bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions
Authors: Moreau Clara A , Kumar Kuldeep , Harvey Annabelle , Huguet Guillaume , Urchs Sebastian G W , Schultz Laura M , Sharmarke Hanad , Jizi Khadije , Martin Charles-Olivier , Younis Nadine , Tamer Petra , Martineau Jean-Louis , Orban Pierre , Silva Ana Isabel , Hall Jeremy , van den Bree Marianne B M , Owen Michael J , Linden David E J , Lippé Sarah , Bearden Carrie E , Almasy Laura , Glahn David C , Thompson Paul M , Bourgeron Thomas , Bellec Pierre , Jacquemont Sebastien
Published: September 2022

Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks.

We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions.

Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.
Infective endocarditis on interventricular communication as cause of massive haemoptysis: a case report
Authors: Rodríguez Torres Diego José , Segura-Rodríguez Diego , Escobar Eduardo Moreno , Orta Rocío García
Published: September 2022

Background

Haemoptysis is a rare symptom associated with endocarditis. We describe the unusual clinical manifestation of endocarditis on regurgitant bicuspid aortic valve and (probably) secondarily on a perimembranous ventricular septal defect (VSD) as massive haemoptysis.

Case summary

A 24-year-old male with aortic coarctation, bicuspid aortic valve, and VSD since birth. Previously asymptomatic, he came after an episode of haemoptysis. A computed tomography (CT) scan showed a cavitated lesion in lung. Streptococo viridans was identified in serial blood cultures. Transthoracic echocardiography showed a bicuspid aortic valve with vegetations, suggesting infectious involvement, and severe aortic insufficiency. Transoesophageal echocardiography (TEE) study showed a bicuspid aortic valve with complete fusion of coronary valves. An elongated oscillating tumour, 9.5 mm in length, was observed in the centre of the ventricular side of the non-coronary valve. Another vegetation was seen on the VSD. During his hospital stay and under antibiotic treatment, he reported abdominal pain. Computed tomography examination showed splenic infarction. In the echocardiogram no vegetation masses were observed on the aortic valve or on the VSD closure aneurysm.

Discussion

The main debate about this patient’s treatment concerned the indication of surgery, especially after the onset of fever with splenic septic embolism while under appropriate antibiotic treatment. He was stable, with no signs of heart failure and the echocardiogram repeated after the septic splenic embolism showed no residual vegetations on the aortic valve or VSD, and the TEE study ruled out a local complication. Finally, the multidisciplinary team decided against surgical management.
Recurrent giant cell myocarditis after heart transplant: a case report
Authors: Frankel Eitan S , Hajduczok Alexander G , Rajapreyar Indranee N , Brailovsky Yevgeniy
Published: September 2022

Background

Giant cell myocarditis (GCM) is a rare but well-known cause of fulminant myocarditis. Despite optimal medical therapy, many patients progress to orthotopic heart transplant (OHT). We present a case of recurrent GCM following OHT, including complex considerations in patient management and infectious sequelae.

Case summary

A 33-year-old previously healthy male presented with 2 months of worsening shortness of breath. Transthoracic echocardiogram (TTE) demonstrated a left ventricular ejection fraction of 30–35%. After ruling out an ischaemic aetiology, he was discharged on guideline-directed medical therapy and later presented with productive cough, worsening dyspnoea on exertion, and diarrhoea. He was found to have elevated troponins and N-terminal pro-brain natriuretic peptide, lactic acidosis, progression of severe bi-ventricular dysfunction on TTE and right heart catheterization, and low cardiac index (1.0 L/min/m2) requiring inotropes. He then required left ventricular assist device as a bridge to OHT. Pathology of the apical core diagnosed GCM as the cause of his fulminant heart failure. He eventually underwent heart transplantation, which was complicated by recurrent GCM. Treatment required intensification of his immunosuppressive regimen, which led to multiple infectious sequelae including norovirus, Shiga-like toxin producing Escherichia coli, and disseminated nocardia of the lung and brain. As of the most recent follow-up, the patient is currently clinically stable.

Discussion

Although recurrent GCM after OHT has been reported in the literature, the prognosis is not well understood and there are no clear guidelines regarding management. This case summarizes clinical considerations, treatment strategies, and adverse effects of recurrent GCM treatment.
Incorporating clinical parameters to improve the accuracy of angiography-derived computed fractional flow reserve
Authors: Gosling Rebecca C , Gunn Eleanor , Wei Hua Liang , Gu Yuanlin , Rammohan Vignesh , Hughes Timothy , Hose David Rodney , Lawford Patricia V , Gunn Julian P , Morris Paul D
Published: September 2022

Aims

Angiography-derived fractional flow reserve (angio-FFR) permits physiological lesion assessment without the need for an invasive pressure wire or induction of hyperaemia. However, accuracy is limited by assumptions made when defining the distal boundary, namely coronary microvascular resistance (CMVR). We sought to determine whether machine learning (ML) techniques could provide a patient-specific estimate of CMVR and therefore improve the accuracy of angio-FFR.

Methods and results

Patients with chronic coronary syndromes underwent coronary angiography with FFR assessment. Vessel-specific CMVR was computed using a three-dimensional computational fluid dynamics simulation with invasively measured proximal and distal pressures applied as boundary conditions. Predictive models were created using non-linear autoregressive moving average with exogenous input (NARMAX) modelling with computed CMVR as the dependent variable. Angio-FFR (VIRTUheart™) was computed using previously described methods. Three simulations were run: using a generic CMVR value (Model A); using ML-predicted CMVR based upon simple clinical data (Model B); and using ML-predicted CMVR also incorporating echocardiographic data (Model C). The diagnostic (FFR ≤ or >0.80) and absolute accuracies of these models were compared. Eighty-four patients underwent coronary angiography with FFR assessment in 157 vessels. The mean measured FFR was 0.79 (±0.15). The diagnostic and absolute accuracies of each personalized model were: (A) 73% and ±0.10; (B) 81% and ±0.07; and (C) 89% and ±0.05, P < 0.001.

Conclusion

The accuracy of angio-FFR was dependent in part upon CMVR estimation. Personalization of CMVR from standard clinical data resulted in a significant reduction in angio-FFR error.
Automated interpretation of stress echocardiography reports using natural language processing
Authors: Zheng Chengyi , Sun Benjamin C , Wu Yi-Lin , Ferencik Maros , Lee Ming-Sum , Redberg Rita F , Kawatkar Aniket A , Musigdilok Visanee V , Sharp Adam L
Published: September 2022

Aims

Stress echocardiography (SE) findings and interpretations are commonly documented in free-text reports. Reusing SE results requires laborious manual reviews. This study aimed to develop and validate an automated method for abstracting SE reports in a large cohort.

Methods and results

This study included adult patients who had SE within 30 days of their emergency department visit for suspected acute coronary syndrome in a large integrated healthcare system. An automated natural language processing (NLP) algorithm was developed to abstract SE reports and classify overall SE results into normal, non-diagnostic, infarction, and ischaemia categories. Randomly selected reports (n = 140) were double-blindly reviewed by cardiologists to perform criterion validity of the NLP algorithm. Construct validity was tested on the entire cohort using abstracted SE data and additional clinical variables. The NLP algorithm abstracted 6346 consecutive SE reports. Cardiologists had good agreements on the overall SE results on the 140 reports: Kappa (0.83) and intraclass correlation coefficient (0.89). The NLP algorithm achieved 98.6% specificity and negative predictive value, 95.7% sensitivity, positive predictive value, and F-score on the overall SE results and near-perfect scores on ischaemia findings. The 30-day acute myocardial infarction or death outcomes were highest among patients with ischaemia (5.0%), followed by infarction (1.4%), non-diagnostic (0.8%), and normal (0.3%) results. We found substantial variations in the format and quality of SE reports, even within the same institution.

Conclusions

Natural language processing is an accurate and efficient method for abstracting unstructured SE reports. This approach creates new opportunities for research, public health measures, and care improvement.
Prevalence of asystole during tilt test-induced vasovagal syncope may depend on test methodology
Authors: Russo Vincenzo , Parente Erika , Groppelli Antonella , Rivasi Giulia , Tomaino Marco , Gargaro Alessio , Giacopelli Daniele , Ungar Andrea , Parati Gianfranco , Fedorowski Artur , Sutton Richard , van Dijk J Gert , Brignole Michele
Published: September 2022

This review addresses tilt-testing methodology by searching the literature which reports timing of asystole and loss of consciousness (LOC). Despite the Italian protocol being the most widely adopted, its stipulations are not always followed to the letter of the European Society of Cardiology guidelines. The discrepancies permit reassessment of the incidence of asystole when tilt-down is early, impending syncope, compared with late, established LOC. Asystole is uncommon with early tilt down and diminishes with increasing age. However, if LOC is established as test-end, asystole is more common, and it is age-independent. Thus, the implications are that asystole is commonly under-diagnosed by early tilt-down. The prevalence of asystolic responses observed using the Italian protocol with a rigorous tilt down time is numerically close to that observed during spontaneous attacks by electrocardiogram loop recorder. Recently, tilt-testing has been questioned as to its validity but, in selection of pacemaker therapy in older highly symptomatic vasovagal syncope patients, the occurrence of asystole has been shown to be an effective guide for treatment. The use of head-up tilt test as an indication for cardiac pacing therapy requires pursuing the test until complete LOC. This review offers explanations for the findings and their applicability to practice. A novel interpretation is offered to explain why pacing induced earlier may combat vasodepression by raising the heart rate when sufficient blood remains in the heart.
Variation in general practice referral rate to acute medicine services and association with hospital admission. A retrospective observational study
Authors: Lyall Marcus J , Beckett Dan , Price Anna , Strachan Mark W J , Jamieson Clare , Morton Catriona , Begg Drummond , Simpson Johanne , Lone Nazir , Cameron Allan
Published: September 2022

Background

Variation in general practice (GP) referral rates to outpatient services is well described however variance in rates of referral to acute medical units is lacking.

Objective

To investigate variance in GP referral rate for acute medical assessment and subsequent need for hospital admission.

Methods

A retrospective cohort study of acute medical referrals from 88 GPs in Lothian, Scotland between 2017 and 2020 was performed using practice population size, age, deprivation, care home residence, and distance from hospital as explanatory variables. Patient-level analysis of demography, deprivation, comorbidity, and acuity markers was subsequently performed on referred and clinically assessed acute medical patients (n = 42,424) to examine how practice referral behaviour reflects clinical need for inpatient hospital care.

Results

Variance in GP referral rates for acute medical assessment was high (2.53-fold variation 1st vs. 4th quartile) and incompletely explained by increasing age and deprivation (adjusted R2 0.67, P < 0.001) such that significant variance remained after correction for confounders (2.15-fold). Patients from the highest referring quartile were significantly less likely to require hospital admission than those from the third, second, or lowest referring quartiles (adjusted odds ratio 1.28 [1.21–1.36, P < 0.001]; 1.30 [1.23–1.37, P < 0.001]; 1.53 [1.42–1.65, P < 0.001]).

Conclusions

High variation in GP practice referral rate for acute medical assessment is incompletely explained by practice population socioeconomic factors and negatively associates with need for urgent inpatient care. Identifying modifiable factors influencing referral rate may provide opportunities to facilitate community-based care and reduce congestion on acute unscheduled care pathways.
Transcription factors regulating the fate and developmental potential of a multipotent progenitor in Caenorhabditis elegans
Authors: Soukup Evan M , Bettinger Jill C , Mathies Laura D
Published: September 2022

Multipotent stem and progenitor cells have the capacity to generate a limited array of related cell types. The Caenorhabditis elegans somatic gonadal precursors are multipotent progenitors that generate all 143 cells of the somatic gonad, including complex tissues and specialized signaling cells. To screen for candidate regulators of cell fate and multipotency, we identified transcription factor genes with higher expression in somatic gonadal precursors than in their differentiated sister, the head mesodermal cell. We used RNA interference or genetic mutants to reduce the function of 183 of these genes and examined the worms for defects in the somatic gonadal precursor cell fate or the ability to generate gonadal tissue types. We identify 8 genes that regulate somatic gonadal precursor fate, including the SWI/SNF chromatin remodeling complex gene swsn-3 and the Ci/GLI homolog tra-1, which is the terminal regulator of sex determination. Four genes are necessary for somatic gonadal precursors to generate the correct number and type of descendant cells. We show that the E2F homolog, efl-3, regulates the cell fate decision between distal tip cells and the sheath/spermathecal precursor. We find that the FACT complex gene hmg-4 is required for the generation of the correct number of somatic gonadal precursor descendants, and we define an earlier role for the nhr-25 nuclear hormone receptor-encoding gene, in addition to its previously described role in regulating the asymmetric division of somatic gonadal precursors. Overall, our data show that genes regulating cell fate are largely different from genes regulating developmental potential, demonstrating that these processes are genetically separable.
Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens
Authors: Dvir Elad , Shohat Shahar , Flint Jonathan , Shifman Sagiv
Published: September 2022

A major challenge in genetic studies of complex diseases is to determine how the action of risk genes is restricted to a tissue or cell type. Here, we investigate tissue specificity of gene action using CRISPR screens from 786 cancer cell lines originating from 24 tissues. We find that the expression pattern of the gene across tissues explains only a minority of cases of tissue-specificity (9%), while gene amplification and the expression levels of paralogs account for 39.5% and 15.5%, respectively. In addition, the transfer of small molecules to mutant cells explains tissue-specific gene action in blood. The tissue-specific genes we found are not specific just for human cancer cell lines: we found that the tissue-specific genes are intolerant to functional mutations in the human population and are associated with human diseases more than genes that are essential across all cell types. Our findings offer important insights into genetic mechanisms for tissue specificity of human diseases.
Blind broad-band (0–10 Hz) numerical prediction of the 3-D near field seismic response of anMW6.0 extended fault scenario: application to the nuclear site of Cadarache (France)
Authors: Castro-Cruz D , Gatti F , Lopez-Caballero F , Hollender F , El Haber E , Causse M
Published: September 2022

In this paper, physics-based numerical simulation (PBS) is employed to render a broad-band (0–10 Hz) realization of the near-field seismic response of the experimental nuclear site of Cadarache, located nearby the active Middle Durance Fault (southeastern France). The sensitivity of the earthquake numerical model to geological features is investigated by comparison with geophysical measurements and past aftershock and by highlighting the amplification induced by the soft sediments below Cadarache. The blind prediction of an MW6 target earthquake is approached by synthesizing four different finite-fault scenarios. The outcome is compared to the standard ground motion prediction equations (GMPEs), unveiling a possible GMPE overestimation of the pseudospectral acceleration ordinates at short natural periods, supporting the actual need to integrate synthetic and empirical predictions when direct observations are not available.
In vitro activity of imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal (SUPERIOR and STEP studies)
Authors: Hernández-García Marta , García-Castillo María , Melo-Cristino José , Pinto Margarida F , Gonçalves Elsa , Alves Valquíria , Vieira Ana Raquel , Ramalheira Elmano , Sancho Luísa , Diogo José , Ferreira Rui , Cruz Hugo , Chaves Catarina , Bou Germán , Cercenado Emilia , Delgado-Valverde Mercedes , Oliver Antonio , Pitart Cristina , Rodríguez-Lozano Jesús , Tormo Nuria , Díaz-Regañón Jazmín , Pássaro Leonor , Duarte Joana , Cantón Rafael ,   STEP and SUPERIOR study groups, Oliver Antonio , Mulet Xavier , Cercenado Emilia , Bou Germán , Fernández M Carmen , Pascual Álvaro , Delgado Mercedes , Gimeno Concepción , Tormo Nuria , Calvo Jorge , Rodríguez-Lozano Jesús , Alonso Ana Ávila , Vila Jordi , Marco Francesc , Pitart Cristina , del Castillo María García , García-Fernández Sergio , Hernández-García Marta , Cantón Rafael , Díaz-Regañón Jazmín
Published: September 2022

Objectives

To study the in vitro activity of imipenem/relebactam and comparators and the imipenem/relebactam resistance mechanisms in a Pseudomonas aeruginosa collection from Portugal (STEP, 2017–18) and Spain (SUPERIOR, 2016–17) surveillance studies.

Methods

P. aeruginosa isolates (n = 474) were prospectively recovered from complicated urinary tract (cUTI), complicated intra-abdominal (cIAI) and lower respiratory tract (LRTI) infections in 11 Portuguese and 8 Spanish ICUs. MICs were determined (ISO broth microdilution). All imipenem/relebactam-resistant P. aeruginosa isolates (n = 30) and a subset of imipenem/relebactam-susceptible strains (n = 32) were characterized by WGS.

Results

Imipenem/relebactam (93.7% susceptible), ceftazidime/avibactam (93.5% susceptible) and ceftolozane/tazobactam (93.2% susceptible) displayed comparable activity. The imipenem/relebactam resistance rate was 6.3% (Portugal 5.8%; Spain 8.9%). Relebactam restored imipenem susceptibility to 76.9% (103/134) of imipenem-resistant isolates, including MDR (82.1%; 32/39), XDR (68.8%; 53/77) and difficult-to-treat (DTR) isolates (67.2%; 45/67). Among sequenced strains, differences in population structure were detected depending on the country: clonal complex (CC)175 and CC309 in Spain and CC235, CC244, CC348 and CC253 in Portugal. Different carbapenemase gene distributions were also found: VIM-20 (n = 3), VIM-1 (n = 2), VIM-2 (n = 1) and VIM-36 (n = 1) in Spain and GES-13 (n = 13), VIM-2 (n = 3) and KPC-3 (n = 2) in Portugal. GES-13-CC235 (n = 13) and VIM type-CC175 (n = 5) associations were predominant in Portugal and Spain, respectively. Imipenem/relebactam showed activity against KPC-3 strains (2/2), but was inactive against all GES-13 producers and most of the VIM producers (8/10). Mutations in genes affecting porin inactivation, efflux pump overexpression and LPS modification might also be involved in imipenem/relebactam resistance.

Conclusions

Microbiological results reinforce imipenem/relebactam as a potential option to treat cUTI, cIAI and LRTI caused by MDR/XDR P. aeruginosa isolates, except for GES-13 and VIM producers.
Improving sow welfare and outcomes in the farrowing house by identifying early indicators from pre-farrowing assessment
Authors: Vargovic Laura , Athorn Rebecca Z , Hermesch Susanne , Bunter Kim L
Published: September 2022

Poor outcomes reflect low performance during the farrowing and lactation periods and unanticipated sow removals. Since the period around farrowing has the highest risk for sow health issues, monitoring of sows in that time-period will improve both welfare and productivity. The aim of this study was to identify the most relevant risk factors for predicting poor outcomes and the implication for sow welfare. Identifying these factors could potentially enable management interventions to decrease incidences of compromised welfare or poor performance. Data from 1,103 sows sourced from two nucleus herds were recorded for a range of variables investigated as potential predictors of poor outcomes in the farrowing house. Poor outcomes (scored as binary traits) reflected three categories in a sow’s lifecycle: farrowing, lactation, and removals. Univariate logistic regression was used to identify predictors in the first instance. Predictors from univariate analyses were subsequently considered together in multi-variate models. The least square means representing predicted probabilities of poor outcomes were then reported on the observed scale. Several predictors were significant across two different environments (farms) and for all three categories. These predictors included feed refusal (lack of appetite), crate fit, locomotion score, and respiration rate. Normal appetite compared to feed refusals reduced the risk of farrowing failure (13.5 vs. 22.2%, P = 0.025) and removals (10.4 vs. 20.4%, P < 0.001). Fit in the crate was significant (P < 0.001) for farrowing and lactation outcomes, and was more informative than parity. Sows with sufficient space had two to three times reduced risk of poor outcomes compared to restrictive crates relative to sow dimensions. Sows with good locomotion score pre-farrowing had two to three times less risk of farrowing failure (P = 0.025) and reduced piglet mortality (P < 0.001), weaned two piglets more relative to affected sows (P < 0.001), and were less likely to be removed before weaning (3.24 vs. 12.3%, P = 0.014). Sows with higher respiration rates had a significantly (P < 0.001) reduced risk of poor farrowing outcomes. This study demonstrated it is possible to predict poor outcomes for sows prior to farrowing, suggesting there are opportunities to decrease the risk of poor outcomes and increase overall sow welfare.
Contribution of Alate and Apterous Morphs to Demographic Characteristics, and Stable Stage Distribution ofAcyrthosiphon pisum(Hemiptera: Aphididae) on Four Different Alfalfa Varieties
Authors: Luo Lan , Liu Zhao-Liang , Yuan Jing , Chi Hsin , Yuan Zhong-Lin
Published: September 2022

Life table data of the green pea aphid, Acyrthosiphon pisum (Harris) reared on four different resistant alfalfa varieties, i.e., 5S43, TG4 CW044026 (abbreviated as TG4), TG7 CW2883 (abbreviated as TG7), and Aurora were analyzed using the age-stage, two-sex life table. A higher proportion of alate adults were observed on 5S43, TG7, and Aurora; while a higher proportion of apterous adults occurred on TG4. The contributions of alate aphids to the finite rate of increase (λ), intrinsic rate of increase (r), and net reproductive rate (R0) were higher than apterous aphids on 5S43, TG7, and Aurora, while apterous aphids contributed more to λ, r, and R0 on TG4. The highest population parameters were observed on TG4 (r = 0.208 d−1, λ = 1.231 d−1, and R0 = 18.8 offspring/individual), while the lowest values were on TG7 (r = 0.129 d−1, λ = 1.138 d−1, and R0 = 9.9 offspring/individual). Because the age-stage, two-sex life table is capable of describing the stage differentiation, it enables the calculation of the stable stage distribution (SSD). A higher proportion of adult A. pisum was observed in SSD than in fourth instar nymphs. Population simulation showed the stage structure will approach SSD. Because the R0 and the mean generation time (T) values do not reflect the population growth rate, their use as population fitness parameters should be avoided. These findings can be utilized in helping to select resistant alfalfa varieties to effectively manage the pea aphid.
Response of Parasitic Wasp Cotesia glomerata L. (Hymenoptera: Braconidae) to Cabbage Plants of Two Varieties: Olfactory Spectra of Males and Females
Authors: Blažytė-Čereškienė Laima , Aleknavičius Dominykas , Apšegaitė Violeta , Būda Vincas
Published: September 2022

The parasitoid Cotesia glomerata L. (Hymenoptera: Braconidae) oviposits in larvae of the large cabbage white butterfly (Pieris brassicae L.). Many parasitoids are attracted by volatile organic compounds (VOCs) emitted by the plant that the host insects feed on. The objectives of the study were to identify the VOCs in leaves of two varieties of cabbage (white cabbage, Brassica oleracea var. capitata f. alba and cauliflower, B. oleracea var. botrytis) damaged by P. brassicae caterpillars which elicit antennal responses of C. glomerata, and characterize the olfactory spectra of females and males. Leaf extracts were analyzed by using gas chromatography equipped with an electroantennographic detector (GC–EAD) and GC–mass spectrometry. In total, 32 olfactory-active compounds for C. glomerata in cauliflower and 24 in white cabbage were revealed. The females perceived more compounds than males. Hexan-1-ol, (E)-3-hexen-1-ol, (E)-2-octenal, benzylcianide, tetradecanal, and two unidentified compounds elicited EAG responses in females but not in males. Females were more sensitive to (E)-3-hexenal, (Z)-3-hexenal, and pentadecenal, whereas males showed higher sensitivity to (Z)-3-hexenyl butanoate, heptanal, (Δ)-2-pentenal, (E)-2-hexenol, and octanal. The olfactory spectrum of C. glomerata was expanded from 18 to 41 VOCs emitted by different varieties of cabbage damaged by P. brassicae caterpillars. Eight EAG-active VOCs were common for all cabbage varieties. In tritrophic interactions, benzylcyanide can serve as an important signal for C. glomerata females indicating damage of cabbage caused by P. brassicae caterpillars. The data are useful for development of a push–pull strategy for P. brassicae control, based on parasitoid behavior regulation by VOCs.
Staged surgical repair of severe pulmonary stenosis post radiofrequency ablation
Authors: Murray Lewis William , Gopal Rakesh , Gimpel Damian , Szpytma Malgorzata (Maggie) , Crouch Gareth
Published: September 2022

We present a case of a 68-year-old man who presents with worsening cough and dyspnoea 12 months after undergoing radiofrequency ablation therapy for atrial fibrillation. Investigation revealed complete occlusion of the left lower pulmonary vein and partial stenosis of the left upper pulmonary vein. He underwent a stage surgical resection with the first stage being a left lower lobectomy for the non-viable lobe followed by a repair of the left upper pulmonary vein via anastomosis with the left atrial appendage. This staged procedure yielded excellent results and avoided the need for a left-sided pneumonectomy.
Small bowel obstruction caused by hemorrhagic metastatic melanoma: case report and literature review
Authors: Wu Fanyi , Lee M Sung , Kim Daniel E
Published: September 2022

Melanoma is one of the most common cancers and causes of death from skin cancer. It is also one of the most common malignancies to metastasize to the gastrointestinal tract. However, the incidence of gastrointestinal metastases from unknown primary cutaneous melanoma is reported to be 4–9%. Despite advances in diagnostic techniques, only 1.5–4.4% of metastases to the gastrointestinal tract are detected before death. We report a patient with no prior history of melanoma who presented with both gastrointestinal hemorrhage and small bowel obstruction. Diagnostic laparoscopy, followed by small bowel resection, was performed after a red blood cell radionuclide scan showed active hemorrhage. Pathologic examination confirmed metastatic melanoma of the jejunum. Additional small bowel resections were required for recurrent gastrointestinal bleeding, confirming two additional metastases. A review of the literature on small intestinal melanoma causing hemorrhage and obstruction is discussed.
The financial aspects of offshore decommissioning and Brazilian regulatory system in the light of the transnational legal order
Authors: Braga Luciana , Pinto Helder
Published: September 2022

This article discusses the financial aspects of offshore decommissioning, highlighting the regulatory challenges to balance public interest protection and investment attraction. The Brazilian regulatory system for offshore decommissioning is chosen to exemplify how Brazil is tackling these issues. To detail this system, this article adopts the Transnational Legal Order approach, by Halliday and Shaffer, which offers an integrated view of the regulatory system, detailing it in three categories of rules: national, international and transnational.
Enriching contextualized semantic representation with textual information transmission for COVID-19 fake news detection: A study on English and Persian
Authors: Ghayoomi Masood
Published: September 2022

The COVID-19 pandemic provided an infodemic situation to face people in the society with a massive amount of information due to accessing social media, such as Twitter and Instagram. These platforms have made the information circulation easy and paved the ground to mix information and misinformation. One solution to prevent an infodemic situation is avoiding false information distribution and filtering the fake news to reduce the negative impact of such news in the society. This article aims at studying the properties of fake news in English and Persian using the textual information transmitted through language in the news. To this end, the properties existed in a text based on information theory, stylometry information from raw texts, readability of the texts, and linguistic information, such as phonology, syntax, and morphology, are studied. In this study, we use the XLM-RoBERTa representation with a convolutional neural network classifier as the basic model to detect English and Persian COVID-19 fake news. In addition, we propose different learning scenarios such that different feature sets are concatenated with the contextualized representation. According to the experimental results, adding any of the textual information to the basic model has improved the performance of the classifier for both English and Persian. Information about readability of the texts and stylometry features have been the most effective features for detecting English fake news and improved the performance by 2.72% based on F-measure. Augmenting this feature setting with the information amount and linguistic morphological information improved the performance of the classifier by 3.79% based on F-measure for Persian.
Synthesis of point-modified mRNA
Authors: Hertler Jasmin , Slama Kaouthar , Schober Benedikt , Özrendeci Zeynep , Marchand Virginie , Motorin Yuri , Helm Mark
Published: September 2022

Synthetic mRNA has recently moved into the focus of therapeutic and vaccination efforts. Incorporation of modified nucleotides during in vitro transcription can improve translation and attenuate immunogenicity, but is limited to triphosphate nucleotides which are accepted by RNA polymerases, and their incorporation is either random or complete. In contrast, site-specific modification, herein termed ‘point modification’ in analogy to point mutations, holds significant technical challenge. We developed fundamental techniques for isolation of long, translatable and internally point-modified mRNAs. Enabling concepts include three-way-one-pot splint ligations, and isolation of mRNA by real-time elution from agarose gels. The use of blue light permitted visualization of mRNA in pre-stained gels without the photochemical damage associated with the use of hard UV-radiation. This allowed visualization of the mRNA through its migration in the agarose gel, which in turn, was a prerequisite for its recovery by electroelution into precast troughs. Co-eluting agarose particles were quantified and found to not be detrimental to mRNA translation in vitro. Translation of EGFP-coding mRNA into functional protein was quantified by incorporation of 35S-labelled methionine and by in-gel EGFP fluorescence. This enabled the functional analysis of point modifications, specifically of ribose methylations in the middle of a 1371 nt long mRNA.
PL01.3.A Radiomic features and DNA methylation attributes in primary CNS lymphoma
Authors: Nenning K , Gesperger J , Nemc A , Roetzer-Pejrimovsky T , Choi S , Preusser M , Nam D , Bock C , Langs G , Woehrer A ,   ABTR-PCNSL study group
Published: September 2022

Background

Clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma (PCNSL), but the derived risk models do not fully explain the observed variation in outcome. Here we present an extended framework of phenotype-epigenotype correlations that reveal novel prognostic constellations and enable prioritizing epigenetic therapy.

Material and Methods

In this retrospective discovery and validation study, we leverage radiomic feature-driven analysis of medical images and supervised bioinformatic integration of DNA methylation profiles. We integrate both data modalities synergistically using machine learning-based prediction and cross-domain alignment. Ultimately, we validate the most relevant biological associations in tumor tissues and cell lines.

Results

We leverage a cohort of 191 patients across 9 sites in Austria and an external validation site in South Korea, and use T1-weighted contrast-enhanced magnetic resonance imaging to derive a radiomic risk score that consists of 20 mostly textural features. We determine the risk score as strong and independent predictive factor (multivariate HR=6.56), and confirm its prognostic value in an external validation cohort. Radiomic features align with DNA methylation sites in distinct, biologically meaningful ways, and radiomic risk is predictable from selected DNA methylation sites (AUC=0.78). Ultimately, gene-regulatory differences between radiomically-defined risk groups converge on bcl6 binding activity, which is posed as testable treatment strategy in a subset of patients.

Conclusion

The radiomic risk score is a robust and complementary predictor of survival and is reflected at the level of DNA methylation in PCNSL. Assessing risk and selecting epigenetic treatment based on imaging phenotypes represents a huge step forward, and the ability to define radiomic risk groups provides a concept on which to advance prognostic modeling and precision therapy for this aggressive brain cancer.
PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?
Authors: Schmassmann P , Roux J , Martins T A , Ritz M , Shekarian T , McDaid M , Hutter H Läubli G
Published: September 2022

Background

Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM.

Material and Methods

We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout.

Results

TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003).

Conclusion

These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
PL02.4.A International validation study of an EORTC instrument measuring instrumental activities of daily living (IADL) in patients with brain tumours: EORTC IADL-BN32
Authors: Oort Q , Koekkoek J , Aaronson N K , Boele F W , Brannan C , Capela A , Hjermstad M , Klein M , Lips I , Narita Y , Pace A , Petranovic D , Pichler J , Reijneveld J C , Sato H , Seidel C , Shamieh O , Sikkes S A M , Talacchi A , Uitdehaag B M J , Urbanic T , Young T , Taphoorn M J B , Dirven L
Published: September 2022

Background

Brain tumour patients often have neurocognitive deficits which can result in problems with activities in daily living that are cognitively complex. Currently, no valid and reliable brain tumour-specific instrument to measure these instrumental activities of daily living (IADL) is available, but such an instrument is being developed. This study aimed to validate the EORTC IADL-BN32 questionnaire, comprising five multi-item and two single item scales, in a large set of international brain tumour patients.

Material and Methods

This international study was conducted in 10 countries worldwide. Primary and metastatic brain tumour patients and their proxies were requested to complete the EORTC IADL-BN32 and a subjective cognitive questionnaire (MOS COG-R) at multiple time points. Several psychometric properties were evaluated with baseline data, including the structural validity (bi-factor confirmatory factor analysis [CFA]), reliability (internal consistency), construct validity (known groups comparisons) and patient-proxy congruency (intra-class correlation coefficients [ICC], Spearman's correlation).

Results

At baseline, 326 patients ( 30% low-grade glioma, 37% high-grade glioma (HGG) and 33% brain metastases) and 311 proxies completed the EORTC IADL-BN32. The bi-factor CFA was found to have a satisfactory model fit (CFI=0.92 and TLI=0.90), and other parameters indicated a good fit (RMSEA=0.08 and SRMR=0.05), thereby validating the preliminary scale structure, but also an IADL sum score. The multi-item scales showed good (0.9>α≥0.8) to excellent (α≥0.9) internal consistency (range α=0.86-0.97). Known groups comparisons analyses regarding patient’s cognitive status (indications vs. no cognitive impairment), subjective cognitive complaints (MOS COG-R ≤30 vs. >30), basic ADL (Barthel Index <100 vs. 100) and performance status (KPS <70 vs. ≥70) showed significant differences on all IADL outcome measures in line with a priori defined hypotheses. On a group level, patient and proxy ratings had moderate to strong correlations, however, proxies tended to report more problems on all scales. The ICCs showed moderate to good congruency between patients and proxies (range ICC: 0.63-0.81).

Conclusion

The evaluated psychometric properties support the current scale structure of the EORTC IADL-BN32. Additional psychometric properties with longitudinal data are needed, such as test-retest reliability and responsiveness, to further validate the EORTC-IADL BN32 questionnaire.
KS01.5.A Impact of reduced treatment volumes on pattern of tumor recurrence and radiation dose to normal brain parenchyma in glioblastoma
Authors: Minniti G , Giraffa M , Capone L , Raza G , Russo I , Navarria P , Tini P , Romano A , Bozzao A , Paolini S , Esposito V
Published: September 2022

Background

to analyze GBM recurrence pattern after standard chemoradiotherapy according to different target volume delineations. We hypothesized that reduced target volume margins may result in similar pattern of failure.

Material and Methods

207 patients with GBM who recurred after standard chemoradiation were evaluated. According to the Advisory Committee for Radiation Oncology Practice (ACROP) committee of the European Organisation for Research and Treatment of Cancer (EORTC) target volume delineation guideline, the clinical target volume (CTV) used for treatment planning consisted of residual tumor and resection cavity plus 2-cm margin. MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. The recurrent lesions were defined as in-field, marginal, or distant if >80%, 20-80%, or <20% of the intersecting volume was included in the 95% isodose line. For each patient a theoretical plan consisting of a reduced CTV using 1-cm margin was created and patterns of failure evaluated.

Results

The median overall survival and progression-free survival were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180 patients, marginal in 5 patients, and distant in 22 patients. Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred in-field and distant in 75.6% and 18.6% of methylated patients and in 91.8% and 6% of unmethylated patients, respectively (p=0.0046). Patterns of failure were similar between the different treatment plans. Reduced target volumes were associated with significantly lower doses of 20-50 Gy to normal brain and hippocampi (p=0.0001).

Conclusion

Most of patients treated with standard chemioradiotherapy have in-field recurrences; however, an increased risk of distant recurrences occurs in methylated tumors. The use of target delineation using 1-cm CTV margin is associated with smaller volumes of normal brain and hippocampi irradiated to high doses, without significant changes in the pattern of failure. The impact of different target delineation in terms of efficacy and risk of late radiation-induced toxicity should be assessed prospectively.