bluuebunny/crossref_metadata_2025 huggingface dataset:
Building Capacity and Infrastructure at Hospitals Implementing Minimally Invasive Tissue Sampling: Experience and Lessons Learned From Nepal, Rwanda, and Tanzania
Authors: Subedi Nuwadatta , Bhattarai Suraj , Mremi Alex , Ntakirutimana Gervais , Ndayisaba Marie Claire , Rugwizangoga Belson , Mbarushimana Djibril , Hategekimana Elisée , Tuyizere Vestine , Paganelli Christina
Published: September 2021

Background

Minimally invasive tissue sampling (MITS) is a useful tool to determine cause of death in low- and middle-income countries (LMICs). In 2019 the MITS Surveillance Alliance supported the implementation of small-scale postmortem studies using MITS in several LMICs.

Methods

In this article we describe the preparations, challenges, and lessons learned as part of implementing MITS across 4 study sites in 3 countries: Nepal, Rwanda, and Tanzania. We describe the process for building capacity to conduct MITS, which consisted of training in MITS sample collection, individual site assessment to determine readiness and gaps prior to implementation, site visits as sites began implementation of MITS, and feedback based on remote evaluation of histology slides via an online portal.

Results

The 4 study sites each conducted 100 MITS, for a total of 400. All 4 sites lacked sufficient infrastructure and facilities to conduct MITS, and upgrades were required. Common challenges faced by sites included that clinical autopsies were neither routinely conducted nor widely accepted. Limited clinical records made cause of death determination more difficult. Lessons learned included the importance of sensitization of the community and medical staff to MITS to enhance understanding and increase consent.

Conclusions

The study sites accomplished MITS and utilized the available support systems to overcome the challenges. The quality of the procedures was satisfactory and was facilitated through the organized capacity-building programs.
Risk of Neurodegenerative Diseases in Patients with Inflammatory Bowel Disease: A Nationwide Population-based Cohort Study
Authors: Kim Ga Hee , Lee Yeong Chan , Kim Tae Jun , Kim Eun Ran , Hong Sung Noh , Chang Dong Kyung , Kim Young-Ho
Published: September 2021

Background and Aims

Although recent studies have reported that inflammatory bowel disease [IBD] is associated with the development of neurodegenerative diseases via chronic intestinal inflammation and the gut-brain axis, there is insufficient evidence supporting this notion. The aim of this study was to determine the risk of neurodegenerative diseases including Parkinson’s disease [PD] and Alzheimer’s disease [AD] in patients with IBD.

Methods

Using the National Health Insurance Service data for the entire Korean population, we identified patients with IBD and controls from 2009 to 2011 and followed them up until 2017. We selected the controls in a 1:4 ratio based on age and sex for comparison with cases.

Results

Of 24 830 IBD patients and 99 320 non-IBD controls, 98 IBD patients and 256 controls developed PD, and 644 IBD patients and 2303 controls developed AD. The overall neurodegenerative disease risk was higher in IBD patients (PD: adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.24-1.97; AD: adjusted HR, 1.14; 95% CI, 1.05-1.25). Younger IBD patients aged 40-65 years had a higher risk of PD compared with controls [adjusted HR, 2.34; 1.63-3.35]. In contrast, patients aged ≥65 years had an increased risk of AD compared with controls [adjusted HR, 1.14; 1.04-1.25]. In a nested case-control study of the IBD cohort, patients aged ≥65 years and the female sex were risk factors for AD, whereas living in an urban area was protective against AD.

Conclusions

The risk of neurodegenerative diseases was higher in IBD patients than in the non-IBD population.
Diagnosis and Outcome of Extranodal Primary Intestinal Lymphoma in Inflammatory Bowel Disease: An ECCO CONFER Case Series
Authors: Phillips Frank , Verstockt Bram , Ribaldone Davide Giuseppe , Guerra Ivan , Teich Niels , Katsanos Konstantinos , Filip Rafal , Molnar Tamas , Karmiris Konstantinos ,   ECCO CONFER Investigators, Kopylov Uri , Ellul Pierre , Sanchez Maria Chaparro , Goren Idan , Gecse Krisztina , Beaugerie Laurent , Bossuyt Peter , Sebastian Shaji
Published: September 2021

Background

There is a small but measurable increased risk of lymphoma in inflammatory bowel disease [IBD], with a suggestion that primary intestinal lymphoma [PIL] in IBD is associated with inflamed tissue and immunosuppressant use, mainly thiopurines.

Methods

This multicentre case series was supported by the European Crohn’s and Colitis Organisation [ECCO] and performed as part of the Collaborative Network of Exceptionally Rare case reports [CONFER] project. Clinical data were recorded in a standardized case report form.

Results

Fifteen patients with intestinal lymphoma from eight centres were included (12 males, 11 patients with Crohn’s disease [CD], mean age 47.8 [±16.4 SD, range 26–76] years at lymphoma diagnosis). Lymphoma type was diffuse large B-cell lymphoma [DLBCL] in eight, Hodgkin’s disease in two, mucosa-associated lymphoid tissue [MALT] lymphoma in three, and single cases of immunoblastic lymphoma and indolent T-cell lymphoma. Lymphoma was located within the IBD-affected area in ten patients. At lymphoma diagnosis, nine patients had a history of azathioprine or anti-tumour necrosis factor [TNF] use. Lymphoma was diagnosed at a mean time of 10.4 [±7.07, 1–24] years after IBD diagnosis in 11 patients, prior to IBD in two and concurrently in two. Sustained remission over a median follow-up time of 6.5 [1.5–20] years was achieved in ten patients after treatment; five of them had started biological therapy [including anti-TNFs, vedolizumab and ustekinumab] for active CD subsequent to their PIL treatment.

Conclusion

In this small case series, two-thirds of patients developed lymphoma in the IBD-affected area, and almost two-thirds had a history of thiopurine or anti-TNF use. Biologics were restarted without recurrence of lymphoma in half of the remitters.
Case report of cardiogenic shock in COVID-19 myocarditis: peculiarities on diagnosis, histology, and treatment
Authors: Fiore Giorgio , Sanvito Francesca , Fragasso Gabriele , Spoladore Roberto
Published: September 2021

Background

The year 2020 was dramatically characterized by SARS-CoV-2 pandemic outbreak. COVID-19-related heart diseases and myocarditis have been reported.

Case summary

A 45-year-old healthy male was admitted to the intensive care unit of our hospital because of cardiogenic shock. A diagnosis of COVID-19 infection and myocarditis was done. We present here several peculiarities about diagnostic workup, myocardial histological findings, choice of treatment, and the patient clinical course at 3 and 8 months of follow-up.

Discussion

COVID-19 myocardial damage and myocarditis are mainly linked to the cytokine storm with mild myocardial inflammatory infiltrate and very unusual platelet microclots in the setting of the microvascular obstructive thrombo-inflammatory syndrome. Counteracting the inflammatory burden with an interleukine-1 inhibitor appeared safe and led to a dramatic and stable improvement of cardiac function.
A life-threatening reverse Takotsubo syndrome in a young breastfeeding woman: a case report
Authors: Pires Carla Marques , Rocha Sérgia , Salomé Nuno , Azevedo Pedro
Published: September 2021

Background

Takotsubo syndrome (TTS) is characterized by transient left ventricular (LV) dysfunction and is usually triggered by emotional, physical, or combined stress. This syndrome has been increasingly recognized, although it remains a challenging and often misdiagnosed disorder.

Case summary

A 36-year-old breastfeeding woman was admitted with sudden dyspnoea and oppressive chest pain. On admission, she was lethargic, hypotensive, and tachycardic. The electrocardiogram showed rapid atrial fibrillation and diffuse ST-segment depression. The transthoracic echocardiogram (TTE) revealed severe LV systolic dysfunction, with midventricular and basal akinesis, compensatory apical hyperkinesia, and without intraventricular gradient. Emergent coronary angiogram showed normal coronary arteries. A presumptive diagnosis of reverse TTS with cardiogenic shock (CS) was made. The patient was transferred to the intensive care unit after intubation and inotropic and vasopressor support was initiated. During hospitalization, rapid clinical improvement was observed. In 3 days, the patient was weaned from haemodynamic support and extubated. Furthermore, β-blocker and angiotensin receptor blocker were initiated and tolerated. Cabergoline was also administered to inhibit lactation. The presumptive diagnosis was further strengthened by cardiac magnetic resonance and all triggering factors were excluded. At hospital discharge she was asymptomatic and the follow-up TTE was normal, which confirmed the diagnosis of reverse TTS.

Discussion

We present a case of a young woman, 8 months after delivery, which developed a life-threatening reverse TTS without triggering factor identified. Reverse TTS is a rare variant of TTS with different clinical features and is more likely to be complicated by pulmonary oedema and CS.
Impact of antenatal care visits on childhood immunization: a propensity score-matched analysis using nationally representative survey
Authors: Krishnamoorthy Yuvaraj , Rehman Tanveer
Published: September 2021

Background

Evidence has suggested a relationship between antenatal care (ANC) visits and childhood immunization coverage. However, evaluating its impact using observational data suffers from the problem of selection bias. Hence, we adopted propensity score-matched (PSM) analysis for studying the impact of ANC visits on childhood immunization.

Methods

Data regarding ANC visits and childhood immunization were collected from a nationally representative survey, National Family Health Survey-4 (NFHS-4). We performed PSM analysis with logit model using the psmatch2 command package in STATA to find the average treatment effect on the population (ATE), treated (ATT), and untreated (ATU).

Results

In total, 5,430 participants were included in the analysis. Radius matching with caliper width of 0.01 was used to match the groups. The ATT values in the intervention and control groups were 0.71 and 0.47, respectively, indicating that the immunization coverage was increased by 24% because of ANC visits. The ATU values in the intervention and control groups were 0.40 and 0.65, respectively. This indicates that for the women who did not make the ANC visits, the chance of getting their children immunized would have increased by 25% if they had made four or more visits. The final ATE estimate was 0.25 among the study participants. Quality of matching was good with no significant difference in characteristics between the two groups.

Conclusion

Findings from our study imply that policymakers in India should focus on further improving the ANC coverage as it has a significant impact on improving childhood immunization coverage.
Pandemic-related racial discrimination and its health impact among non-Indigenous racially minoritized peoples in high-income contexts: a systematic review
Authors: Yashadhana Aryati , Derbas Alexia , Biles Jessica , Grant Julian
Published: September 2021

This study aims to review articles reporting the perspectives and experiences of pandemic-related discrimination among racially minoritized peoples in high-income contexts. We searched online databases (Medline, EMBASE, PsycINFO, Web of Science, and ProQuest) for peer-reviewed articles published between January 2002 and October 2020. Eligible studies reported either quantitative or qualitative accounts of pandemic-related discrimination from the perspectives of racially minoritized peoples in high-income contexts. Two authors screened 30% of titles/abstracts, and all full-text articles. Each article included for extraction underwent a quality assessment by two reviewers. Data were extracted and categorized thematically using NVivo 12, followed by a secondary analysis informed by critical race theory. Of the 1289 articles screened, 16 articles from five countries met the inclusion criteria. Racial discrimination is heightened during pandemic periods, due to the social association of specific racial groups with pandemic diseases including COVID-19, SARS (Asian), H1N1 (Hispanic) and Ebola (African). Fear based responses to racially minoritized peoples during pandemic periods included verbal/physical abuse, hypersurveillance, and avoidance, often occurring in public spaces. Pandemic-related racism had subsequent impacts on mental health and health care accessibility. Various coping strategies, including community support, avoidance, and problem solving, were documented in response to racial discrimination. Racialized discrimination and violence is a serious threat to the health and wellbeing of racially minoritized peoples, particularly due to its increase during pandemic periods. Racism must be recognized as a public health issue, and efforts to address its increased impact in pandemic contexts should be made, including ensuring that adequate representation of racially minoritized groups is present in policy, planning, and implementation.
Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction
Authors: Wang Dandan , Dao Maria , Muntean Brian S , Giles Andrew C , Martemyanov Kirill A , Grill Brock
Published: September 2021

GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.
Total arch replacement in octogenarians
Authors: Hachiro Kohei , Kinoshita Takeshi , Suzuki Tomoaki , Asai Tohru
Published: September 2021

OBJECTIVES

We investigated the effect of a preoperative age ≥80 years on postoperative outcomes in patients who underwent isolated elective total arch replacement using mild hypothermic lower body circulatory arrest with bilateral antegrade selective cerebral perfusion.

METHODS

A total of 140 patients who had undergone isolated elective total arch replacement between January 2007 and December 2020 were enrolled in the present study. We compared postoperative outcomes between 30 octogenarian patients (≥80 years old; Octogenarian group) and 110 non-octogenarian patients (≤79 years old; Non-Octogenarian group).

RESULTS

Overall 30-day mortality and hospital mortality were 0% in both groups, and there was no significant difference in overall survival between the 2 groups (log-rank test, P = 0.108). Univariable Cox proportional hazard analysis showed that age as continuous variable was only the predictor of mid-term all-cause death (hazard ratio 1.08, 95% confidence interval 1.01–1.16; P = 0.037), but not in the Octogenarians subgroup (P = 0.119).

CONCLUSIONS

Preoperative age ≥80 years is not associated with worse outcomes postoperatively after isolated elective total arch replacement with mild hypothermic lower body circulatory arrest and bilateral antegrade selective cerebral perfusion.
Analysis of a Galerkin finite element method for the Maxwell–Schrödinger system under temporal gauge
Authors: Ma Chupeng , Zhang Yongwei , Cao Liqun
Published: September 2021

This paper is concerned with the numerical solution of the Maxwell–Schrödinger system under the temporal gauge, which describes light–matter interactions. We first propose a semidiscrete finite element scheme for the system and establish stability estimates for the finite element solution. Due to the lack of control over its divergence we cannot get $\textbf{H}^{1}$$a \;priori$ estimates for the vector potential, making it difficult to obtain error estimates by usual techniques. We apply an exhaustion argument to overcome this difficulty and derive error estimates for the finite element approximation. An energy-conserving time-stepping scheme is proposed to solve the semidiscrete system.
Evaluation of amoxicillin, metronidazole and gentamicin dosage regimens for use in antibiotic prophylaxis in colorectal surgery
Authors: da Silva Neto M J J , MacKay G , Agaram R , MacLeod M , Watson D G , Thomson A H
Published: September 2021

Objectives

To evaluate amoxicillin, metronidazole and gentamicin dosage regimens for antibiotic prophylaxis in colorectal surgery.

Methods

The study was conducted in 20 patients undergoing colorectal surgery. Patients received one or two doses of amoxicillin 1000 mg, metronidazole 500 mg and gentamicin 3 mg/kg ideal body weight, banded by height. Antibiotic concentrations were measured up to 7 h post dose. Population pharmacokinetic (PopPK) analysis with NONMEM followed by Monte Carlo simulation of different dosage regimens was used to estimate the PTA for potential organisms associated with surgical site infections (SSIs).

Results

A median of 5 (range 3–6) concentrations were available per patient. CL and V of all antibiotics were related to weight; gentamicin CL was also related to CLCR. The administered doses maintained the desired PTA up to 8 h for the Streptococcus anginosus group but not for enterococci, Bacteroides fragilis group, MSSA, and Escherichia coli. An additional 500 mg amoxicillin every 4 h was sufficient to achieve the PTA for most relevant organisms but 2 hourly dosing was required for patients at risk of infective endocarditis. A metronidazole dose of 1000 mg was required for patients >85 kg. In patients with CLCR >50 mL/min, 5 mg/kg gentamicin (with an additional 2.5 mg/kg in prolonged surgery at 6 h) maintained PTA targets for >10 h.

Conclusions

PopPK analysis with Monte Carlo simulation identified prophylactic antibiotic regimens that would maintain the PTA for organisms associated with SSIs during short- and long-duration colorectal surgery.
Genetic evaluation of ESBL-producingEscherichia coliurinary isolates in Otago, New Zealand
Authors: Hapuarachchi Isuri U , Hannaway Rachel F , Roman Tabatha , Biswas Ambarish , Dyet Kristin , Morgan Xochitl , Ussher James E
Published: September 2021

Objectives

The incidence of infections with ESBL-producing Escherichia coli (ESBL-Ec) in New Zealand is increasing. ESBL-Ec most commonly cause urinary tract infections and are seen in both community and hospitalized patients. The reason for the increasing incidence of ESBL-Ec infections is unknown.

Methods

In this study, 65 urinary ESBL-Ec isolates from the Otago region in 2015 were fully genetically characterized to understand the mechanisms of transmission. The ESBL gene, E. coli STs, plasmid types and genetic context (e.g. insertion sequences) of ESBL genes were determined by a combination of whole genome and plasmid sequencing. The phylogenetic relationships of the isolates were compared with ESBL-Ec isolates sequenced as part of the 2016 nationwide survey.

Results

Significant diversity of E. coli strains, plasmids, and the genetic context of ESBL genes was seen. However, there was evidence of common mobile genetic elements in unrelated ESBL-Ec.

Conclusions

Multiple introductions of ESBL resistance genes or resistant bacterial strains with limited horizontal transmission of mobile genetic elements accounts for the increased incidence of ESBL-Ec in this low prevalence area. Future studies should investigate modes of transmission of ESBL-Ec in the Otago region.
Genome-wide Analysis of Alternative Gene Splicing Associated with Virulence in the Brown Planthopper Nilaparvata lugens (Hemiptera: Delphacidae)
Authors: Liu Kai , Su Qin , Kang Kui , Chen Meng , Wang Wei-Xia , Zhang Wen-Qing , Pang Rui
Published: September 2021

Alternative splicing of protein coding genes plays a profound role in phenotypic variation for many eukaryotic organisms. The development of high-throughput sequencing and bioinformatics algorithms provides the possibility of genome-wide identification of alternative splicing events in eukaryotes. However, for the brown planthopper Nilaparvata lugens, a destructive pest of rice crops, whole-genome distribution of alternative splicing events and the role of alternative splicing in the phenotypic plasticity of virulence have not previously been estimated. Here, we developed an analysis pipeline to identify alternative splicing events in the genome of N. lugens. Differential expression analysis and functional annotation were performed on datasets related to different virulence phenotypes. In total, 27,880 alternative splicing events corresponding to 9,787 multi-exon genes were detected in N. lugens. Among them, specifically expressed alternative splicing transcripts in the virulent Mudgo population were enriched in metabolic process categories, while transcripts in the avirulent TN1 population were enriched in regulator activity categories. In addition, genes encoding odorant receptor, secreted saliva protein and xenobiotic metabolic P450 monooxygenase showed different splicing patterns between Mudgo population and TN1 population. Host change experiment also revealed that an isoform of a P450 gene could be specially induced by the stimulation of resistant rice variety Mudgo. This research pioneered a genome-wide study of alternative gene splicing in the rice brown planthopper. Differences in alternative splicing between virulent and avirulent populations indicated that alternative splicing might play an important role in the formation of virulence phenotypes in N. lugens.
Beyond Agency as Good: Complicity and Displacement after the Siege of Sarajevo
Authors: GoluboviĆ Jelena
Published: September 2021

Forced migration scholars have increasingly documented the agency of displaced persons. However, this scholarship has attended primarily to the positive or constructive dimensions of agency, documenting migrants’ capacities for resilience, resistance, and problem-solving. In this paper, I argue that forced migration scholarship should extend to recognize the darker dimensions of agency, such as complicity in acts of violence. Drawing on emerging work on ‘complex victimhood’ in conflict studies scholarship, which grapples with the difficult simultaneity of victimhood and complicity, I begin to articulate a figure of the ‘complex migrant’. As a case study, I draw on fieldwork with Bosnian Serb women who were part of the 1996 displacement of Serbs from Sarajevo, when the divided city was re-unified following nearly four years of siege by Bosnian Serb forces. Against the figure of the ideal refugee/victim, I outline the numerous deviations that made Serbs illegible as refugees. I also demonstrate how my interlocutors asserted the qualities of the ideal victim in their narratives to make their losses legible. I argue that a complex victimhood framework is useful for analysing other understudied retributive displacements. I also suggest that it can work to gradually disempower discourses that blame migrants when they fail to live up to the ideal of the good victim.
Hair interacts with SlZFP8-like to regulate the initiation and elongation of trichomes by modulating SlZFP6 expression in tomato
Authors: Zheng Fangyan , Cui Long , Li Changxing , Xie Qingmin , Ai Guo , Wang Junqiang , Yu Huiyang , Wang Taotao , Zhang Junhong , Ye Zhibiao , Yang Changxian
Published: September 2021

Trichomes are specialized glandular or non-glandular structures that provide physical or chemical protection against insect and pathogen attack. Trichomes in Arabidopsis have been extensively studied as typical non-glandular structures. By contrast, the molecular mechanism underlying glandular trichome formation and elongation remains largely unknown. We previously demonstrated that Hair is essential for the formation of type I and type VI trichomes. Here, we found that overexpression of Hair increased the density and length of tomato trichomes. Biochemical assays revealed that Hair physically interacts with its close homolog SlZFP8-like (SlZFP8L), and SlZFP8L also directly interacts with Woolly. SlZFP8L-overexpressing plants showed increased trichome density and length. We further found that the expression of SlZFP6, which encodes a C2H2 zinc finger protein, is positively regulated by Hair. Using chromatin immunoprecipitation, yeast one-hybrid, and dual-luciferase assays we identified that SlZFP6 is a direct target of Hair. Similar to Hair and SlZFP8L, the overexpression of SlZFP6 also increased the density and length of tomato trichomes. Taken together, our results suggest that Hair interacts with SlZFP8-like to regulate the initiation and elongation of trichomes by modulating SlZFP6 expression in tomato.
Fibrational bisimulations and quantitative reasoning: Extended version
Authors: Sprunger David , Katsumata Shin-ya , Dubut Jérémy , Hasuo Ichiro
Published: September 2021

Bisimulation and bisimilarity are fundamental notions in comparing state-based systems. Their extensions to a variety of systems have been actively pursued in recent years, a notable direction being quantitative extensions. In this paper we enhance a categorical framework for such extended (bi)simulation notions. We use coalgebras as system models and fibrations for organizing predicates—following the seminal work by Hermida and Jacobs. Endofunctor liftings are crucial predicate-forming ingredients; the first contribution of this work is to extend several extant lifting techniques from particular fibrations to $\textbf {CLat}_\wedge $-fibrations over $\textbf {Set}$. The second contribution of this work is to introduce endolifting morphisms as a mechanism for comparing predicates between fibrations. We apply these techniques by deriving some known properties of the Hausdorff pseudometric and approximate bisimulation in control theory.
Widely distributed exogenic materials of varying compositions and morphologies on asteroid (101955) Bennu
Authors: Tatsumi Eri , Popescu Marcel , Campins Humberto , de León Julia , García Juan Luis Rizos , Licandro Javier , Simon Amy A , Kaplan Hannah H , DellaGiustina Daniella N , Golish Dathon R , Lauretta Dante S
Published: September 2021

Using the multiband imager MapCam on board the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security–Regolith Explorer) spacecraft, we identified 77 instances of proposed exogenic materials distributed globally on the surface of the B-type asteroid (101955) Bennu. We identified materials as exogenic on the basis of an absorption near 1 $\mu$m that is indicative of anhydrous silicates. The exogenic materials are spatially resolved by the telescopic camera PolyCam. All such materials are brighter than their surroundings, and they are expressed in a variety of morphologies: homogeneous, breccia-like, inclusion-like, and others. Inclusion-like features are the most common. Visible spectrophotometry was obtained for 46 of the 77 locations from MapCam images. Principal component analysis indicates at least two trends: (i) mixing of Bennu's average spectrum with a strong 1-$\mu$m band absorption, possibly from pyroxene-rich material, and (ii) mixing with a weak 1-$\mu$m band absorption. The end member with a strong 1-$\mu$m feature is consistent with Howardite-Eucrite-Diogenite (HED) meteorites, whereas the one showing a weak 1-$\mu$m feature may be consistent with HEDs, ordinary chondrites, or carbonaceous chondrites. The variation in the few available near-infrared reflectance spectra strongly suggests varying compositions among the exogenic materials. Thus, Bennu might record the remnants of multiple impacts with different compositions to its parent body, which could have happened in the very early history of the Solar system. Moreover, at least one of the exogenic objects is compositionally different from the exogenic materials found on the similar asteroid (162173) Ryugu, and they suggest different impact tracks.
Profile comparison of the 6–9 μm polycyclic aromatic hydrocarbon bands in starburst-dominated galaxies
Authors: Canelo Carla M , Sales Dinalva A , Friaça Amâncio C S , Pastoriza Miriani , Menéndez-Delmestre Karín
Published: September 2021

Polycyclic aromatic hydrocarbons (PAHs) are of great astrochemical and astrobiological interest due to their potential to form prebiotic molecules. We analyse the 7.7 and 8.6 $\mu$m PAH bands in 126 pre-dominantly starburst-dominated galaxies extracted from the Spitzer/IRS ATLAS project. Based on the peak positions of these bands, we classify them into the different A, B, and C Peeters’ classes, which allows us to address the potential characteristics of the PAH-emitting population. We compare this analysis with previous work focused on the 6.2 $\mu$m PAH band for the same sample. For the first time in the literature, this statistical analysis is performed on a sample of galaxies. In our sample, the 7.7 $\mu$m complex is equally distributed in A and B object’s class while the 8.6 $\mu$m band presents more class B sources. Moreover, 39 per cent of the galaxies were distributed into A class objects for both 6.2 and 7.7 $\mu$m bands and only 18 per cent received the same A classification for the three bands. The ‘A A A’ galaxies presented higher temperatures and less dust in their interstellar medium. Considering the redshift range covered by our sample, the distribution of the three bands into the different Peeters’ classes reveals a potential cosmological evolution in the molecular nature of the PAHs that dominate the interstellar medium in these galaxies, where B class objects seem to be more frequent at higher redshifts and, therefore, further studies have to be addressed.
Inelastic rate coefficients for collisions of C4H− with H2
Authors: Balança Christian , Quintas-Sánchez Ernesto , Dawes Richard , Dumouchel Fabien , Lique François , Feautrier Nicole
Published: September 2021

Carbon-chain anions were recently detected in the interstellar medium. These very reactive species are used as tracers of the physical and chemical conditions in a variety of astrophysical environments. However, the local thermodynamic equilibrium conditions are generally not fulfilled in these environments. Therefore, collisional as well as radiative rates are needed to accurately model the observed emission lines. We determine in this work the state-to-state rate coefficients of C4H− in collision with both ortho- and para-H2. A new ab initio 4D potential energy surface was computed using explicitly correlated coupled-cluster procedures. This surface was then employed to determine rotational excitation and de-excitation cross-sections and rate coefficients for the first 21 rotational levels (up to rotational level j1 = 20) using the close-coupling method, while the coupled-state approximation was used to extend the calculations up to j1 = 30. State-to-state rate coefficients were obtained for the temperature range 2–100 K. The differences between the ortho- and para-H2 rate coefficients are found to be small.
Galaxy assembly bias and large-scale distribution: a comparison between IllustrisTNG and a semi-analytic model
Authors: Hadzhiyska Boryana , Liu Sonya , Somerville Rachel S , Gabrielpillai Austen , Bose Sownak , Eisenstein Daniel , Hernquist Lars
Published: September 2021

In this work, we compare large scale structure observables for stellar mass selected samples at z = 0, as predicted by two galaxy models, the hydrodynamical simulation IllustrisTNG and the Santa-Cruz semi-analytic model (SC-SAM). Although both models have been independently calibrated to match observations, rather than each other, we find good agreement between the two models for two-point clustering and galaxy assembly bias signatures. The models also show a qualitatively similar response of occupancy and clustering to secondary halo parameters other than mass, such as formation history and concentration, although with some quantitative differences. Thus, our results demonstrate that the galaxy–halo relationships in SC-SAM and TNG are quite similar to first order. However, we also find areas in which the models differ. For example, we note a strong correlation between halo gas content and environment in TNG, which is lacking in the SC-SAM, as well as differences in the occupancy predictions for low-mass haloes. Moreover, we show that higher order statistics, such as cumulants of the density field, help us to accurately describe the galaxy distribution and discriminate between models that show degenerate behaviour for two-point statistics. Our results suggest that SAMs are a promising cost-effective and intuitive method for generating mock catalogues for next generation cosmological surveys.
The MOSDEF survey: the dependence of H α-to-UV SFR ratios on SFR and size at z ∼ 2
Authors: Fetherolf Tara , Reddy Naveen A , Shapley Alice E , Kriek Mariska , Siana Brian , Coil Alison L , Mobasher Bahram , Freeman William R , Sanders Ryan L , Price Sedona H , Shivaei Irene , Azadi Mojegan , de Groot Laura , Leung Gene C K , Zick Tom O
Published: September 2021

We perform an aperture-matched analysis of dust-corrected H α and UV star formation rates (SFRs) using 303 star-forming galaxies with spectroscopic redshifts 1.36 < zspec < 2.66 from the MOSFIRE Deep Evolution Field survey. By combining H α and H β emission line measurements with multiwaveband resolved Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey/3D-HST imaging, we directly compare dust-corrected H α and UV SFRs, inferred assuming a fixed attenuation curve shape and constant SFHs, within the spectroscopic aperture. Previous studies have found that H α and UV SFRs inferred with these assumptions generally agree for typical star-forming galaxies, but become increasingly discrepant for galaxies with higher SFRs (≳100 M⊙ yr−1), with H α-to-UV SFR ratios being larger for these galaxies. Our analysis shows that this trend persists even after carefully accounting for the apertures over which H α and UV-based SFRs (and the nebular and stellar continuum reddening) are derived. Furthermore, our results imply that H α SFRs may be higher in the centres of large galaxies (i.e. where there is coverage by the spectroscopic aperture) compared to their outskirts, which could be indicative of inside-out galaxy growth. Overall, we suggest that the persistent difference between nebular and stellar continuum reddening and high H α-to-UV SFR ratios at the centres of large galaxies may be indicative of a patchier distribution of dust in galaxies with high SFRs.
PL03.3.A Development and characterization of CD317-specific CAR T cells as an innovative immunotherapeutic strategy against glioblastoma
Authors: Hänsch L , Peipp M , Myburgh R , Silginer M , Weiss T , Gramatzki D , Vasella F , Manz M , Weller M , Roth P
Published: September 2021

BACKGROUND

Due to the limited success of existing therapies for gliomas, innovative therapeutic options are urgently needed. Chimeric antigen receptor (CAR) T cell therapy has been successful in patients with hematological malignancies. However, using this treatment against solid tumors such as glioblastomas is more challenging. Here, we generated CAR T cells targeting the transmembrane protein CD317 (BST-2, HM1.24) which is overexpressed in glioma cells and may therefore serve as a novel target antigen for CAR T cell-based immunotherapy.

MATERIAL AND METHODS

CAR T cells targeting CD317 were generated by lentiviral transduction of human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells was determined in lysis assays using different glioma target cell lines with varying CD317 expression levels. The efficiency of CD317-CAR T cells to control tumor growth in vivo was evaluated in clinically relevant orthotopic xenograft glioma mouse models.

RESULTS

We created a second-generation CAR construct targeting CD317 and observed strong anti-glioma activity of CD317-CAR T cells in vitro. Glioma cells with a CRISPR/Cas9-mediated CD317 knockout were resistant to CD317-specific CAR T cells, demonstrating their target antigen-specificity. Since CD317 is also expressed by T cells, transduction with a CD317-directed CAR resulted in fratricide of the transduced T cells. Silencing of CD317 in CAR T cells by integrating a specific shRNA into the CAR vector significantly increased the viability, proliferation and cytotoxic function of the CAR T cells. Importantly, intratumoral treatment with CD317-CAR T cells prolonged the survival and cured a significant fraction of glioma-bearing nude mice.

CONCLUSION

We demonstrate strong CD317-specific anti-tumor activity of CD317-CAR T cells against various glioma cell lines in vitro and in xenograft glioma models in vivo. These data lay a scientific basis for the subsequent evaluation of this therapeutic strategy in clinical neuro-oncology.
KS01.5.A Allergic airway inflammation impacts tumor take and delays experimental glioblastoma progression
Authors: Poli A , Oudin A , Muller A , Hunewald O , Domingues O , Nazarov P V , Puard V , Baus V , Azuaje F , Dittmar G , Zimmer J , Michel T , Niclou S P , Ollert M
Published: September 2021

BACKGROUND

Numerous epidemiological studies have highlighted the protective role of immunoglobulin E-mediated allergic diseases on glioblastoma (GBM) susceptibility and prognosis. However, the mechanistic explanations behind these phenomena remain unexplored. Our objective was to set up a preclinical model and investigate the mechanisms underlying such protection to improve our understanding of the crosstalk between immune system and brain tumor development.

MATERIAL AND METHODS

A mouse model of allergic airway inflammation (AAI) induced by repeated nasal instillation of House Dust Mite extract was initiated before intracranial implantation of GL261 glioma cells, in both immunocompetent (C57BL/6) and immunodeficient (RAG-KO) mice. Tumor take and tumor growth were monitored by MRI. Central (microglia) and peripheral (spleen, bone marrow) immune cells were characterized by flow cytometry. The response of microglia was further assessed by RNA sequencing. Impact of candidate genes on patient survival was characterized by Cox regression analysis using data from TCGA and CGGA.

RESULTS

Following AAI induction in C57BL/6 mice, engraftment of GL261 cells in the brain was delayed and tumor growth rate was reduced. This correlated with an increase in survival of the mice and was accompanied by increased effector memory T-cells in the circulation. Of note, the survival benefit was lost in RAG-KO mice devoid of adaptive immunity. At the level of the brain, we observed enhanced secretion of TNFα and IL6 in microglia ex vivo. AAI induced a transcriptional reprogramming of microglia towards a pro-inflammatory-like state. We identified an allergy-related microglia gene signature that is associated with improved prognosis of glioma patients.

CONCLUSION

Our results demonstrate that AAI limits both tumor take and GBM progression in mice, providing a preclinical model to study the role of allergic inflammation in GBM susceptibility and prognosis, respectively. At the functional level, we identify a potentiation of microglial and adaptive anti-tumoral immunity. Further investigations are warranted to shed light on the reciprocal crosstalk between microglial reprogramming and peripheral immunity in the context of allergies and brain tumors.
OS06.7A METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy
Authors: Zhu L , Blanco-Aparicio C , Bertero L , Soffietti R , Weiss T , Muñoz J , Sepúlveda J , Weller M , Pastor J , Valiente M
Published: September 2021

BACKGROUND

The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options.

MATERIAL AND METHODS

We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures - PDOCs -). We have also used METPlatform to perform unbiased proteomics of brain metastases in situ to identify potential novel mediators of this disease and explore resistance mechanisms to targeted therapy. Finally, we have exploited METPlatform as “avatars” to predict response to therapy in patients with primary brain tumors.

RESULTS

We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we show that brain tumor PDOCs predict the response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer.

CONCLUSION

Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.
OS09.7.A Quality of life outcomes in patients with incidental and operated meningiomas: the QUALMS study
Authors: Keshwara S M , Islim A I , Millward C P , Gillespie C S , Richardson G E , Mustafa M A , George A M , Mills S J , Brodbelt A R , Jenkinson M D
Published: September 2021

BACKGROUND

Long-term Health-Related Quality of Life (HRQoL) is an important measure of patient wellbeing. There is a paucity of studies evaluating HRQoL in meningioma patients.

MATERIAL AND METHODS

Cross-sectional study of adult patients with an incidental or symptomatic intracranial meningioma. Patients with less than 5 years of follow-up, a history of craniospinal radiation or neurofibromatosis type 2 were excluded. HRQoL was evaluated with SF-36, EORTC QLQ-C30 and EORTC QLQ-BN20 questionnaires. Outcome determinants were evaluated using a multi-variable linear regression analysis, adjusted for patient, tumour and treatment characteristics, and duration of follow-up.

RESULTS

699 patients were invited to participate and 246 responded: 118 (48%) had an incidental meningioma. Mean age at diagnosis was 56.8 years (SD=13) and 81% were female. Median time from diagnosis to completion of questionnaire was 8.5 years (IQR 6.8–11.5). During follow-up, 158 patients (64.2%) had at least one operation for their meningioma and 47 patients (19.1%) had radiotherapy. Of those operated, 126 (79.7%) had WHO grade 1 and 24 (15.2%) had grade 2 meningiomas. Compared to normative population values, meningioma patients reported a worse SF-36 general health score (mean 61.9 vs 56.5, P=0.003) but a similar QLQ-C30 global health score (mean 62.3 vs 65.8, P=0.039), worse SF-36 and QLQ-C30 physical functioning scores (mean 74.1 vs 64.6, P<0.001 and mean 81.8 vs 76.5, P=0.007) and similar SF-36 and QLQ-C30 emotional health scores (mean 72.2 vs 70.9, P=0.367 and mean 71.0 vs 71.9, P=0.960). QLQ-C30 cognitive functioning was worse (mean 80.5 vs 71.4, P<0.001). Compared to the meningioma literature, QLQ-BN20 seizure burden was similar (mean 2.0 vs 1.6, P=0.760). A worse performance status at diagnosis was associated with an inferior QLQ-C30 global health score (β-coefficient=-4.9 [95% CI -9.1-(-)0.6] P=0.024). Number of surgeries was significantly associated with a worse QLQ-C30 cognitive functioning score (β-coefficient=-7.0 [95% CI -13.2-(-)0.9], P=0.025). Anti-epileptic drug use was associated with a significantly worse QLQ-C30 emotional health score (β-coefficient=-10.9 [95% CI -21.7-(-)0.01], P=0.050).

CONCLUSION

Meningioma patients have long-term HRQoL impairments affecting their physical and cognitive functions. An understanding that multiple surgeries affects cognitive function, and the need for anti-epileptic drugs equate to poorer emotional health, could help target appropriate therapies and support in the future.
P04.09 Frequent inactivating mutations of PBRM1 in meningioma with papillary features
Authors: Williams E , Brastianos P , Santagata S , Cahill D , Ramkissoon S , Juratli T
Published: September 2021

BACKGROUND

Papillary meningiomas (PM) are rare WHO grade III tumors that are associated with frequent recurrences and metastatic disease in spite of surgery and radiation. Due to their low incidence and scarcity of tumor tissues available for genomic analyses, the genetic alterations associated with PM remain unclear.

MATERIAL AND METHODS

We mined data collected as part of our clinical comprehensive genomic profiling (CGP) initiative which has to date analyzed 8 PM (>50% papillary morphology) and 22 meningiomas with focal papillary features (10–50%) amongst over 500 additional meningiomas of other subtypes. The samples were analyzed in a CAP/CLIA-accredited laboratory (Foundation Medicine, Cambridge, MA). GCP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >650x for 236 or 315 genes plus the introns from 19 or 28 genes frequently involved in cancer.

RESULTS

In our cohort of 8 PMs, we identified three cases with inactivation of PBRM1; two cases with a truncating mutation in PBRM1 and one with homozygous deletion of PBRM1. Of the 22 meningiomas with only focal papillary features, 8 cases were PBRM1-mutant. Thus, 11 of 30 cases (36.7%) with at least focal (>10%) papillary morphology had inactivation of PBRM1.In the entire cohort of 562 meningiomas, we identified five additional cases with inactivating alterations in PBRM1 that did not display overt papillary morphology in the H&E sections available for analysis. Thus, 11 of 16 PBRM1-mutant cases (69%) occurred in meningioma with papillary histologic features as opposed to 19 of 546 wild-type cases (3.5%), supporting a significant association between papillary features and PBRM1 mutation (p<0.0001). The majority of PBRM1-mutant meningiomas occurred in female patients (n=10/16, 62.5%), and median age was 51 years. Most cases were located supratentorially (n=10).

CONCLUSION

We identified the tumor suppressor gene PBRM1 as a recurrently altered gene in meningiomas with papillary histomorphology. Further investigational studies are needed to assess outcomes of PBRM1-mutant meningioma and to determine whether mutation is an independent negative prognostic biomarker.