms of the Chinese healthcare system; offering PAP increased the likelihood that atezolizumab would be cost-effective. In some areas of China with higher levels of economic development, atezolizumab was likely to be cost-effective. To improve the cost-effectiveness of atezolizumab, drug prices would need to be reduced.
NTRK fusion protein expression is absent in a large cohort of diffuse large B-cell lymphoma
Authors: Ghandili Susanne , Dierlamm Judith , Bokemeyer Carsten , von Bargen Clara Marie , Weidemann Sören Alexander 
Published: March 2023

BackgroundEven though two NTRK-targeting drugs are available for the treatment of irresectable, metastatic, or progressive NTRK-positive solid tumors, less is known about the role of NTRK fusions in lymphoma. For this reason, we aimed to investigate if NTRK fusion proteins are expressed in diffuse large B-cell lymphoma (DLBCL) by systemic immunohistochemistry (IHC) screening and additional FISH analysis in a large cohort of DLBCL samples according to the ESMO Translational Research and Precision Medicine Working Group recommendations for the detection of NTRK fusions in daily practice and clinical research.MethodsA tissue microarray of 92 patients with the diagnosis of DLBCL at the University Hospital Hamburg between 2020 and 2022 was built. The clinical data were taken from patient records. Immunohistochemistry for Pan-NTRK fusion protein was performed and positive staining was defined as any viable staining. For FISH analysis only results with quality 2 and 3 were evaluated.ResultsNTRK immunostaining was absent in all analyzable cases. No break apart was detectable by FISH.ConclusionOur negative result is consistent with the very sparse data existing on NTRK gene fusions in hematologic neoplasms. To date, only a few cases of hematological malignancies have been described in which NTRK-targeting drugs may provide a potential therapeutic agent. Even though NTRK fusion protein expression was not detectable in our sample cohort, performing systemic screenings for NTRK fusions are necessary to define further the role of NTRK fusions not only in DLBCL but in a multitude of lymphoma entities as long as the lack of reliable data exists.
Advanced lung cancer inflammation index predicts survival outcomes of hepatocellular carcinoma patients receiving immunotherapy
Authors: Li Qian , Ma Fei , Wang Ju feng 
Published: March 2023

ObjectiveWe evaluate the predictive significance of the Advanced Lung Cancer Inflammation Index (ALI) in patients with advanced hepatocellular carcinoma (HCC) following therapy with immune checkpoint drugs.MethodsIn 2018-2020, 98 patients with advanced hepatocellular carcinoma who were treated with immune checkpoint inhibitors at our hospital were compiled. Using the receiver operating characteristic (ROC) curve, the appropriate cut-off point for ALI was determined. Kaplan-Meier analysis, the Cox proportional hazards model, and Nomogram plots highlighted the relationship between ALI and overall survival (OS). The model was validated using calibration plots, receiver operating characteristic curves (ROC), and decision curve analysis (DCA), which was performed on 52 patient sets by external validation.ResultsThe AUC for ALI was 0.663. The best cutoff value was 36.5, with a median overall survival (OS) of 473 days for patients with ALI≤ 36.5 and 611 days for those with ALI &gt; 36.5. Univariate analysis revealed that the presence or absence of local treatment, alpha-fetoprotein (AFP), and ALI were prognostic factors; LASSO regression analysis identified four candidate variables. Multifactorial COX analysis revealed that high ALI was an independent prognostic factor for overall survival in both groups (HR = 0.411; 95% CI: 0.244-0.651; P&lt;0.001). In addition, the Nomogram model that included ALI was able to predict the success of immunotherapy in patients with advanced liver cancer more accurately.ConclusionALI is a novel prognostic marker in immunotherapy-treated patients with advanced hepatocellular cancer.
Diaphragmatic ultrasound and patent ductus arteriosus in the newborn: A retrospective case series
Authors: Dassios Theodore , Arattu Thodika Fahad M. S. , Nanjundappa Mahesh , Williams Emma , Bell Aaron J. , Greenough Anne 
Published: March 2023

BackgroundPatent ductus arteriosus (PDA) and diaphragmatic dysfunction are frequently seen in newborn infants but their relationship remains unknown. We aimed to use point of care ultrasound to compare diaphragmatic kinetics in infants with a PDA compared to in those without a PDA.MethodsM-mode ultrasonography was used to measure the mean inspiratory velocity (VI) in newborn infants with and without a haemodynamically significant PDA admitted in the Neonatal Unit at King's College Hospital during a three month period.ResultsSeventeen diaphragmatic ultrasound studies were reviewed from 14 infants with a median (IQR) gestational age of 26.1 (25.8–30.6) weeks, birth weight of 780 (660–1385) gr at a postnatal age of 18 (14–34) days. Eight scans had evidence of a PDA. The median (IQR) VI was significantly lower in scans with a PDA [1.01 (0.78–1.86) cm/s] compared to the ones without a PDA [3.21 (2.80–3.59) cm/s, p &lt; 0.001]. The median (IQR) gestational age was lower in infants with a PDA [25.8 (25.6–27.3) weeks] compared to infants without a PDA [29.0 (26.1–35.1) weeks, p = 0.007]. Using multivariable linear regression analysis the VI was independently associated with a PDA (adjusted p &lt; 0.001) but not with the gestational age (adjusted p = 0.659).ConclusionsPatent ductus arteriosus was associated with a lower mean inspiratory velocity in neonates and this effect was independent of gestational age.
Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development
Authors: Ayoun Alsoud Rami , Svensson Robin J. , Svensson Elin M. , Gillespie Stephen H. , Boeree Martin J. , Diacon Andreas H. , Dawson Rodney , Aarnoutse Rob E. , Simonsson Ulrika S. H. 
Published: March 2023

Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10–40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
PBPK-based dose finding for sildenafil in pregnant women for antenatal treatment of congenital diaphragmatic hernia
Authors: Macente Julia , Nauwelaerts Nina , Russo Francesca M. , Deprest Jan , Allegaert Karel , Lammens Bart , Hernandes Bonan Rodolfo , Turner Jessica M. , Kumar Sailesh , Diniz Andrea , Martins Frederico S. , Annaert Pieter 
Published: March 2023

Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, dosing should be initiated at 130 mg/day, under therapeutic drug monitoring. Additional experimental measurements should be performed to confirm accurate fetal (and maternal) values for fu. Additional characterization of pharmacodynamics in this specific population is required and may lead to further optimization of the dosing regimen.
The effect of transcutaneous electrical stimulation of the submental area on the cardiorespiratory response in normal and awake subjects
Authors: Alsharifi Abdulaziz , Kaltsakas Georgios , Pengo Martino F. , Parati Gianfranco , Serna-Pascual Miquel , Rafferty Gerrard , Steier Joerg 
Published: March 2023

Background: Electrical stimulation has recently been introduced to treat patients with Obstructive sleep apnoea There are, however, few data on the effects of transcutaneous submental electrical stimulation (TES) on the cardiovascular system. We studied the effect of TES on cardiorespiratory variables in healthy volunteers during head-down-tilt (HDT) induced baroreceptor loading.Method: Cardiorespiratory parameters (blood pressure, heart rate, respiratory rate, tidal volume, airflow/minute ventilation, oxygen saturation, and end-tidal CO2/O2 concentration) were recorded seated, supine, and during head-down-tilt (50) under normoxic, hypercapnic (FiCO2 5%) and poikilocapnic hypoxic (FiO2 12%) conditions. Blood pressure (BP) was measured non-invasively and continuously (Finapres). Gas conditions were applied in random order. All participants were studied twice on different days, once without and once with TES.Results: We studied 13 healthy subjects (age 29 (12) years, six female, body mass index (BMI) 23.23 (1.6) kg·m−2). A three-way ANOVA indicated that BP decreased significantly with TES (systolic: p = 4.93E-06, diastolic: p = 3.48E-09, mean: p = 3.88E-08). Change in gas condition (systolic: p = 0.0402, diastolic: p = 0.0033, mean: p = 0.0034) and different postures (systolic: 8.49E-08, diastolic: p = 6.91E-04, mean: p = 5.47E-05) similarly impacted on BP control. When tested for interaction, there were no significant associations between the three different factors electrical stimulation, gas condition, or posture, except for an effect on minute ventilation (gas condition/posture p = 0.0369).Conclusion: Transcutaneous electrical stimulation has a substantial impact on the blood pressure. Similarly, postural changes and variations in inspired gas impact on blood pressure control. Finally, there was an interaction between posture and inspired gases that affects minute ventilation. These observations have implications on our understanding of integrated cardiorespiratory control, and may prove beneficial for patients with SDB who are assessed for treatment with electrical stimulation.
Impact of cultural intelligence on the cross-cultural adaptation of international students in China: The mediating effect of psychological resilience
Authors: Chu Kequn , Zhu Fengshu 
Published: March 2023

IntroductionCultural intelligence can affect the cross-cultural adaptation of international students in China, but the mechanism of its influence is still unclear. This study examines the mediating effect of the psychological resilience of international students in China in the process of cultural intelligence affecting cross-cultural adaptation. We used the cultural intelligence scale, psychological resilience scale, and cross-cultural adaptation scale to measure 624 foreign students in China.Results(1) There is a significant positive correlation between the cultural intelligence, psychological resilience, and cross-cultural adaptation of international students in China. (2) Resilience plays a mediating effect in the influence of the cultural intelligence of international students in China on cross-cultural adaptation.ConclusionThe cultural intelligence of international students in China can directly affect their cross-cultural adaptation and can also affect their cross-cultural adaptation through the mediating effect of psychological resilience.
Assessing manifestations of bossing in the context of personality traits of business managers
Authors: Stefko Robert , Birknerova Zuzana , Zbihlejova Lucia , Nebesky Lubomir 
Published: March 2023

IntroductionAbusive supervision or bossing represents a specific form of mobbing as a long-term, systematic negative action by superiors toward subordinates.MethodsFrom the point of view of the operationalization of this construct, the original BOSSm18 methodology is presented in the paper in the context of the B5 methodology, which enables specification of personality traits in terms of the original Big Five concept.ResultsBased on the research dataset of 636 business managers, the paper presents the results of the basic psychometric parameters of the methodology and the content specification of the extracted factors. The research findings support a multidimensional understanding of the bossing construct.DiscussionThe limiting factors of the interpretation and generalization of the results relate to the consideration of cultural contexts and situational conditions of perception of bossing manifestations.
The paradoxical effects of professional stereotypes on the quality of care by interprofessional teams: The contingent effects of team faultlines, team stereotypes, and championship behaviors
Authors: Sheffer Hilel Galia , Drach-Zahavy Anat , Endevelt Ronit 
Published: March 2023

BackgroundDespite calls for interprofessional teamwork to ensure quality care in healthcare settings, interprofessional teams do not always perform effectively. There is evidence that professional stereotypes inhibit effective interprofessional teamwork, but they haven’t been explored as a phenomenon that impacts team’s performance and quality of care.ObjectivesTo focus on professional stereotypes emerging in interprofessional teams and examine the contingency effects of interprofessional team’s faultlines, professional stereotypes, and leader’s championship behaviors on team’s quality of care.MethodsA cross-sectional nested sample of 59 interprofessional teams and 284 professionals, working in geriatric long-term-care facilities in Israel. Additionally, five to seven of the residents of each facility were randomly sampled to obtain the outcome variable. Data collection employed a multisource (interprofessional team members), multimethod (validated questionnaires and data from residents’ health records) strategy.ResultsThe results indicated that faultlines are not directly harmful to team’s quality of care; instead, they are likely to impact quality of care only when team stereotypes emerge. Furthermore, whereas teams typified by high professional stereotypes require person-oriented championship leadership, for teams typified by low team stereotypes, championship leadership harms the quality of care they provide.ConclusionThese findings have implications for handling interprofessional teams. Practically, leaders must be well-educated to better analyze team members’ needs and maintain the appropriate leadership style.