bluuebunny/crossref_metadata_2025 huggingface dataset:
P15.03.A The value of 7 Tesla MR spectroscopic imaging for improved preoperative determination of the tumor grade and IDH status in gliomas: preliminary data
Authors: Hangel G , Sharma S , Cadrien C , Furtner J , Furtner J , Roetzer-Pejrimovsky T , Preusser M , Bogner W , Rössler K , Trattnig S , Widhalm G
Published: September 2022

Introduction

A new generation of MR spectroscopic imaging (MRSI) methods using 7T scanners have demonstrated the capability to resolve more neuro- and oncometabolites at higher resolutions than clinical routine MRSI. In a cohort of glioma patients, we explored the automated preoperative and noninvasive classification of IDH-mutation status and tumor grade based on 7T MRSI.

Methods

This retrospective study included 36 patients (15 female) with histologically confirmed diffusely infiltrating glioma WHO grade 2-4 (9 grade 2, 9 grade 3 and 18 grade 4) and known IDH status (21 IDH1-mut, 15 IDH-wt) with an available 7T MRSI scan of sufficient data quality. The 3D MRSI scan had a 3.4 mm isotropic resolution and 15 minutes acquisition time. 12 spectral components were classified voxel-wise, including choline, glutamine and glycine. Within a tumor segmentation based on routine 3T imaging, we used a random forest algorithm for the voxel-wise classification of IDH mutation and grade (into low or high grade). Training used the leave-one-out cross validation method (i.e., for every patient data set, the other 35 datasets were used as training set) and feature selection out of the available combinations for metabolite ratios (e.g., glutamine to choline). The resulting voxel classifications were aggregated into a mean probability per patient that was the base for receiver-operator characteristic (ROC) curves both for grade and IDH status.

Results

The classification algorithm obtained an area under the curve (AUC) for IDH determination of 0.85 (e.g., 75% sensitivity and 95% specificity). For grade determination, the AUC was 0.88 (e.g., 87% sensitivity and 89% specificity). In comparison, the AUC per voxel would have resulted in an AUC of 0.66 for both. Further, classification by individual metabolite ratios resulted in lower AUCs in all cases.

Conclusions

According to our preliminary data, preoperative 7T MRSI is capable to determine the correct glioma grade and IDH status with high sensitivity and specificity by leveraging the extended metabolic panel width and voxel amount. By increasing this cohort in future, we intend to confirm our initial results and we also plan to extend classification to more molecular-pathological features (e.g., TERT). Thus, even a voxel-wise classification of tumor microenvironments could be attempted. Further improvements in 7T MRSI methodology such as absolute instead of relative quantification would also aid these attempts.

In summary, 7T MRSI has shown its potential for improved preoperative characterization of gliomas.
P17.05.A Re-irradiation with bevacizumab for large volume chemo-refractory glioblastoma after prior high-dose chemoradiotherapy
Authors: Horsley P , Tong E , Wheeler H , Venkatesha V , Chan J , Kastelan M , Back M
Published: September 2022

Background

There are limited options for salvage treatment of glioblastoma. The role of re-irradiation (reRT) for large-volume chemo-refractory relapse is not established due to concerns regarding potential toxicity, which may be overcome with use of bevacizumab.

Material and Methods

Patients who received initial post-operative chemoradiotherapy with 60Gy (EORTC-NCIC protocol) for glioblastoma across two centres from 2007-2021 were entered into a prospective database. Patients with progressive chemo-refractory disease, including some progressing on bevacizumab, were considered for reRT. Pseudoprogression and late RT necrosis was actively excluded using sequential MRI and PET. Clinico-pathologic characteristics of the reRT cohort and patients who had progressed but did not undergo reRT were compared. Kaplan-Meier survival analysis was used to assess overall (OS) and progression-free survival (PFS) from diagnosis in the overall and reRT cohorts as well as OS post-reRT. Factors associated with improved survival post-reRT were assessed.

Results

Of 447 patients treated for glioblastoma, 372 had progressed of which 71 received reRT. Median follow up for surviving patients was 26 and 37 months from diagnosis for the reRT and overall cohorts respectively. Median PFS and OS from initial diagnosis were 11.6 (95% CI: 9.4-14.2) and 23.6 (95% CI: 21.0-33.1) months respectively for re-RT patients, compared to 11.8 (95% CI: 11.0-12.5) and 18.0 (95% CI 17.0-19.1) months for the overall cohort. The reRT subgroup were more likely to be younger (median 53 vs. 59 years, p<0.001), have ECOG performance status at diagnosis 0-1 (86% vs. 69%, p=0.002) and have MGMT promoter methylation (54% vs. 40% p=0.083). There was no difference in extent of initial resection (p=0.59). The most common reRT schedule was 15 fractions to a total dose of either 40 Gy (32 patients) or 35 Gy (28 patients). Sixty (85%) had progression on bevacizumab prior to reRT; bevacizumab was continued during reRT in these cases. A further 10 (14%) received salvage bevacizumab after reRT. Median reRT PTV volume was 135cc (IQR 69-207cc). Median OS following reRT was 7.1 months (95% CI: 6.3-7.9). Six (8%) patients were admitted to hospital within 30 days of reRT, only one due to reRT toxicity. Median OS post-reRT was 7.7, 6.4 and 6.0 months for patients aged <50, 50-70 and >70 years respectively (p=0.021) and 8.1 vs. 6.3 months for patients with ECOG performance status of 0-1 and 2-3 respectively (p=0.039). Distant versus local progression (p=0.87), anatomical location of disease (p=0.65), MGMT methylation status (p=0.77) and PTV volume (p=0.91) did not predict post-reRT survival.

Conclusion

Large volume reRT for patients with recurrent glioblastoma is feasible, well-tolerated, associated with favourable overall survival and produces meaningful post-radiotherapy survival times.
P17.11.A Experience of ketogenic diet with support of liquid formula 3:1 and high-grade gliomas: Case series
Authors: Zapata Laguado M I , Luna-Meza A , Gonzalez Hurtado D , Aya Ramos L
Published: September 2022

Background

High-grade gliomas, including glioblastoma, are the most common primary malignant brain tumors in adults. Despite the efforts to develop new therapies, treatment options remain limited and the prognosis is poor. Ketogenic diet, is an emerging complementary therapy for high-grade gliomas. It is hypothesized that through the change of the energy source from glucose to ketones and the inability of glioma cells to metabolize ketone bodies with the same ease due to inefficient oxidative phosphorylation, tumor growth is slowed. The feasibility of a ketogenic diet is a matter of concern. Its influence on the quality of life of patients with advanced cancers showing that even though it may cause constipation and reflux, quality of life is generally not affected

Material and Methods

We reported a case series of patients with high-grade gliomas using ketogenic diet with liquid formula 3:1 ratio (KDS) as a complementary treatment. We describe baseline characteristics, and EORTC-QLQ30 score and symptom evaluation

Results

We describe the case of 3 patients (2 women and 1 man) with diagnoses of grade 4 glioblastoma (2) and grade 3 oligodendroglioma (1), mean age 46.7 years (38- 56 years), ECOG 1 (2) and ECOG2 (1), gross tumor resection (1 glioblastoma patient), subtotal resection (1 glioblastoma patient), and biopsy (1 oligodendroglioma patient). All patients received radiotherapy, 66.7% (n=2) stupp protocol, and 33.3% (n=1) received hypofractionated therapy and adjuvant treatment with temozolomide. All patients received first line with temozolomide, and 33.3% received a total of four lines of chemotherapy. All the patients were fed orally and managed with KDS at the last progression. Median follow up time was 4 months. KDS didn’t impact corporal weight and a positive impact was noted in seizure episodes (> 3 per day before vs < 3 per day after DKS) and quality of life (EORTC-QLQ30 61,3 [60 - 66,8] at the begining vs 70,9 [69,8 - 71,2] at the last visit). Regarding tolerance, one patient presented diarrhea and/or constipation grade 1 the first 5 days of treatment. Compliance was measured by days with a median adherence of 90%. Current disease status is stable disease (RANO criteria) in the three patients.

Conclusion

KDS could be an interesting therapy complementary to standard treatment in patients with high grade gliomas, especially in those patients who debut with seizures, improving quality of life and number of convulsive crises. More studies in adult patients are required to confirm this hypothesis
P17.18.B Augmentative craniotomy in recurrent glioblastoma. Preliminary clinical and radiological outcomes
Authors: Arcidiacono U A , Berra L , Serraino A , Cedrone G , Venditti E , Armocida D , Quinzi A , Brunetto F , D'Angelo L , Di Norcia V , Frati A , Familiari P , Santoro A
Published: September 2022

Background

The compression of peritumoral healthy tissue in brain tumor patients is considered a major cause of life-threatening neurologic symptoms. This condition is associated with an increase in intracranial pressure. The literature reports that GBM has a mass effect in 72% of autoptic brains of patients who died of brain tumor, with herniation in 50% of all cases.

Material and methods

We present a preliminary clinical series on 5 cases. The patients are chosen based on criteria of recurrent glioblastoma without the possibility of a gross total resection with a recurrence after STUPP protocol. The surgeries include cytoreduction and augmentative craniotomy. The aim is to increase the intracranial volume and reduce the intracranial pressure in evolving glioblastoma. Clinical and radiological follow-up considers different objective scales and contrast enhancement MRI performed every 3 months. We evaluate KPS, survival rate, complication rate, quality of life using QOL-BN20 and neuropsychological assessment.

Results

The 12 months of follow-up shows a mean survival rate of 9 months after the surgery. This procedure has no negative impact on the survival rate, complication rate, and quality of life reduction. The neuropsychological evaluation does not show an impact on self-perception of aesthetic appearance. The surgery does not show surgical wound complications. The mean operative time was 225 minutes and was comparable with standard recurrence glioblastoma procedure.

Conclusion

This work has the main limitation of being preliminary results on small population. However, these results show encouraging outcomes and could be an innovative and salvage therapy for recurrent and incurable glioblastoma. Further follow-up and study must be performed.
P18.03.B Long term effects of therapeutic embolization of radiographically suspected meningiomas regarding tumour- and necrosis volume as well as patients' symptoms
Authors: Pedersen M , Eibl T , Nania A , Voit-Höhne H , Schrey M , Steiner H , Holtmannspötter M
Published: September 2022

Background

Preoperative embolization of radiographically suspected intracranial meningiomas is performed to reduce intraoperative blood loss and to facilitate resection. However, there is paucity of evidence examining the effect of embolization as a sole intervention on the tumor volume and the patient's neurocognitive symptoms. The objective of this study was to investigates the influence of therapeutic embolization on tumor- and necrosis volume and neurocognitive symptoms in absence of surgical intervention.

Material and Methods

Between January 2019 and June 2021, 4 patients (median age 82, 1 female) with 5 radiographically suspected intracranial meningiomas, underwent endovascular embolization with liquid embolizate and coils, without subsequent surgery. Indication for embolization was history of previous multiple surgery contraindicating further surgical intervention or patients will. Neurological status (on admission, discharge from hospital and 5 months after embolization), medical history, medication, MRI (location, tumor- and necrosis volume, development of edema, complications), DSA (extent of embolization, arterial supply) and procedural complications were recorded. In 3 patients with 4 tumors, an MRI scan was performed. The calculation of tumor- and necrosis volume was done manually with a semiautomatic segmentation tool. One patient with one tumor received CT scans due to a cardiac pacemaker and was therefore excluded from volumetric analysis.

Results

The average tumor volume was 44,83 ± 13,82 cm3 on admission, 45,33 ± 16,3 cm3 5 days after embolization (+1%) and 39,93 ± 29,39 cm3 (-11%) after 5 months. The average necrosis diameter was 41,76 ± 9,33 mm after 5 days and 6,05 ± 6,43 mm after 5 months. The perifocal oedema decreased in 2/3 Patients. Tumor blood supply was via 2,4 ± 1,34 vessels, 1,2 ± 0,45 vessels were embolised. On admission, 3 patients showed neurocognitive symptoms. At discharge and in the follow-up, in 2 patients the symptoms had improved, one patient experienced a complete symptom regression. In one patient the embolization was complicated by dissection of the middle meningeal artery. The same patients perifocal oedema increased in the further clinical course with accompanying deterioration of the pre-existing hemiparesis from moderate to severe. Supported with dexamethasone medication, the oedema and symptoms declined to a mild residual paresis. None of the patients developed a long-term neurocognitive deficit related to embolization.

Conclusion

Therapeutic endovascular embolization of radiographically suspected intracranial meningiomas reduced the tumor volume and led to long-term improvement of pre-existing neurocognitive symptoms. In the future, these effects should be verified in larger studies.
P18.06.B ETS-Transcription Factor inhibitors are effective inTERT promoter mutated meningioma cells in vitro
Authors: Neumayer K , Kastler L , Laaber M , Roschger C , Lenz S , Lötsch-Gojo D , Berger W , Gruber A , Spiegl-Kreinecker S
Published: September 2022

Background

TERT promoter mutations in meningiomas were recently found to be strongly prognostic and associated with malignant progression and risk of recurrence. As result, the mutation in the TERT promoter generates a binding site for E twenty-six (ETS) transcription factors. Consequently, ETS-transcription factor inhibition might represent a novel strategy to impede meningioma growth. In a prior study we could demonstrate effectiveness of the ETS-transcription factor inhibitor YK-4-279 in TERT promoter mutant meningiomas. Recently, TK216 the clinical derivative of YK-4-279 was developed. Therefore, we aimed to clarify whether TK216 might have an increased effect as compared to YK-4-279 in TERT promoter mutated meningioma cells in vitro.

Methods

A meningioma-derived cell line (BTL695) generated from a TERT promoter mutated (C228T) anaplastic meningioma served as cell model for the experiments. BTL695 was characterized by high telomerase activity and TERT mRNA expression as analysed by the TRAP assay and RT-PCR, respectively. Genomic aberrations were verified using Ion Torrent Oncomine Comprehensive Assay v3-based next-generation sequencing (NGS). The sensitivity of BTL695 to YK-4-279 and TK216 was determined using an MTT-based viability assay (EZ4U). To elucidate the effectiveness of TK216 on cell cycle and apoptosis, cells were stained with PI and annexin V, respectively, and measured by flow cytometry. The effect of TK216 on the protein expression of the cleaved poly(ADP-ribose) polymerase-1 (PARP-1), indicative for apoptosis, was investigated by western blot. Additionally, a TK216-resistant cell model (BTL695res) was generated and analysed by NGS.

Results

BTL695 was significantly more sensitive to TK216 as compared to YK-4-279 (p<0.0001) characterized by the distinctly lower IC50 value of TK216 exposed cells (0.7 µM TK216; 1.6 µM YK-4-279). Flow cytometry analysis revealed a TK216 induced G2M cell cycle arrest and increased apoptosis rate, which was additionally verified by the expression of cleaved PARP-1 expression using western blot. Genomic aberrations were found in 18 genes including NF2, CDKN2A/B, ARID1A and PTEN. Interestingly, although the majority of genomic alterations was persistent in the TK216 resistant cell model, a p53 mutation was newly acquired as compared to the parental cell line.

Conclusion

In summary, our results indicate that ETS transcription factor inhibition by TK216 exerts antitumour activity in our TERT promoter mutant meningioma cell model. Additionally, the sensitivity against TK216 is superior to YK-4-279 and therefore TK216 may represent a promising new therapeutic option for patients with aggressive, TERT promoter mutated meningioma.
P18.07.A Hippo signaling pathway is strongly involved in meningioma tumorigenesis
Authors: Mougel G , Mondielli G , Appay R , Querdray A , Roche C , Jijon A , Konstantinova I , Soude A , Graillon T , Barlier A
Published: September 2022

Background

Recurrent and aggressive meningiomas remain an unmet medical need in neuro-oncology. In mammals, Hippo signaling pathway is responsible for the growth of organs by regulating cell proliferation and apoptosis. The tumor suppressor NF2 protein belongs to the core of the Hippo pathway and a defect of its gene is present in 50% of meningiomas. Absence of NF2 keeps Hippo pathway inactive allowing the translocation of YAP/TAZ to the nucleus and the formation of a complex with TEADs. This complex then promotes the transcription of anti-apoptotic and proliferative genes such as CTGF, CYR61 and AXL. Here we present experimental results on human meningioma fragments and primary cell cultures supporting that Hippo pathway plays a critical role in meningioma tumorigenesis.

Material and Methods

The role of the Hippo pathway was studied on 57 meningiomas, well characterized at clinical, histological and molecular level. The genomic profile, target transcripts of the complex YAP/TAZ-TEADs, cell viability, and cell proliferation were analyzed after siRNA transfection targeting YAP, TAZ, YAP+TAZ and TEADs.

Results

Fifty-seven meningiomas were randomly selected including 27 WHO grade II and III tumors. Thirty (53%) presented a defect on the NF2 gene (NF2def) including 19(65%) grade II/III. NF2def meningiomas presented a significant increase of expression levels of Hippo pathway target transcripts CTGF, CYR61 and AXL in comparison with NF2 wild-type tumors (p<0.0001, p=0.0072 and p=0.0191, respectively). This increase was not correlated with the grade, the sex or with the cerebral localization of the meningiomas. On the other side, IHC analysis suggested this increase was correlated with the nuclear localization of YAP. Disturbing the YAP/TAZ-TEADs complex using siRNA on 10 meningiomas (5 NF2 wild-type and 5 NF2 def) induced a significant decrease on cell proliferation but not on cell viability. This decrease was more important when TAZ was turned off in comparison to turning off of YAP.

Conclusion

Our experimental results strongly support the importance of the Hippo pathway in meningioma tumorigenesis, supporting its relevance as a new target in meningioma therapy. A.Barlier reports receiving research grants from Inventiva Pharma. No potential conflicts of interest were disclosed by the other authors.
P18.08.B Fully automatic meningioma segmentation using T1-weighted contrast-enhanced MR images only
Authors: Boelders S M , De Baene W , Rutten G J M , Gehring K , Ong L L
Published: September 2022

Background

Manual segmentation of brain tumors requires expertise, is time-consuming, and is subject to inter-rater variability. Fully automatic brain tumor segmentation is possible for glioma and meningioma when volumetric T1, T1 contrast-enhanced (T1c), T2, and Fluid-attenuated inversion recovery (FLAIR) MRIs are available. In clinical care of meningiomas, however, often only volumetric T1c scans are available. In this work, we trained a deep learning network to segment meningiomas using only T1c scans for use in clinical research.

Material and Methods

NnU-Net, a deep learning model that is optimized for medical image segmentation, was trained to segment meningiomas from T1c images. This was performed on a large clinically collected meningioma dataset (n=374) of T1c scans with semi-automatically generated enhancing tumor masks and additional data from the BraTS2020 glioma dataset. Model performance was compared against inter-rater reliability, between different models, between anatomical tumor locations, and against models using multiple MRI modalities.

Results

The best performing model obtained a Dice score of 0.90. This performance was 0.03 points lower when compared to inter-rater reliability (Dice=0.93) and almost equal to models using multiple MRI modalities. Model performance split over anatomical tumor locations was between 0.90 and 0.97 (Dice).

Conclusion

Fully automatic meningioma segmentation using only T1c images is possible with an accuracy that is similar to inter-rater reliability and models using multiple imaging modalities.
P18.10.B Natural history of meningiomas - a serial volumetric analysis of 240 tumors
Authors: Thomann P , Häni L , Vulcu S , Schütz A , Frosch M , Jesse C M , El-Koussy M , Söll N , Hakim A , Raabe A , Schucht P
Published: September 2022

Background

The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, we aimed to create the basis for practicable clinical pathways for the management of these tumors.

Material and Methods

We volumetrically analyzed meningiomas radiologically diagnosed at our institution between 2003 and 2015. For this purpose, we used exclusively thin-layered MR images (i.e. ≤ 2mm slice thickness). The primary endpoint was tumor growth defined as a 14.35% increase in tumor volume. We identified predictive clinical and radiological characteristics and used the significant variables from a multivariable regression model to construct a decision tree based on the exhaustive Chi-squared Automatic Interaction Detection (exhaustive CHAID) algorithm.

Results

Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR=0.979 (0.958-1.000), p=0.048) and presence of calcification (OR=0.442 (0.224-0.872), p=0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR=4.415 (2.056-9.479), p<0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2-signal intensity and presence of calcifications with a proportion of growing tumors of 34.1% in the low risk group, 60.0% in the intermediate risk group and 80.2% in the high risk group. Median tumor volume doubling time (Td) was 185.7 months in the low risk, 100.1 months in the intermediate risk and 51.7 months in the high risk group (p<0.001). While 0% of meningiomas in the low and intermediate risk group had a Td of ≤12 months, 8.9% in the high risk group did so (p=0.021).

Conclusion

Most meningiomas demonstrated growth during follow-up. The presence or absence of calcifications and the signal intensity on T2-weighted imaging allow a practical and simple stratification of meningiomas into low, intermediate and high risk tumors. Small tumors in the low or intermediate risk categories can be monitored with longer follow-up intervals, whereas in the high risk category proactive management decisions can be justified.
P18.11.A Active beam scanning proton therapy for large skull base benign meningiomas: long-term results
Authors: Amelio D , Lo Faro L , Corsini F , Donner D , Chioffi F , Volpin F , Volpin L , Chierichetti F , Sarubbo S , Scartoni D
Published: September 2022

Purpose

To report long-term results of active beam scanning proton therapy (PT) for large skull base benign meningiomas

Material and Methods

Eighty-two patients (pts) with large skull base meningiomas were treated with PT between April 2015 and December 2021. Median age was 62 years (range, 48-82) while KPS ranged between 60 and 100 (median 90); 60 were female (73%), and 22 were male (27%). Thirty-two pts (39%) had histologically proven World Health Organization (WHO) Grade I tumors. In remaining pts diagnosis was based on the typical imaging appearance of benign meningioma. All patients received PT for residual, progressive or non-operable lesions. Newly diagnosed tumors received total dose of 50 GyRBE (RBE: relative biologic effectiveness) while progressing meningiomas 54 GyRBE. All the treatments were delivered at 2 GyRBE per fraction. All pts were treated with active beam scanning PT using 3 fields with single field optimization technique. Treatment planning was based on morphological magnetic resonance imaging (MRI) with contrast enhancement medium administration. All pts received also 68-Ga-DOTATOC-PET. Gross tumor volume ranged from 21 to 64 cc. Toxicity was assessed according to Common Terminology Criteria for Adverse Events version 4.0. Median follow-up time was 40 months (range, 3-83).

Results

All pts completed the treatment without breaks. Registered acute side effects include grade 1 (19%) and grade 2 (8%) skin erythema, grade 1 (5%) and grade 2 (5%) alopecia, grade 1 (40%) fatigue, grade 1 (5%) and grade 2 (10%) conjunctivitis, grade 1 (10%) pain, grade 1 (5%) blurred vision, grade 1 (10%) headache, and grade 2 (5%) skin hyperpigmentation. One pts (1%) experienced grade 3 pain. There were no further grade 3 or higher acute toxicities. Registered late side effects include grade 1 (2%) and grade 2 (5%) alopecia, grade 1 (21%) fatigue, grade 1 (5%) and grade 2 (5%) headache, grade 1 (6%) dizziness, grade 1 (3%) blurred vision, grade 1 (3%) and grade 2 (6%) pain, grade 1 (2%) dry eye, and grade 1 (5%) skin hyperpigmentation. Two pts (2%) experienced grade 3 pain. Two further pts (2%) experienced grade 3 optic neuropathy. There were no further grade 3 or higher late toxicities. During follow-up one pts (1%) with cavernous sinus meningioma experienced complete obstruction of intracavernous carotid artery with mild transient symptoms that resolved in few days and brain tissue ischemia detected at MRI (grade 2). Before irradiation this pts already had a meningioma-related near-complete obstruction of the intracavernous carotid artery and received a vascular surgery evaluation. Currently, absolute tumor control is 99%. Moreover, relief of symptoms recorded before irradiation occurred in 40% of pts.

Conclusion

PT is safe and effective treatment for pts with large skull base benign meningiomas.
The Value of Employee Satisfaction in Disastrous Times: Evidence from COVID-19
Authors: Shan Chenyu , Tang Dragon Yongjun
Published: September 2022

Employee treatment is an important but challenging element of corporate environmental, social, and governance policies. Satisfying employee needs can increase corporate productivity, but is also costly to shareholders. Using unique data of Chinese publicly listed firms, we show that having satisfied employees is valuable to the firm. Specifically, firms with higher employee satisfaction scores withstand COVID-19 better, in terms of stock market performance. Such an effect is more pronounced for firms with more intangible assets and in knowledge-based industries. Moreover, higher employee satisfaction scores predict better operating performance. While not fully revealed in tranquil times, the effect of employee satisfaction is materialized when the firms experience negative shocks, such as COVID-19. Our findings suggest that firms can do well in crisis periods by doing good in normal times.
Evolutions of Metabolic Parameters Following Switches of Psychotropic Drugs: A Longitudinal Cohort Study
Authors: Piras Marianna , Ranjbar Setareh , Laaboub Nermine , Grosu Claire , Gamma Franziska , Plessen Kerstin Jessica , von Gunten Armin , Conus Philippe , Eap Chin Bin
Published: September 2022

Background

Several psychotropic drugs can induce weight gain and metabolic alterations. The authors compared metabolic evolutions of patients switching versus continuing psychotropic treatments with different risk profiles.

Methods

Patients either switched from a high- to a medium- (N = 36) or low-risk drug (N = 27), from a medium- to a low-risk drug (N = 71), or to a same-risk drug (N = 61). Controls were kept using either a high- (N = 35), medium- (N = 155), or low-risk drug (N = 47). The evolution over 2 years of weight and metabolic parameters was analyzed using linear mixed-effect models, also examining the influence of polygenic risk scores for body mass index (BMI) or BMI and psychiatric disorders.

Study Results

High-, medium-, or low-risk controls gained on average 1.32%, 0.42%, and 0.36% more weight per month than patients switching from or within these risk categories (P < .001, P < .001, and P = .003, respectively). High-to-high or high-to-medium switches resulted in a greater weight increase than switching to lower-risk categories (+0.77% and + 0.39% respectively, P < .001). No difference was found between switching medium-to-medium and medium-to-low (P ≈ 1). Switching high-to-low resulted in 10% weight loss after 2 years, with the greatest loss occurring the first 6 months after the switch. Compared with high-risk controls, lower total cholesterol (−0.27 mmol/l, P = .043) in the high-to-low group, and lower glucose (−0.44 mmol/l, P = .032) and systolic blood pressure (−5.50 mmHg, P = .034) in the low-to-low group were found. Polygenic scores were not associated with weight changes in controls or after switching.

Conclusion

Psychotropic switches to a lower- or same-risk drug can attenuate weight gain, with only switching high to low resulting in weight loss.
Noninvasive diagnostic value of indocyanine green retention test in patients with esophagogastric varices in liver cirrhosis
Authors: Zhou Lina , Lin Yong , Pan Chen , Han Xiao , Huang Zuxiong , Sun Fang , Zhou Rui , Lin Chun
Published: September 2022

Objective

This study aimed to evaluate the value of the indocyanine green retention test (ICG-R15) as a noninvasive predictor of gastroesophageal varices (GOV) in cirrhosis.

Methods

A total of 629 patients with cirrhosis who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University between June 2016 and September 2020 (450 in the trial group and 179 in the validation group) were selected. The trial group was divided into a GOV group and a non-GOV group based on gastroscopic findings. The two group’s ICG results, clinical hematological, biochemical, and ultrasound parameters were compared. A predictive model for the noninvasive diagnosis of GOV was developed by applying binary logistic regression analysis and compared with previous common noninvasive diagnostic methods, followed by model validation in a validation group.

Results

ICG-R15 is positively correlated with the degree of varicose veins. Univariate and multifactorial logistic regression analyses showed that PLT, PT, ICG-R15, splenic length, splenic vein diameter, and the presence of ascites were independent predictors of GOV. Predictive equation 1 for GOV was constructed based on the above factors: Logistic (Y1) = 1.327 × PLT + 0.691 × PT + 1.110 × ICG-R15 + 0.581 × SVD + 0.815 × SD + 1.130 × presence of ascites − 2.133, which predicted GOV in cirrhosis with an AUC of 0.861, sensitivity 84.5%, and specificity 74.1%. As the internal diameter of the splenic vein and the long diameter of the spleen are influenced by subjective factors and data are not easily available, we removed these two factors and constructed the prediction equation logistic (Y2) = 1.516 × PLT + 0.856 × PT + 1.135 × R15 + 1.297 × presence of ascites − 1.513. AUC for predicting GOV was also high at 0.850, with a sensitivity of 75.3% and a specificity of 83.2%. Similar results were obtained in the validation group. However, the previous GOV prediction models ARPI, AAR, FIB-4, Lok, FI, and King had AUCs of 0.731, 0.643, 0.781, 0.763, 0.735, and 0.730, respectively, in our trial group, with only low-to-moderate diagnostic efficacy.

Conclusion

ICG-R15 correlates with the severity of GOV in cirrhosis, and the models based on it can further improve the noninvasive diagnostic efficacy of GOV.
Efficacy and safety of transjugular intrahepatic portosystemic shunt for the treatment of schistosomiasis-induced portal hypertension: a retrospective case series
Authors: Huang Songjiang , Liu Jiacheng , Yao Jinghong , Zhao Jianbo , Wang Yingliang , Ju Shuguang , Wang Chaoyang , Yang Chongtu , Bai Yaowei , Xiong Bin
Published: September 2022

Background and aim

The aim of this study was to evaluate the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of portal hypertension caused by schistosomiasis.

Methods

This study included 43 patients with schistosomiasis-induced portal hypertension treated with TIPS in our institution from December 2015 to May 2021. The demographic, imaging, clinical and follow-up data of patients were recorded retrospectively to evaluate the efficacy and safety of the procedure.

Results

All patients were successfully implanted with stents to establish shunt, and 90.7% of the patients were in good postoperative condition with no complications. After TIPS, the Yerdel grade of portal vein thrombosis decreased, and the portal pressure gradient decreased from 27.0 ± 4.9 mmHg to 11.3 ± 3.8 mmHg (P < 0.001). Bleeding was effectively controlled, with a postoperative rebleeding rate of 9.3%, which was an 87.9% reduction from the preoperative rate. The cumulative incidence of postoperative refractory ascites, shunt dysfunction, overt hepatic encephalopathy (OHE) and death were all similar to those of TIPS for nonschistosomiasis portal hypertension. There were no differences in liver and kidney function and blood coagulation indexes before and 3 months after TIPS. Albumin was identified as an independent risk factor for mortality after TIPS for schistosomal liver fibrosis.

Conclusion

TIPS can be used as a well-tolerated and effective treatment for schistosomiasis-induced portal hypertension, effectively reduce portal pressure gradient and improve portal vein thrombosis.
Mild traumatic brain injury elicits time- and region-specific reductions in serotonin transporter protein expression and uptake capacity
Authors: O’Connell Christopher J. , Reeder Evan L. , Collins Sean M. , Lungani Kainat , Norman Sophia V. , Robson Matthew J.
Published: September 2022

The monoamine neurotransmitter serotonin (5-HT) is important for the regulation of behavior, and aberrations in 5-HT signaling are linked to several neuropsychiatric and neurodevelopmental disorders. 5-HT signaling is dependent on and tightly regulated by the functional activity of the 5-HT transporter (SERT). Neurotrauma is known to structurally and functionally impact 5-HT neuronal tracts and 5-HT signaling; however, the extent to which various forms of neurotrauma alter homeostatic 5-HT signaling through the modulation of SERT expression and/or functional uptake capacity is currently not well characterized. We aimed to better characterize the protein expression and uptake activity of SERT following mild traumatic brain injury (mTBI). A murine model of blast-induced mTBI was utilized to characterize alterations in SERT expression and function following injury. mTBI was found to decrease (≈26%) the protein levels of SERT 3 days postinjury (DPI) in the dorsal raphe nucleus (DRN), the primary locale of 5-HT neuronal cell bodies within the central nervous system. Concomitant reductions in midbrain SERT-dependent radiolabeled 5-HT uptake were observed 3 DPI (≈24%). No alterations in SERT expression were observed 10 DPI in the DRN. Additionally, no alterations in SERT expression or function were observed in prefrontal cortex samples at any time point observed. This data reveals time- and location-dependent alterations in SERT expression and function following mTBI. These studies illustrate the critical importance of ongoing research efforts to characterize the molecular effects of various forms of neurotrauma on SERT protein expression and function, which may yield novel drug targets within 5-HT systems.
Duganella vulcania sp. nov., Rugamonas fusca sp. nov., Rugamonas brunnea sp. nov. and Rugamonas apoptosis sp. nov., isolated from subtropical streams, and phylogenomic analyses of the genera Janthinobacterium, Duganella, Rugamonas, Pseudoduganella and Massilia
Authors: Lu Huibin , Song Da , Deng Tongchu , Mei Chengfang , Xu Meiying
Published: September 2022

Six Gram-stain-negative, catalase- and oxidase-positive, rod-shaped and motile strains (FT81WT, FT82W, FT107W, FT3ST, LX20WT and LX47WT) sharing high 16S rRNA gene sequence similarities with species of the genera

Janthinobacterium

(97.0–98.3 %),

Duganella

(96.3–98.8 %),

Rugamonas

(97.8–98.6 %),

Pseudoduganella

(96.8–97.5 %) and

Massilia

(94.5–98.6 %) were isolated from subtropical streams in PR China. The phylogenetic trees reconstructed using the 16S rRNA gene sequences indicated that the species of above five genera often mix together, indicating that the taxonomic statuses of some species were questionable. Phylogenomic reconstruction based on 369 single-copy orthologous clusters indicated that the species of the genus

Janthinobacterium

form a distinct cluster, strains FT81WT, FT82W and FT107W form a tight cluster with the species of the genus

Duganella

, and strains FT3ST, LX20WT and LX47WT form a tight cluster with the species of genus

Rugamonas

, and the species of genus

Pseudoduganella

form a tight cluster with

Massilia guangdongensis

,

Massilia ginsengisoli

,

Massilia rivuli

,

Massilia namucuonensis

,

Massilia aquatica

sensu Lu et al.,

Massilia buxea

,

Massilia armeniaca

,

Massilia plicata

,

Massilia flava

,

Massilia lurida

,

Massilia dura

,

Massilia lutea

,

Massilia umbonata

,

Massilia albidiflava

and

Massilia violacea

. It should be noted that

Massilia aquatica

Lu et al. 2020 non

Massilia aquatica

Holochová et al. 2020 is a later homonym and an illegitimate name. The GTDB Release 202 also supported the proposal that

M. guangdongensis

,

M. ginsengisoli

,

M. rivuli

,

M. namucuonensis

,

M. aquatica

sensu Lu et al.,

M. buxea

,

M. armeniaca

,

M. plicata

,

M. flava

,

M. lurida

,

M. dura

,

M. lutea

,

M. umbonata

,

M. albidiflava

and

M. violacea

should be transferred into the genus

Pseudoduganella

. The calculated pairwise orthologous average nucleotide identity by usearch (OrthoANIu) values were between 95.0 % and 95.6 % among strains FT81WT, FT82W and FT107W, but were less than 91.5 % among strains FT3ST, LX20WT, LX47WT and other related strains. Combining the results of phylogenomic analyses, phenotypic, biochemical and genotypic characteristics, strains FT81WT, FT82W and FT107W should represent a novel species of the genus

Duganella

, and strains FT3ST, LX20WT and LX47WT should represent three novel species of the genus

Rugamonas

, for which the names Duganella vulcania sp. nov. (type strain FT81WT=GDMCC 1.1679T =KACC 21471T), Rugamonas fusca sp. nov. (type strain FT3ST=GDMCC 1.1907T =KACC 21952T), Rugamonas brunnea sp. nov. (type strain LX20WT=GDMCC 1.1911T =KACC 21956T) and Rugamonas apoptosis sp. nov. (type strain LX47WT=GDMCC 1.1914T =KACC 21959T) are proposed.
Effect of Application of Titanium Dioxide in the Management of Fusarium Wilt and Fruit Yield of Some Tomato Accessions
Authors: Olanrewaju R. O. , Popoola A. R. , Afolabi C. G. , Bodunde J. G. , Ganiyu S. A.
Published: September 2022

Tomato (Solanum lycopoersicum L.) is often threatened by wilt disease caused by Fusarium oxysporium f.sp lycopersici. Titanium dioxide (TiO2) has been reported to promote plant growth and reduce disease severity. This experiment was carried out to investigate the effects of TiO2 application on incidence and severity of Fusarium wilt as well as yield indices of three susceptible tomato accessions. A 3 × 5 factorial experiment fitted into Completely Randomized Design and Randomized Complete Block Design in both the screenhouse and the field, respectively. All experiments were set up with three replications. The treatments consisted of three tomato accessions (CPTTO/19/191, CPTTO/19/193 and CPTTO/19/195) and TiO2 with four concentrations (0.3, 0.7, 1.0 and 1.3 ml/l) was applied using soil drenching. Plots without TiO2 application served as the control. In both screenhouse and the field experiments, application of 1.3 ml/l TiO2 significantly reduced the incidence and severity of Fusarium wilt with better yield of tomato fruit in the three accessions than the control plots and pots. The study concluded that application of TiO2 at 1.3 ml/l reduced incidence and severity of Fusaruim wilt of tomato and increased the yield of tomato.
RosettaDDGPrediction for high-throughput mutational scans: from stability to binding
Authors: Sora Valentina , Laspiur Adrian Otamendi , Degn Kristine , Arnaudi Matteo , Utichi Mattia , Beltrame Ludovica , De Menezes Dayana , Orlandi Matteo , Rigina Olga , Sackett Peter Wad , Wadt Karin , Schmiegelow Kjeld , Tiberti Matteo , Papaleo Elena
Published: September 2022

Reliable prediction of free energy changes upon amino acidic substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein-protein interaction. Moreover, advances in experimental mutational scans allow high-throughput studies thanks to sophisticated multiplex techniques. On the other hand, genomics initiatives provide a large amount of data on disease-related variants that can benefit from analyses with structure-based methods. Therefore, the computational field should keep the same pace and provide new tools for fast and accurate high-throughput calculations of ΔΔGs. In this context, the Rosetta modeling suite implements effective approaches to predict the change in the folding free energy in a protein monomer upon amino acid substitutions and calculate the changes in binding free energy in protein complexes. Their application can be challenging to users without extensive experience with Rosetta. Furthermore, Rosetta protocols for ΔΔG prediction are designed considering one variant at a time, making the setup of high-throughput screenings cumbersome. For these reasons, we devised RosettaDDGPrediction, a customizable Python wrapper designed to run free energy calculations on a set of amino acid substitutions using Rosetta protocols with little intervention from the user. RosettaDDGPrediction assists with checking whether the runs are completed successfully aggregates raw data for multiple variants, and generates publication-ready graphics. We showed the potential of the tool in selected case studies, including variants of unknown significance found in children who developed cancer, proteins with known experimental unfolding ΔΔGs values, interactions between target proteins and a disordered functional motif, and phospho-mimetic variants. RosettaDDGPrediction is available, free of charge and under GNU General Public License v3.0, athttps://github.com/ELELAB/RosettaDDGPrediction.
Rising above the noise: The influence of population dynamics on the evolution of acoustic signaling
Authors: Suswaram Megha , Bhat Uttam , Yeakel Justin D.
Published: September 2022

Acoustic signaling is employed by many sexually reproducing species to select for mates and enhance fitness. However, signaling in dense populations can create an auditory background, or chorus, which can interfere with a signal receiver’s phonotactic selectivity, or the ability to distinguish signals. Feedback between the strength of an individual’s signal, phonotactic selectivity, and population size, may interactin complex ways to impact the evolution of the signaling trait within a population, potentially leading to the emergence of silence. Here we formulate a general model that captures the dynamic feedback between individual acoustic signalers, phonotactic selectivity, and the populationlevel chorus to explore the eco-evolutionary dynamics of an acoustic trait. We find that population dynamics has a significant influence on the evolutionary dynamics of the signaling trait, and that very sharp transitions separate conspicuous from silent populations. Our framework also reveals that increased phonotactic selectivity promotes the stability of signaling populations. We suggest that understanding the relationship between factors influencing population size such as environmental productivity, as well as factors influencing phonotactic selectivity such as anthropogenic noise, are central to understanding the complex mosaic of acoustically signaling and silent populations.
Ecology and age, but not genetic ancestry, predict fetal loss in a wild baboon hybrid zone
Authors: Fogel Arielle S. , Oduor Peter O. , Nyongesa Albert W. , Kimwele Charles N. , Alberts Susan C. , Archie Elizabeth A. , Tung Jenny
Published: September 2022

Objectives

Pregnancy failure and fetal loss represent a major fitness cost for any mammal, particularly those with slow life histories such as primates. Here, we quantified the risk of fetal loss in wild hybrid baboons, including genetic, ecological, and demographic sources of variance. We were particularly interested in testing the hypothesis that hybridization imposes a cost by increasing fetal loss rates. Such an effect would help explain how baboons maintain taxonomic integrity despite interspecific gene flow.

Materials and Methods

We analyzed pregnancy outcomes for 1,020 pregnancies observed over 46 years in a natural yellow baboon-anubis baboon hybrid zone. Fetal losses and live births were scored based on near-daily records of female reproductive state and the appearance of live neonates. We modeled the probability of fetal loss as a function of a female’s genetic ancestry (based on whole-genome resequencing data), age, number of previous fetal losses, dominance rank, group size, climate, and habitat quality using binomial mixed effects models.

Results

Female genetic ancestry did not predict the likelihood of fetal loss. Instead, the risk of fetal loss is elevated for very young and very old females. Fetal loss is most robustly predicted by ecological factors, including poor habitat quality and extreme heat during pregnancy.

Discussion

Our results suggest that gene flow between yellow baboons and anubis baboons is not impeded by an increased risk of fetal loss for hybrid females. Instead, ecological conditions and female age are key determinants of this component of female reproductive success.

Research Highlights

Female baboons do not experience fetal loss as a cost of hybridization.

Heat stress, poor habitat quality, and young and old age elevate the risk of fetal loss, emphasizing roles for ecology and life history in determining birth outcomes.

Graphical Abstract

Neonate drawings by Emily Nonnamaker.
Evidence of prezygotic isolation, but not assortative mating, between locally adapted populations ofFundulus heteroclitusacross a salinity gradient
Authors: Brennan Reid S. , Whitehead Andrew
Published: September 2022

Selection along environmental gradients can drive reproductive isolation and speciation. Among fishes, salinity is a major factor limiting species distributions and, despite its importance in generating species diversity, transitions between marine and freshwater are rare. Here, we tested for mechanisms of reproductive isolation between locally adapted freshwater and brackish water-native populations of killifish,Fundulus heteroclitus, from either side of a hybrid zone along a salinity gradient. There was evidence for pre-zygotic endogenous reproductive isolation with reduced fertilization success between crosses of freshwater-native males and brackish water-native females. Exogenous pre-zygotic isolation was also present where females had highest fertilization in their native salinity. We used a replicated mass spawning design to test for mate choice in both brackish and fresh water. After genotyping 187 parents and 2,523 offspring at 2,347 SNPs across the genome, 85% of offspring were successfully assign to their parents. However, no reinforcing mate choice was observed. These results therefore demonstrate emerging, yet limited, reproductive isolation and incipient speciation across a marine to freshwater salinity gradient and suggest that both endogenous and exogenous mechanisms, but not assortative mating, contribute to divergence.