bluuebunny/crossref_metadata_2025 huggingface dataset:
The prevalence of left and right bundle branch block morphology ventricular tachycardia amongst patients with arrhythmogenic cardiomyopathy and sustained ventricular tachycardia: insights from the European Survey on Arrhythmogenic Cardiomyopathy
Authors: Belhassen Bernard , Laredo Mikael , Roudijk Rob W , Peretto Giovanni , Zahavi Guy , Sen-Chowdhry Srijita , Badenco Nicolas , Te Riele Anneline S J M , Sala Simone , Duthoit Guillaume , van Tintelen J Peter , Paglino Gabriele , Sellal Jean-Marc , Gasperetti Alessio , Arbelo Elena , Andorin Antoine , Ninni Sandro , Rollin Anne , Peichl Petr , Waintraub Xavier , Bosman Laurens P , Pierre Bertrand , Nof Eyal , Miles Chris , Tfelt-Hansen Jacob , Protonotarios Alexandros , Giustetto Carla , Sacher Frederic , Hermida Jean-Sylvain , Havranek Stepan , Calo Leonardo , Casado-Arroyo Ruben , Conte Giulio , Letsas Konstantinos P , Zorio Esther , Bermúdez-Jiménez Francisco J , Behr Elijah R , Beinart Roy , Fauchier Laurent , Kautzner Josef , Maury Philippe , Lacroix Dominique , Probst Vincent , Brugada Josep , Duru Firat , de Chillou Christian , Bella Paolo Della , Gandjbakhch Estelle , Hauer Richard , Milman Anat
Published: July 2021

Aims

In arrhythmogenic cardiomyopathy (ACM), sustained ventricular tachycardia (VT) typically displays a left bundle branch block (LBBB) morphology while a right bundle branch block (RBBB) morphology is rare. The present study assesses the VT morphology in ACM patients with sustained VT and their clinical and genetic characteristics.

Methods and results

Twenty-six centres from 11 European countries provided information on 954 ACM patients who had ≥1 episode of sustained VT spontaneously documented during patients’ clinical course. Arrhythmogenic cardiomyopathy was defined according to the 2010 Task Force Criteria, and VT morphology according to the QRS pattern in V1. Overall, 882 (92.5%) patients displayed LBBB-VT alone and 72 (7.5%) RBBB-VT [alone in 42 (4.4%) or in combination with LBBB-VT in 30 (3.1%)]. Male sex prevalence was 79.3%, 88.1%, and 56.7% in the LBBB-VT, RBBB-VT, and LBBB + RBBB-VT groups, respectively (P = 0.007). First RBBB-VT occurred 5 years after the first LBBB-VT (46.5 ± 14.4 vs 41.1 ± 15.8 years, P = 0.011). An implanted cardioverter-defibrillator was more frequently implanted in the RBBB-VT (92.9%) and the LBBB + RBBB-VT groups (90%) than in the LBBB-VT group (68.1%) (P < 0.001). Mutations in PKP2 predominated in the LBBB-VT (65.2%) and the LBBB + RBBB-VT (41.7%) groups while DSP mutations predominated in the RBBB-VT group (45.5%). By multivariable analysis, female sex was associated with LBBB + RBBB-VT (P = 0.011) while DSP mutations were associated with RBBB-VT (P < 0.001). After a median follow-up of 103 (51–185) months, death occurred in 106 (11.1%) patients with no intergroup difference (P = 0.176).

Conclusion

RBBB-VT accounts for a significant proportion of sustained VTs in ACM. Sex and type of pathogenic mutations were associated with VT type, female sex with LBBB + RBBB-VT, and DSP mutation with RBBB-VT.
Potential Effect of Low-Rise, Downcast Artificial Lights on Nocturnally Migrating Land Birds
Authors: Cabrera-Cruz Sergio A , Larkin Ronald P , Gimpel Maren E , Gruber James G , Zenzal Theodore J , Buler Jeffrey J
Published: July 2021

Artificial light at night (ALAN) on tall or upward-pointed lighting installations affects the flight behavior of night-migrating birds. We hypothesized that common low-rise lights pointing downward also affect the movement of nocturnal migrants. We predicted that birds in flight will react close to low-rise lights, and be attracted and grounded near light sources, with a stronger effect on juveniles during their autumn migration. We conducted a controlled longitudinal experiment with light-emitting diode floodlights and considered nearby structures that turn on lights at night. We analyzed 1501 high-resolution 3D nocturnal flight paths of free-flying migrants and diurnally captured 758–2009 birds around experimental lights during spring and autumn 2016, and spring 2017. We identified change points along flight paths where birds turned horizontally or vertically, and we considered these indicative of reactions. Flight paths with and without reactions were generally closer to our experimental site in spring than in autumn when the lights were on. Reactions were up to 40% more likely to occur in autumn than in spring depending on the threshold magnitude of turning angle. Reactions in spring were up to ∼60% more likely to occur at ∼35 m from the lights than at >1.5 km. In autumn, some vertical reactions were ∼40% more likely to occur at ∼50 m from the lights than at >2.2 km. Interactions between distance to lights and visibility or cloud cover were consistent with known effects of ALAN on nocturnal migrants. Under poor visibility, reactions were up to 50% more likely to occur farthest from structures in spring, but up to 60% more likely to occur closest to lights in autumn. Thus, the effects of ALAN on night-migrating land birds are not limited to bright lights pointing upward or lights on tall structures in urban areas. Diurnal capture rates of birds were not different when lights were on or off for either season. To our knowledge, this is the first study to show that low-rise lights pointing downward affect night-migrating birds. Although the interpreted reactions constitute subtle modifications in the linearity of flight paths, we discuss future work that could verify whether the protection of nocturnal migrants with lights-out programs would have greater impact if implemented beyond urban areas and include management of low-rise lights.
Stabilization of a class of switched dynamic systems: the Riccati-equation-based Approach
Authors: Bonilla M , Aguillón, N A , Ortiz Castillo M A , Jacques Loiseau Jean , Malabre M , Azhmyakov V , Salazar S
Published: July 2021

Our paper deals with the stabilization of a class of time-dependent linear autonomous complex systems with a switched structure. The initially given switched dynamic system is assumed to be controlled by a specific state feedback strategy associated with the linear quadratic regulator (LQR) type control. The proposed control design guarantees stabilization of the closed-loop system for all of the possible location transitions. In the solution procedure of the Algebraic Riccati Equation related to the LQR control strategy, only the knowledge of the algebraic structure related to the switched system are needed. We prove that the proposed optimal LQR type state feedback control design stabilizes the closed-loop switched system for every possible active location. The theoretical approach proposed in this paper is finally applied to a model of the Single Wing Quadrotor Aircraft, when changing from its Quadrotor Flight Envelope to its Airplane Flight Envelope.
An HDG method for dissimilar meshes
Authors: Solano Manuel , Terrana Sébastien , Nguyen Ngoc-Cuong , Peraire Jaime
Published: July 2021

We present a hybridizable discontinuous Galerkin (HDG) method for dissimilar meshes. The method is devised by formulating HDG discretizations on separate meshes and gluing these HDG discretizations through appropriate transmission conditions that weakly enforce the continuity of the numerical trace and the numerical flux across the dissimilar interfaces. The transmission conditions are based upon transferring the numerical flux from the first mesh to the second mesh and the numerical trace from the second mesh to the first one. The transfer of the numerical trace/flux from one mesh to the other relies on the extrapolation of the approximate flux, and is made to be consistent with the HDG methodology for conforming meshes. Stability of the HDG method is shown and the error analysis of the HDG method is established. Numerical results are presented to validate the theoretical results.
Deep Sequencing to Detect Diversity of Trypanosoma cruzi Infection in Patients Coinfected With Human Immunodeficiency Virus and Chagas Disease
Authors: Bowman Natalie M , Balasubramanian Sujata , Gilman Robert H , Parobek Christian , Calderon Maritza , Waltmann Andreea , Messenger Louisa A , Sanchez Leny , Bern Caryn , Juliano Jonathan J ,   Working Group on Chagas Disease in Bolivia and Peru, Clark Daniel , Flores Jorge , Colanzi Roni , Choi Jeong , Galdos Gerson , Dorn Mauricio , Gandarilla Omar , Fortuny Enzo , Palumbo Anne , Ferrufino Lisbeth , Pajuelo Monica , Reimer Melissa , Mendoza Guerrero Sandra
Published: July 2021

Chagas disease, caused by Trypanosoma cruzi, can reactivate and cause severe acute disease in immunocompromised patients such as those infected with human immunodeficiency virus (HIV). We conducted amplicon deep sequencing of a 327-bp fragment of the tcscd5 gene using an Ion Torrent PGM directly from clinical samples from HIV patients with high parasitemia. We describe the within-host diversity, both characterizing the discrete typing unit of the infections and confirming the presence of multistrain infections, directly from clinical samples. This method can rapidly provide information on the genetic diversity of T. cruzi infection, which can have direct impacts on clinical disease.
Clinical characteristics and management of olecranon and prepatellar septic bursitis in a multicentre study
Authors: Charret Laurie , Bart Géraldine , Hoppe Emmanuel , Dernis Emmanuelle , Cormier Grégoire , Boutoille David , Le Goff Benoit , Darrieutort-Laffite Christelle
Published: July 2021

Background

No current guidelines are available for managing septic bursitis (SB).

Objectives

To describe the clinical characteristics and management of olecranon and prepatellar SB in five French tertiary care centres.

Methods

This is a retrospective observational multicentre study. SB was diagnosed on the basis of positive cultures of bursal aspirate. In the absence of positive bursal fluid, the diagnosis came from typical clinical presentation, exclusion of other causes of bursitis and favourable response to antibiotic therapy.

Results

We included 272 patients (median age of 53 years, 85.3% male and 22.8% with at least one comorbidity). A microorganism was identified in 184 patients (67.6%), from bursal fluids in all but 4. We identified staphylococci in 135 samples (73.4%), streptococci in 35 (19%) and 10 (5.5%) were polymicrobial, while 43/223 bursal samples remained sterile (19.3%). Forty-nine patients (18%) were managed without bursal fluid analysis. Antibiotic treatment was initially administered IV in 41% and this route was preferred in case of fever (P = 0.003) or extensive cellulitis (P = 0.002). Seventy-one (26%) patients were treated surgically. A low failure rate was observed (n = 16/272, 5.9%) and failures were more frequent when the antibiotic therapy lasted <14 days (P = 0.02) in both surgically and medically treated patients.

Conclusions

Despite variable treatments, SB resolved in the majority of cases even when the treatment was exclusively medical. The success rate was equivalent in the non-surgical and the surgical management groups. However, a treatment duration of <14 days may require special attention in both groups.
Salicylic Acid Induced Resistance in Drought-Stressed Pistachio Seedlings Influences Physiological Performance of Agonoscena pistaciae (Hemiptera: Aphalaridae)
Authors: Reyhani Haghighi Sajjad , Hosseininaveh Vahid , Talebi Khalil , Maali-Amiri Reza , Stelinski Lukasz L
Published: July 2021

Induced host plant resistance is a potential approach to insect and disease management. Salicylic acid (SA) acts as a signal molecule to induce resistance in plants against sap-sucking insects. The effects of salicylic acid-induced resistance against common pistachio psylla, Agonoscena pistaciae Burckhardt and Lauterer, were investigated in well-watered and drought-stressed pistachio, Pistacia vera L. cv. Akbari, seedlings. Agonoscena pistaciae exhibited a significant preference for plants treated with SA as compared with untreated controls or those subjected to drought stress. Plants subjected to both drought stress and SA treatment were equivalently colonized as compared with control plants but were more attractive than those subjected to drought stress alone. Psyllid mortality increased on plants subjected to simultaneous drought stress and SA treatment as compared with controls. Salicylic acid treatment mediated production of defensive enzymes in plants, including superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR), guaiacol peroxidase (GPX) and polyphenol oxidase (PPO), as well as that of other metabolites such as phenol, malondialdehyde (MDA), H2O2, free amino acids, and pigments via phenylpropanoid pathways under conditions of drought. Despite increases in activity of detoxification (glutathione S transferase, carboxylesterase) and antioxidative (SOD, CAT, APX, phenoloxidase, GPX) enzymes in psyllids, reduced survival of A. pistaciae on drought stressed and SA-treated plants was likely caused by excessive H2O2 and high phenolic content in treated plants. Based on our results, we postulate that salicylic acid-induced defense against A. pistaciae under drought conditions could be manipulated to enhance antibiosis against this key pest in pistachio orchards.
Investor–State Mediation and the Belt and Road Initiative: Examining the Conditions for Settlement
Authors: McLaughlin Mark
Published: July 2021

Despite the dominance of arbitration in the realm of investor-state disputes, the variety of proposals for reform suggest considerable stakeholder discontent with the current framework. One suggested reform is the introduction of investor–state mediation, which has been supported by the conclusion of the Singapore Convention on Mediation and the proposal by the International Centre for Settlement of Investment Disputes (ICSID) of a set of mediation rules. This article examines the respective merits of arbitration and mediation to settle investment disputes related to the Belt and Road Initiative. Many of the principles underpinning the implementation of the Belt and Road Initiative sit uncomfortably alongside an adversarial adjudicative mechanism, and access to arbitration is limited in some investment treaties. It is argued that, in some instances, mediation may be more attuned to the unique conditions of the Belt and Road Initiative. Stakeholders have done considerable work to enhance the legitimacy of mediation within the field of investor–state dispute settlement, but it remains dormant in practice and comparatively rare within investment treaties. While a mediated settlement will remain elusive in many instances, it can be encouraged by a series of reforms to treaty drafting, the internal organization of government departments, and the actions of foreign investors.
Atypical ductal hyperplasia of the breast mimics breast cancer presentation treated surgically: a case report and literature review
Authors: Alwagdani Nawaf M , Alnefaie Sahar M , Kurshid Arif , Kewan Hanady
Published: July 2021

Atypical ductal hyperplasia (ADH) is considered a benign lesion with increased malignant potential. ADH represents ~3% of total benign breast biopsy results. A 60-year-old woman with no family history of breast cancer presented with multiple painless lumps in the right breast and palpable right axillary lymph nodes. Ultrasonography and mammography showed typical features of breast cancer. However, core needle biopsy revealed ADH without infiltrating malignancy. Based on a multidisciplinary decision, a right simple mastectomy with sentinel lymph node biopsy was chosen as the best treatment plan. The postoperative histopathology report showed the spread of ductal carcinoma in situ (DCIS) in all quadrants without any evidence of invasive cancer. It is challenging to obtain an accurate diagnosis of clinically palpable and multicentric ADH or DCIS based on preoperative radiological and histological evaluation, especially when dissonance between these two evaluation modalities exists.
Convection and rotation boosted prescription of magnetic braking: application to the formation of extremely low-mass white dwarfs
Authors: Soethe L T T , Kepler S O
Published: July 2021

Extremely low-mass white dwarfs (ELM WDs) are the result of binary evolution in which a low-mass donor star is stripped by its companion leaving behind a helium-core white dwarf (WD). We explore the formation of ELM WDs in binary systems considering the Convection And Rotation Boosted magnetic braking treatment. Our evolutionary sequences were calculated using the Modules for Experiments in Stellar Astrophysics code, with initial masses of 1.0 and 1.2 M⊙ (donor), and 1.4 (accretor), compatible with low-mass X-ray binary (LMXB) systems. We obtain ELM models in the range 0.15–0.27 M⊙ from a broad range of initial orbital periods, 1–25 d. The bifurcation period, where the initial period is equal to the final period, ranges from 20 to 25 d. In addition to LMXBs, we show that ultracompact X-ray binaries (UCXBs) and wide-orbit binary millisecond pulsars can also be formed. The relation between mass and orbital period obtained is compatible with the observational data from He WD companions to pulsars.
Massive protocluster of a periodic maser source G188.95+0.89
Authors: Mutie M M , Chibueze J O , El Bouchefry K , MacLeod G C , Morgan J , Baki P
Published: July 2021

We report the results of ongoing monitoring of the 6.7 GHz CH3OH masers associated with G188.95+0.89. In these observations, five features are periodically varying and at least two exhibit evidence of velocity drifts. It is not clear the cause of these velocity drifts. The spectra have varied significantly since detection in 1991. The 11.45 km s−1 feature has decreased exponentially from 2003. Complementary ALMA 1.3-mm continuum and line observational results are also presented. Eight continuum cores (MM1–MM8) were detected in G188.95+0.89. We derived the masses of the detected cores. G188.95+0.89 MM2 was resolved into two continuum cores (separated by 0.1 arcsec) in ALMA band 7 observations. Also, CH3OH (4(2, 2)-3(1, 2)) thermal emission associated with MM2 is double peaked. We propose the presence of multiple (at least binary) young stellar objects in MM2. SiO emission exhibits a bow-shock morphology in MM2 while strong emission of 12CO at the east and west of MM2 suggests the presence of an east–west bipolar outflow.
Giant star-forming complexes in high-z main-sequence galaxy analogues: the internal structure of clumps in DYNAMO galaxies
Authors: Lenkić Laura , Bolatto Alberto D , Fisher Deanne B , Glazebrook Karl , Obreschkow Danail , Abraham Roberto , Ambachew Liyualem
Published: July 2021

To indirectly study the internal structure of giant clumps in main sequence galaxies at z ∼ 1–3, we target very turbulent and gas-rich local analogues from the DYNAMO sample with the Hubble Space Telescope, over a wavelength range of ∼200–480 nm. We present a catalogue of 58 clumps identified in six DYNAMO galaxies, including the WFC3/UVIS F225W, F336W, and F467M photometry where the (225–336) and (336–467) colours are sensitive to extinction and stellar population age, respectively. We measure the internal colour gradients of clumps themselves to study their age and extinction properties. We find a marked colour trend within individual clumps, where the resolved colour distributions show that clumps generally have bluer (336–467) colours (denoting very young ages) in their centres than at their edges, with little variation in the (225–336) colour associated with extinction. Furthermore, we find that clumps whose colours suggest they are older, are preferentially located closer towards the centres of their galaxies, and we find no young clumps at small galactocentric distances. Both results are consistent with simulations of high-redshift star-forming systems that show clumps form via violent disc instability, and through dynamic processes migrate to the centres of their galaxies to contribute to bulge growth on time-scales of a few 100 Myr, while continually forming stars in their centres. When we compare the DYNAMO clumps to those in these simulations, we find the best agreement with the long-lived clumps.
The physical origins and dominant emission mechanisms of Lyman alpha haloes: results from the TNG50 simulation in comparison to MUSE observations
Authors: Byrohl Chris , Nelson Dylan , Behrens Christoph , Kostyuk Ivan , Glatzle Martin , Pillepich Annalisa , Hernquist Lars , Marinacci Federico , Vogelsberger Mark
Published: July 2021

Extended Lyman alpha emission is now commonly detected around high-redshift galaxies through stacking and even on individual basis. Despite recent observational advances, the physical origin of these Lyman alpha haloes (LAHs), as well as their relationships to galaxies, quasars, circumgalactic gas, and other environmental factors remains unclear. We present results from our new Lyman alpha full radiative transfer code voroiltis which runs directly on the unstructured Voronoi tessellation of cosmological hydrodynamical simulations. We make use of the TNG50 simulation and simulate LAHs from redshift z = 2 to z = 5, focusing on star-forming galaxies with $8.0 \lt \log _{10}{(M_\star /\rm {M}_\odot)} \lt 10.5$. While TNG50 does not directly follow ionizing radiation, it includes an on-the-fly treatment for active galactic nuclei (AGNs) and ultraviolet background radiation with self-shielding, which are important processes impacting the cooling and ionization of the gas. Based on this model, we present the predictions for the stacked radial surface brightness profiles of Ly α as a function of galaxy mass and redshift. Comparison with data from the MUSE UDF at z > 3 reveals a promising level of agreement. We measure the correlations of LAH size and central brightness with galaxy properties, finding that at the masses of $8.5 \le \log _{10} \left(M_\star /\rm {M}_\odot \right) \le 9.5$, physical LAH sizes roughly double from z = 2 to z = 5. Finally, we decompose the profiles into contributions from diffuse emission and scattered photons from star-forming regions. In our simulations, we find rescattered photons from star-forming regions to be the major source in observed LAHs. Unexpectedly, we find that the flattening of LAH profiles at large radii becomes dominated by photons originating from other nearby haloes rather than diffuse emission itself.
Global Genetic Heterogeneity in Adaptive Traits
Authors: Lopez-Arboleda William Andres , Reinert Stephan , Nordborg Magnus , Korte Arthur
Published: July 2021

Understanding the genetic architecture of complex traits is a major objective in biology. The standard approach for doing so is genome-wide association studies (GWAS), which aim to identify genetic polymorphisms responsible for variation in traits of interest. In human genetics, consistency across studies is commonly used as an indicator of reliability. However, if traits are involved in adaptation to the local environment, we do not necessarily expect reproducibility. On the contrary, results may depend on where you sample, and sampling across a wide range of environments may decrease the power of GWAS because of increased genetic heterogeneity. In this study, we examine how sampling affects GWAS in the model plant species Arabidopsis thaliana. We show that traits like flowering time are indeed influenced by distinct genetic effects in local populations. Furthermore, using gene expression as a molecular phenotype, we show that some genes are globally affected by shared variants, whereas others are affected by variants specific to subpopulations. Remarkably, the former are essentially all cis-regulated, whereas the latter are predominately affected by trans-acting variants. Our result illustrate that conclusions about genetic architecture can be extremely sensitive to sampling and population structure.
PseudoGA: cell pseudotime reconstruction based on genetic algorithm
Authors: Mondal Pronoy Kanti , Saha Udit Surya , Mukhopadhyay Indranil
Published: July 2021

Dynamic regulation of gene expression is often governed by progression through transient cell states. Bulk RNA-seq analysis can only detect average change in expression levels and is unable to identify this dynamics. Single cell RNA-seq presents an unprecedented opportunity that helps in placing the cells on a hypothetical time trajectory that reflects gradual transition of their transcriptomes. This continuum trajectory or ‘pseudotime’, may reveal the developmental pathway and provide us with information on dynamic transcriptomic changes and other biological processes. Existing approaches to build pseudotime heavily depend on reducing huge dimension to extremely low dimensional subspaces and may lead to loss of information. We propose PseudoGA, a genetic algorithm based approach to order cells assuming that gene expressions vary according to a smooth curve along the pseudotime trajectory. We observe superior accuracy of our method in simulated as well as benchmarking real datasets. Generality of the assumption behind PseudoGA and no dependence on dimensionality reduction technique make it a robust choice for pseudotime estimation from single cell transcriptome data. PseudoGA is also time efficient when applied to a large single cell RNA-seq data and adaptable to parallel computing. R code for PseudoGA is freely available at https://github.com/indranillab/pseudoga.
Washington Committee for Neurological Surgery: The Evolution of Neurosurgery's Involvement in Public Policy
Authors: Stroink Ann R , Orrico Katie O , Bean James R
Published: July 2021

The American Association of Neurological Surgeons/Congress of Neurological Surgeons Washington Committee was formed in 1975 to establish a means for neurosurgery to influence federal health care policy. In response to growing federal health care legislation and regulation, the Washington Committee expanded from its original six members in 1975 to 35 invited liaisons and members by 2020. The Washington Committee, through the Washington Office, expanded political lobbying capacity into numerous important areas of health care policy, including Current Procedural Terminology coding and Medicare reimbursement, Federal Drug Administration (FDA) regulation, healthcare quality oversight, emergenc medical services, treatment guidelines, treatment outcome registries, medical liability reform, research funding, and information dissemination. Over 45 yr, the Washington Committee has become an indispensable resource for shaping public policy affecting neurosurgery training, research, and practice.
Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma
Authors: Pereira Victor , Torrejon Jacob , Kariyawasam Dulanjalee , Berlanga Pablo , Guerrini-Rousseau Léa , Ayrault Olivier , Varlet Pascale , Tauziède-Espariat Arnault , Puget Stéphanie , Bolle Stéphanie , Beccaria Kevin , Blauwblomme Thomas , Brugières Laurence , Grill Jacques , Geoerger Birgit , Dufour Christelle , Abbou Samuel
Published: July 2021

Background

Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow-up of young patients treated with SMOi for recurrent medulloblastoma.

Methods

Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible.

Results

All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for 3 patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in 2 patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for 1 patient although her final height was below estimated target height.

Conclusions

Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.
Partial substitution of fish oil for linseed oil enhances beneficial fatty acids from rumen biohydrogenation but reduces ruminal fermentation and digestibility in growing goats
Authors: Thanh Lam Phuoc , Phakachoed Noppharat , Suksombat Wisitiporn , Loor Juan J , Hang Tran Thi Thuy
Published: July 2021

This study was performed to investigate effects of partial replacement of fish oil (FO) for linseed oil (LO) on digestibility, ruminal fermentation and biohydrogenation in growing goats. Experiment 1 was carried out in four growing male goats aged 6 months in a 4 × 4 Latin square design. Goats were fed a basal diet supplemented with 25 g/kg dry matter either LO alone or in combination with tuna FO. Treatments were developed by replacing FO for LO at ratios of 0, 5, 10 and 15 g/kg DM corresponding to FO-0, FO-5, FO-10 and FO-15, respectively. Experiment 2 was carried out in an in vitro incubation system including 12 fermenters with the same four treatments. Each fermenter consisted of 40 mL goat ruminal fluid, 160 mL warm buffer, 2 g mixed substrates, and 50 mg FO-0, FO-5, FO-10 or FO-15. Fish oil inclusion reduced (P < 0.05) digestibility and nitrogen retention in Experiment 1. Increasing doses of FO in the diet induced a strong drop (P < 0.001) in ruminal total volatile fatty acid (VFA) concentration and protozoa population at 3 h post incubation, but did not affect individual VFA proportions. Substitution of FO for LO decreased mean concentrations of C18:0 (P = 0.057), c-9,c-12 C18:2 and C18:3n-3 (P < 0.001), but increased (P < 0.001) C20:5n-3 and C22:6n-3. Feeding FO-10 enhanced formation of ruminal c-9,t-11 conjugated linoleic acid (CLA) concentration compared with FO-0. Overall, combined data suggest that to improve ruminal concentrations of C20:5n-3, C22:6n-3, and c-9,t-11 CLA for deposition in tissues or milk with minimal risk of affecting digestibility and ruminal fermentation, a dietary supplementation of 15 g/kg LO and 10 g/kg FO would be suitable.
Tolerance of 2-Benzoxazolinone and Interactions with Grass and Pine Hosts in a Population of Fusarium circinatum
Authors: Carter Jason W. , Gordon Thomas R.
Published: July 2021

Fusarium circinatum, the causal agent of pitch canker in pines and a cryptic endophyte of grasses, was examined for heritable variation in tolerance of the grass defense compound 2-benzoxazolinone (BOA). A diverse population of F. circinatum progeny was assayed for growth rate on potato dextrose agar amended with BOA. Matings were conducted to allow for selection of progeny with lower and higher tolerance of BOA. The results confirmed heritable variation in BOA tolerance in F. circinatum. A subset of differentially tolerant progeny was used for inoculations of growth chamber-grown Zea mays and greenhouse-grown Pinus radiata. No differences were detected in the rate of infection or extent of colonization of Z. mays inoculated with F. circinatum progeny differing in tolerance of BOA. Pitch canker symptoms in inoculated P. radiata trees showed that high BOA-tolerating isolates induced significantly longer lesion lengths than those induced by low BOA-tolerating isolates. Results from this study were consistent with the proposition that F. circinatum evolved from grass-colonizing ancestors and that pathogenicity to pine is a relatively recent evolutionary innovation.
Resistance to Phytophthora infestans Clonal Lineage US-23 in Potato Cultivars and Its Relationship with Early Blight Resistance and Tuber Yield
Authors: Xue Weiya , Haynes Kathleen G. , Qu Xinshun
Published: July 2021

Resistance to late blight caused by Phytophthora infestans clonal lineage US-23 in 217 old and modern potato cultivars was evaluated in field trials in 2016 and 2017 in Pennsylvania. Significant differences in resistance were found among these cultivars (P < 0.0001). Significant interaction between cultivars and environments was found (P < 0.0001). The values of relative area under the disease progress curve ranged from 0 to 0.5841 in 2016 and from 0 to 0.5469 in 2017. Broad-sense heritability of late blight resistance was estimated to be 0.91, with a 95% confidence interval of 0.88 to 0.93. Cluster analysis classified the cultivars into five groups: resistant, moderately resistant, intermediate, moderately susceptible, and susceptible. Thirty cultivars showing resistance and 32 cultivars showing moderate resistance were identified. The 217 cultivars were also evaluated for foliar maturity, tuber yield, and resistance to early blight caused by Alternaria solani. A few cultivars with late blight resistance independent of late maturity were found. Late blight resistance and early blight resistance were positively correlated, and 17 cultivars possessed resistance to both diseases. Yield trade-off associated with late blight resistance was not observed among the cultivars in the absence of disease pressure.
The Vulnerability of Bananas to Globally Emerging Disease Threats
Authors: Drenth André , Kema Gert
Published: July 2021

Banana cultivation has increased significantly over the last century to meet the growing demand for this popular fruit. Originating in Southeast Asia, bananas are now produced in >135 different countries in tropical and subtropical regions of the world. Most of this expansion of production is based on a single banana variety, Cavendish, which makes up almost all the export trade grown in large-scale monocultures and a large part of the local trade and represents >40% of all bananas grown globally. Over the last century several major diseases of the banana have emerged and widely expanded their geographic ranges. Cultivars within the Cavendish variety are highly susceptible to these diseases, including yellow Sigatoka, black leaf streak, Eumusae leaf spot, freckle, Fusarium wilt tropical race 4, banana bunchy top, and the bacterial wilts Moko, Xanthomonas wilt, and banana Blood disease. This review graphically illustrates the emergence and rapid intercontinental spread of these diseases and discusses several major disease epidemics in bananas. Evidently, the large-scale monoculture based on the single variety Cavendish has resulted in an extreme level of genetic vulnerability. The resistance to diversification in the Cavendish production chain and the lack of investment in genetics and plant breeding in the recent past means that currently limited genetic solutions are available to replace the Cavendish banana with a set of market acceptable resistant varieties from a range of different genetic backgrounds.
What Role Should Resistance Play in Training Health Professionals?
Authors: Ellaway Rachel H. , Wyatt Tasha R.
Published: July 2021

The role that resistance plays in medicine and medical education is ill-defined. Although physicians and students have been involved in protests related to the COVID-19 pandemic, structural racism, police brutality, and gender inequity, resistance has not been prominent in medical education’s discourses, and medical education has not supported students’ role and responsibility in developing professional approaches to resistance. While learners should not pick and choose what aspects of medical education they engage with, neither should their moral agency and integrity be compromised. To that end, the authors argue for professional resistance to become a part of medical education.

This article sets out a rationale for a more explicit and critical recognition of the role of resistance in medical education by exploring its conceptual basis, its place both in training and practice, and the ways in which medical education might more actively embrace and situate resistance as a core aspect of professional practice. The authors suggest different strategies that medical educators can employ to embrace resistance in medical education and propose a set of principles for resistance in medicine and medical education.

Embracing resistance as part of medical education requires a shift in attention away from training physicians solely to replicate and sustain existing systems and practices and toward developing their ability and responsibility to resist situations, structures, and acts that are oppressive, harmful, or unjust.
Understanding How Semantic Structures of Individuals With Drug Addiction Transform As a Key to Effective Psychotherapy
Authors: Garifullin Ramil R.
Published: July 2021

Objectives:

Semantic structures, sense-bearing elements, and values of a personality have been widely recognized as important factors in the treatment of patients with drug addiction. This research aims to enhance our understanding of transformations that occur in the system of values of drug-dependent patients, and to identify the values that need to be corrected during drug addiction psychotherapy.

Methods:

The values of 220 male patients with drug addiction aged between 20 and 60 years were studied by analyzing their verbal reactions and emotions expressed during conversations and by neurolinguistic programming.

Results:

The results of the statistical analysis showed that patients with drug addiction have basic values (learned during the normal life experience) that give way to values associated with the drug addiction experience, which is, however, simply gained and not lived through. Their system of values centers on drugs and drug intoxication.

In this research, drug addiction was viewed from the perspective of the semantic (sense-based) approach, which made it possible to develop some recommendations for effective psychotherapy of individuals with drug addiction based on their semantic structures.

Conclusion:

The psychotherapy of patients with drug addiction becomes effective when they are provided with a key value, that is, a value of their life experience, that is strong enough to replace the values of their drug-related experience.
Surgical Reduction of Spondylolisthesis During Lumbar Fusion
Authors: Lambrechts Mark J. , Barber Joshua A. , Beckett Nathan , Smith Caleb J. , Li Jinpu , Goldstein Christina L. , Leary Emily V. , Cook James L. , Choma Theodore J.
Published: July 2021

Study Design:

This was a retrospective cohort study.

Objective:

The objective of this study was to quantify the rates of complication following surgical treatment for symptomatic degenerative and isthmic spondylolisthesis and to examine the association between slip reduction and complication rates.

Summary of Background Data:

It is unclear if the degree of spondylolisthesis reduction during lumbar spine fusion in adults influences the rate of surgical complications.

Methods:

This is a retrospective cohort study of 1-level and 2-level adult fusion patients with degenerative or isthmic spondylolisthesis. The degree of reduction and complications were calculated, and complication rates between those with and without reduction were compared.

Results:

The surgical reduction was improved by 1 Meyerding grade in 56.5% of the 140 patients included in this analysis. Of those patients, 60% had a grade 1 spondylolisthesis. In addition, 62.5% of grade 2 slips had an improvement by 1 grade. Surgical reduction during lumbar fusion did not result in a higher rate of complications compared with in situ fusion.

Conclusions:

During 1-level or 2-level lumbar fusion for degenerative or isthmic spondylolisthesis, a 1-grade reduction of the slip was achieved in 56% of patients in this retrospective case series. Reduction of the spondylolisthesis was not associated with a higher rate of complication when compared with in situ fusion.

Level of Evidence:

Level IV.
BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells
Authors: Sanagawa Akimasa , Hotta Yuji , Mori Nanaka , Tomita Natsumi , Kataoka Tomoya , Tohkin Masahiro , Kimura Kazunori
Published: July 2021

Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91–3.69] and cobimetinib (ROR, 4.40; CI, 3.55–5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15–1.60) and trametinib (ROR, 1.32; CI, 1.11–1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.
Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study
Authors: Shi Qiong , Liu Lin , Zhang Weigang , Zhao Yanhong , Liu Yu , Zhu Guannan , Guo Weinan , Zhao Tao , Zhao Jianhong , Wang Lei , Li Chunying , Gao Tianwen
Published: July 2021

Recombinant human interferon-α1b (IFN-α1b) is the first genetic engineered drug of China and is approved for cancer treatment by Chinese Food and Drug Administration. Although recombinant IFN-α1b is biologically and therapeutically active, its long-term efficacy against advanced melanoma is unknown. Ninety patients who were diagnosed with stage IV melanoma and received recombinant IFN-α1b therapy in our department were included in this study. The safety and efficacy of IFN-α1b were analyzed. IFN-α1b was overall well tolerated, with only 7.8% of the patients showing grade 3 toxicity and none with grade 4 toxicity or treatment-related death. The most common adverse effect was fever (78.9%). Furthermore, increasing the drug dosage showed no increase in the incidence of adverse events. The median overall survival (mOS) of the cohort was 14.1 months (95% confidence interval, 11.3–16.9 months). There was no significant difference of the mOS between samples of various primary sites. In the 42 patients who had not received prior adjuvant interferon therapy, the objective response rate, disease control rate and clinical benefit rate were 7.1, 28.5 and 21.4%, respectively. Our findings suggest that systemic IFN-α1b treatment is a relatively safe therapy and could prolong the survival of patients with unresectable metastatic melanoma.
Effective treatment of a BRAF V600E-mutant epithelioid glioblastoma patient by vemurafenib: a case report
Authors: Lin Zhiying , Xu Haiyan , Yang Runwei , Li Zhiyong , Zheng Haojie , Zhang Zhu , Peng Junxiang , Zhang Xian , Qi Songtao , Liu Yawei , Huang Guanglong
Published: July 2021

Epithelioid glioblastoma (E-GBM) is a recently described variant of glioblastoma (GBM) which is associated with short survival and now added as a provisional entity to WHO 2016 classification of central nervous system tumors. About half of these tumors show the BRAF mutant. Therefore, this is a target of special interest for this group of patients. Meanwhile, unlike conventional glioblastoma, E-GBM lacks specific prognostic markers. We described a case of a long-term surviving 37-years-old men patient diagnosed with a BRAF V600E and TERT mutated E-GBM with wild-type in the isocitrate dehydrogenase gene (IDH wild-type). The tumor displayed atypical exophytic growth, an obvious proliferation of vascular endothelial cells, especially tumor tissue can be seen under subarachnoid space. Notably, tumor tissue was found under subarachnoid space. After postoperative conventional treatment options were exhausted, vemurafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images were consistent with stable disease for the following fifteen months up to now. Whole-exome sequencing analysis and RNA-seq results of formalin-fixed and paraffin-embedded tissue revealed nine mutant genes (AHNAK2, BFSP1, BRAF, CNTNAP3, DNHD1, MTOR, NFATC3, NOM1). For E-GBM patients, the use of BRAF inhibitors combined with inhibitors of these seven genes may be a useful remedial treatment option.
Stromal α-Smooth Muscle Actin Positivity Is Associated With High-Risk Basal Cell Carcinomas
Authors: Krum dos Santos Ana Carolina , Lima Darlan , Marchiori Bakos Renato , da Silva Cartell André , Rangel Bonamigo Renan
Published: July 2021

The presence of myofibroblast differentiation has been proposed as an invading mechanism in basal cell carcinomas. However, small studies regarding α-smooth muscle actin positivity have led to conflicting results. This review of 100 cases examines the association between α-smooth muscle actin positivity on immunohistochemical studies and the clinical and histopathological characteristics of the tumor, including tumor size, thickness, subtype, topography, ulceration, 5-year recurrence rate, and age at diagnosis.
Follicular T-Helper Cells in Marginal Zone Lymphoma: Evidence of an Organoid Immune Response
Authors: Robson Alistair , Bakr Farrah , Rashidghamat Ellie , Willsmore Zena N. , Ally Mina , Greenblatt Danielle , Barlow Richard , Wain E. Mary , Child Fiona , Esdaile Ben , Kempf Werner
Published: July 2021

Introduction:

Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated.

Methods:

Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls.

Results:

All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes.

Conclusion:

MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.