bluuebunny/crossref_metadata_2025 huggingface dataset:
Powerful and interpretable control of false discoveries in two-group differential expression studies
Authors: Enjalbert-Courrech Nicolas , Neuvial Pierre
Published: October 2022

Motivation

The standard approach for statistical inference in differential expression (DE) analyses is to control the false discovery rate (FDR). However, controlling the FDR does not in fact imply that the proportion of false discoveries is upper bounded. Moreover, no statistical guarantee can be given on subsets of genes selected by FDR thresholding. These known limitations are overcome by post hoc inference, which provides guarantees of the number of proportion of false discoveries among arbitrary gene selections. However, post hoc inference methods are not yet widely used for DE studies.

Results

In this article, we demonstrate the relevance and illustrate the performance of adaptive interpolation-based post hoc methods for two-group DE studies. First, we formalize the use of permutation-based methods to obtain sharp confidence bounds that are adaptive to the dependence between genes. Then, we introduce a generic linear time algorithm for computing post hoc bounds, making these bounds applicable to large-scale two-group DE studies. The use of the resulting Adaptive Simes bound is illustrated on a RNA sequencing study. Comprehensive numerical experiments based on real microarray and RNA sequencing data demonstrate the statistical performance of the method.

Availability and implementation

A cross-platform open source implementation within the R package sanssouci is available at https://sanssouci-org.github.io/sanssouci/.

Supplementary information

Supplementary data are available at Bioinformatics online.
Update: Assessing the evolutionary trajectory of the Apaporis caiman (Caiman crocodilus apaporiensis, Medem 1955) via mitochondrial molecular markers
Authors: Balaguera-Reina Sergio A , Angulo-Bedoya Mónica , Moncada-Jimenez Juan F , Webster Mark , Roberto Igor J , Mazzotti Frank J
Published: October 2022

The spectacled caiman (Caiman crocodilus) is currently considered to be a species complex due to the relatively high morphological and molecular diversity expressed across its range. One of the populations of interest, inhabiting the Apaporis River (Colombia), was described based on skull features as an incipient species (C. c. apaporiensis) and has been treated by some authors as a full species. Recent molecular work challenged this hypothesis, because relatively low mitochondrial molecular differentiation was found between the morphologically described Apaporis caiman and C. crocodilus (s.s.) Amazonian populations. Here, we present an update on the topic based on a larger molecular sample size and on analysis of expanded geometric morphometric data that include six newly collected skulls. Morphometric data support the existence of previously recognized morphotypes within the complex in Colombia and demonstrate that the newly collected material can be assigned to the classic Apaporis caiman morphotype. However, our expanded genetic analysis fails to find appreciable mitochondrial molecular divergence of the Apaporis caiman population from the C. c. crocodilus population (COI-CytB: Amazon Peru 0.17 ± 0.06%, CytB-only: Caquetá River Colombia 0.08 ± 0.07%). The Apaporis caiman is interpreted to be a phenotypically distinct member of the cis-Andean C. crocodilus metapopulation that has not yet achieved (or may not be undergoing at all) appreciable genetic differentiation. Thus, it should not be considered a fully independent evolutionary lineage, nor given full species rank.
Biotic and abiotic factors in promoting the starting point of hybridization in the Neotropical flora: implications for conservation in a changing world
Authors: Turchetto Caroline , Segatto Ana Lúcia A , Turchetto-Zolet Andreia C
Published: October 2022

Coevolution between floral traits and specific pollination behaviour is a significant evolutionary force in angiosperm diversification. However, hybridization is also reported to occur between plants with specialist pollination syndromes. Understanding the role of pollinators in plant diversification is crucial, especially in megadiverse regions, such as the Neotropics. In this review, we examine plant hybridization studies in the Neotropics with the aim of providing a perspective on biotic and abiotic factors starting hybrid zone formation. The Pleistocene was the most widely cited time for the occurrence of hybridization facilitated by geographical range shifts, but time-calibrated analyses are needed to recover a more realistic scenario. Our synthesis of hybridization and pollination systems suggested that specialist and generalist pollinators were associated with the starting point of hybridization in the Neotropical flora. Bees and hummingbirds are most likely to be the primary vectors of interspecific gene flow, and even sporadic visits by bees or other generalist pollinators could allow the formation of a new hybrid zone. We highlight that seed and pollen dispersal vectors should be included in an integrative discussion on hybridization in the Neotropical flora. We also provide a preliminary map of hybrid zones in the Neotropics, including Brazilian vegetation cover and losses in the last 30 years, with the aim of encouraging research into human-driven anthropogenic changes and formation and/or shift of hybrid zones through time.
Oral Presentation No. 32 The interplay between VWF, ADAMTS13 and TSP1, and their relation to clinical endpoints
Authors: Warlo Ellen Mathea Kirsch , Kalstad Are A , Myhre Peder L , Solheim Svein , Arnesen Harald , Tveit Arnljot , Seljeflot Ingebjørg , Bratseth Vibeke
Published: October 2022

Introduction

ADAMTS13 cleaves von Willebrand Factor (VWF) into less active fragments. TSP1 binds to VWFs cleavage-site, protecting it from degradation. Low ADAMTS13 and high VWF have been associated with cardiovascular disease (CVD) and atrial fibrillation (AF).

We aimed to investigate the interplay between VWF, ADAMTS13 and TSP1, and assess any relation to endpoints.

Materials and methods

1027 elderly with a recent myocardial infarction (MI) were followed for 2 years. ADAMTS13 antigen (ag) and activity (act), VWF ag and TSP1 were analyzed. The primary endpoint (MACE; n = 210) included MI, stroke, heart failure hospitalization, coronary revascularization and death. The secondary endpoint was new-onset AF (n = 43).

Results

ADAMTS13 ag and act were weakly correlated to VWF (r = 0.10, P = 0.002, both). TSP1 did not correlate to ADAMTS13 or VWF. Patients experiencing a MACE had higher VWF and lower ADAMTS13(ag) at baseline (P < 0.012, both), however not significant after adjusting for covariates. The association with MACE was mainly driven by death (n = 40), with an adjusted OR 2.4 (P = 0.008) for VWF Q4 vs. Q1-3 and OR 0.4 (P = 0.012) for ADAMTS13(ag) Q1 vs. Q2-4. VWF was lower (1.25 vs. 1.39 IU/mL, P = 0.008) and VWF/ADAMTS13(ag)-ratio was lower (1.81 vs. 2.05 x10−3, P = 0.009) in patients with new-onset AF, and these associations persisted in adjusted models.

Conclusion

In elderly patients with a recent MI, levels of VWF, ADAMTS13 and TSP1 did not correlate. ADAMTS13 and VWF associated weakly with MACE, mainly driven by death. Low VWF and VWF/ADAMTS13-ratio were associated with new-onset AF in our population and needs further research.
Poster No. 031 Anti-inflammatory potential of cannabinoid extracts
Authors: Maly Martin , Viktorová Jitka , Ruml Tomáš , Stránská Milena
Published: October 2022

Inflammation plays a substantial role in the process of atherosclerosis. The key players are monocytes transformed to macrophages. Limited experience with anti-inflammatory drugs is described – antibodies for IL-1 (CANTOS) and colchicine (COLCOT, LoDoCo-2 trial). Cannabis extracts are known to have profound anti-inflammatory effect in diseases associated with chronic inflammation, e.g. rheumatoid arthritis. Human monocytic cell line THP-1 was differentiated into macrophages by incubation in the presence of phorbol-12-myristate-13-acetate, which leads to a macrophage-like phenotype characterized by changes in morphology and adhesion. Macrophages were polarized toward M1 pro-inflammatory phenotype responsible for production of several cytokines, esp. TNFα and IL-6.The ability of cannabinoids to decrease production of pro-inflammatory cytokines in polarized macrophages was measured by ELISA. The viability of macrophages after the treatment was verified by resazurin assay., Cannabigerol (CBG) and cannabidiol (CBD) significantly decreased the production of TNFα in dose-dependent manner. 7.5 mg/L of CBG and 1 mg/L of CBD decreased the production of TNFα by 32 and 34%, respectively. CBD, cannabidivarin (CBDV), cannabichromene (CBC), and cannabinol (CBN) significantly decreased also IL-6 production. 7.5 mg/L of CBDV and CBC decreased the production of IL-6 by 38 and 62%, respectively. 2 mg/L of CBD and CBN decreased the production of IL-6 by 33% (both).The concentration of the most potent cannabinoid (CBC) inhibiting IL-6 production by half (IC50) was determined to be 6.7 ± 0.1 mg/L, which is two-times better treatment potential than colchicine (13.4 ± 0.8 mg/L). Cannabinoids might be promising substance in the treatment of subclinical inflammation associated with atherosclerosis.

The project was funded by the Grant No 22–20860S of The Czech Science Foundation.
Oral Presentation No. 068 Plasma fibrinogen independently predicts hypofibrinolysis in severe COVID-19
Authors: Schrick Diana , Tokés-Füzesi Margit , Réger Barbara , Molnár Tihamér
Published: October 2022

High rates of thrombosis are present in patients with SARS-CoV-2 infection. Deeper insight into the prothrombotic state is essential to provide the best thromboprophylaxis care. We aimed to explore associations among platelet indices, conventional hemostasis parameters, and viscoelastometry data.

21 patients with severe COVID-19 and 21 age-matched controls were enrolled. Each patient received 100 mg aspirin therapy at the time of blood sampling. To monitor the aspirin therapy, a platelet function test from hirudin anticoagulated whole blood was performed using the ASPI test by Multiplate analyser. High on-aspirin platelet reactivity (n = 8) was defined with an AUC > 40 cut-off value by ASPI tests. Furthermore, vitro viscoelastometric tests were carried out using a ClotPro analyser in COVID-associated thromboembolic events nor the survival rate showed significant associations with high on-aspirin platelet reactivity status.

Patients presented with higher levels of inflammatory markers, along with evidence of hypercoagulability by ClotPro. H-IPF (%) was significantly higher among non-survivors (n = 18) compared to survivors (P = 0.011), and a negative correlation (P = 0.002) was found between H-IPF and plasminogen level in the total population. The platelet count was significantly higher among patients with high on-aspirin platelet reactivity (P = 0.03). ECA-A10 (P = 0.008), and ECA-MCF (P = 0.016) were significantly higher, while the tPA-CFT (P < 0.001) was significantly lower among patients with high on-aspirin platelet reactivity. However, only fibrinogen proved to be an independent predictor of hypofibrinolysis in severe COVID-19 patients.

Surprisingly, a faster developing, more solid clot formation was observed in aspirin taking COVID-19 patients. In conclusion, an individually tailored thromboprophylaxis is needed to prevent thrombotic complications, particularly in the hypofibrinolytic cluster.
Poster No. 103 Spontaneous coronary artery dissection: when pain and ST-segment elevation persist
Authors: Lopes Rafaela G , Cruz Isabel , Oliveira Inês Pereira , Bragança Bruno , Campos Inês G , Monteiro Joel Ponte , Almeida Carla , Castro Alexandra , Andrade Aurora
Published: October 2022

A 44-year-old female with nonrelevant medical history was admitted due to chest pain. She was hemodynamically stable. Normal physical examination. ECG with ST-segment depression in the inferior leads. Echocardiogram had no contractility abnormalities. High-sensitivity troponin I (hsTnI) of 164.4 pg/mL. Non-ST-segment elevation myocardial infarction (NSTEMI) diagnosis was made. 12 hours later she developed refractory chest pain. Emergent coronariography depicted independent ostia for the anterior descending and circumflex arteries and type 1 spontaneous coronary artery dissection (SCAD) of the circumflex artery. During angiography, pain subsided and a conservative approach was adopted. An hour later, she had recurrent pain refractory to medical treatment and new onset of persistent ST-segment elevation in leads V4-V6. It was decided to perform percutaneous coronary intervention and a drug eluting stent was placed in the proximal circumflex artery. There was distal propagation of the parietal hematoma, but TIMI 3 flow was restored. She was discharged on day 6. 5 days later she was readmitted due to NSTEMI. She had recurrent episodes of chest pain followed by reelevation of hsTnI. Coronary computer tomography depicted distal progression of the dissection with involvement of a first obtuse marginal and distal circumflex. After uptitration of anti-ischemic medication she was discharged. The case underlines the challenging and non-linear approach of SCAD in the setting persistent chest pain. Besides the technical difficulties of angioplasty, with higher risk of restenosis and stent failure, most recommendations support a conservative approach. However, persistent chest pain imply further action, as exemplified in this case report.
Poster No. 109 Prognostic value of white blood cell count variation during in-hospital stay in STEMI patients: Insights from SCALIM Registry
Authors: Boukhris Marouane , Molié Camille Dierx , Chenard Pierre , Gourceyrol Amandine , Gasnier Amandine , Virot Patrice , Aboyans Victor
Published: October 2022

Background

In patients with ST-elevation myocardial infarction (STEMI), white blood cell count (WBCC) is associated with infarct size and cardiovascular outcome. We sought to determine the impact of WBBC variation (?WBCC) during in-hospital stay on long-term outcome after STEMI.

Methods

From 2011 to 2019, consecutive patients with STEMI were enrolled. Those with at least two WBCC during hospitalization were included in this study. ?WBCC was calculated as: [WBCC (admission) – WBCC (before discharge)]. The population was divided into 3 groups according to ?WBCC tertiles. The primary outcome was total mortality.

Results

A total of 1778 patients (mean age 64.5 ± 14.1, 75.7% males), were included and divided in 3 groups: Group 1 (?WBCC < 0.85 103/mm3); Group 2 (?WBCC 0.85–3.31 103/mm3); and Group 3 (?WBCC > 3.31 103/mm3). Patients in Group 1 were the oldest (67.9 ± 13.8, vs. 65.1 ± 13.9 and 60.5 ± 13.7 years in Groups 2 and 3 respectively, P < 0.001). Hypertension, prior coronary artery bypass and cancer were more prevalent in Groups 1 and 2. Troponin peak was the highest in Group 3 (3601 ± 563) than Group 2 and 3 (2810 ± 439 and 2451 ± 467 ng/ml, respectively; P < 0.001).

Five-year survival was the lowest in Group 1 (78.6% vs. 87.2% and 87.5% in Group 2 and 3, respectively; P < 0.001). Adjusted to age, gender, cardiovascular risk factors, MI territory and left ventricular ejection fraction, ?WBCC < 0.85. 103/mm3 was independently associated with all-cause mortality [HR 1.46; 95%CI 1.12–1.91; P = 0.005].

Conclusion

?WBCC < 850/mm3 Is associated with increased mortality. Low ?WBCC during hospitalization could represent an interesting prognostic tool in STEMI patients.
Oral Presentation No. 125 Relation of non-invasively measured ankle-brachial index and pulse-wave velocity towards all-cause mortality in unselected emergency department patients - a prospective cross-sectional study
Authors: Schnaubelt Sebastian , Eibensteiner Felix , Oppenauer Julia , Domanovits Hans , Schlager Oliver
Published: October 2022

Background

Increased pulse-wave velocity (PWV) and decreased ankle-brachial index (ABI) are related to an increased risk of all-cause- as well as cardiovascular mortality. Aim of this study was to assess the predictive value of PWV and ABI in an emergence department (ED) setting.

Methods

We assessed ABI-, brachial-ankle (ba) PWV-, and carotid-femoral (cf) PWV in patients presenting to a high-volume tertiary care ED. Primary outcome was all-cause mortality in the long-term follow-up of these patients, which was evaluated via Austria´s federal statistical office.

Results

We included 1,041 patients (60 ± 17 years; 56.6% males) with various chief complaints (e.g., chest pain, dyspnea, atrial fibrillation). ABI and cfPWV could be measured in 952 (91.5) and 910 (87.4%), respectively. Values of ABI (1.03 ± 0.13) and cfPWV (10.1 ± 2.9 m/s) were found to be pathological in 13.4% and 44.8%, respectively. Median follow-up time was 540 [344–877] days. During this observational period, 8.1% of patients had died; the majority of deaths was classified as cardiovascular events. Overall mortality differed significantly between patients with pathological ABI or elevated cfPWV (P < 0.001) compared with those patients without pathological alterations. Even after multivariate cox-proportional hazard analysis (including age(-groups), sex, BMI and comorbidities), a pathological ABI (HR 0.07 [0.01–0.56], P = 0.01) and cfPWV (HR 1.13 [1.04–1.23], P = 0.003) were associated with overall mortality risk.

Conclusion

In unselected ED patients a pathological ABI or PWV are independent predictors for long-term mortality and may be used as an additional risk stratification tool in the emergency setting.
Poster No. 128 Association of platelet markers with occurrence of thromboembolic and bleeding events following left atrial appendage occlusion
Authors: Aarnink Errol , Rocca Domenico G Della , Cepas Pedro L , Polzin Amin , Branca Luca , Spoon Daniel , Freixa Xavier , Boersma Lucas V A
Published: October 2022

Background

Patients undergoing left atrial appendage occlusion (LAAO) often are at increased risk for bleeding or thromboembolic events. In most implanting centers, baseline blood is drawn as a pre-procedural check-up. However, it is unknown what laboratory parameters have added value in this specific population. Platelet count (PLC) and mean platelet volume (MPV) may identify which patients are at risk for thromboembolic events or bleeding.

Materials and methods

Five implanting centers retrospectively gathered data on pre-procedural platelet markers. Composite endpoints on thromboembolic events (stroke, transient ischemic attack, device-related thrombus and systemic embolism) and bleeding (minor, major, and intracranial hemorrhage) were collected.

Results and conclusions

A total of 1138 patients were included (73 ± 8 years, 63% male, CHA2DS2-VASc: 4.4 ± 1.5; HAS-BLED: 3.2 ± 1.1). Implanted devices consisted of Watchman 2.5/FLX (n = 778), Amplatzer Cardiac Plug/AMULET (n = 315), or another device (n = 45). Baseline PLC was present in 91% and MPV in 41%. PLC was significantly lower in the 97 patients developing a thromboembolic event (206 ± 73 vs. 225 ± 72*10*9/L, P = 0.028), but no difference in MPV was observed (9.7 ± 1.4 vs. 9.5 ± 1.5 fL, P = 0.40). In another 97 patients, significant bleeding was observed during follow-up. No difference in baseline PLC was found (216 ± 79 vs. 207 ± 72*10^9/L, P = 0.30) and a trend towards lower MPV could be observed (9.5 ± 1.3 vs. 9.8 ± 1.5 fL, P = 0.07). Patients developing bleeding more often were discharged with antiplatelet therapy, while patients developing a thromboembolic event more often received anticoagulation therapy. In conclusion, occurrence of a thromboembolic event was associated with lower baseline PLC, which may be explained by PLC being lower in more frail patients.
Poster No. 132 HTAD PATIENT PATHWAY: Strategy for diagnostic work-up of patients and families with (suspected) Heritable Thoracic Aortic Diseases (HTAD). A statement from the HTAD Working Group of VASCERN
Authors: de Backer Julie , Caruana Maryanne , Baars Marieke , Bashiardes Evi , Benke Kalman , Bjorck Erik , Codreanu Andrei , de Moya Rubio Elena , Dumfarth Julia , Evangelista Arturo , Groenink Maarten , Kallenbach Klaus , Kempers Marlies , Keravnu Anna , Loeys Bart , Mosquera Laura Muino , Nagi Edit , Nistri Stefano , Pepe Guglielmina , Hesselink Jolien Roos , Szabolcs Zoltan , Teixido Gisela , Timmermans Janneke , Van de Laar Ingrid , Van Kimmenade Roland , Verstraeten Aline , Von Kodolitsch Yskert , Jondeau Guillaume
Published: October 2022

Background

Timely diagnosis of patients with Heritable Thoracic Aortic Diseases (HTAD) is essential to avoid (often fatal) aortic dissection. Experts of the HTAD rare disease working group of the European Reference Network of Rare Vascular diseases (vascern) aimed to propose a pathway to: (1) improve patient care by diminishing time to diagnosis; (2) facilitate the establishment of a correct diagnosis, using molecular genetics when possible, which may lead to a more personalized treatment; (3) exclude the diagnosis in unaffected persons (family screening); (4) avoid overuse of financial and personnel resources.

Material and methods

This pathway is a consensus at expert level. It was generated based on available guidelines when possible. Discussion items were listed and, where necessary, items were included in a questionnaire sent out for voting and discussion over monthly teleconference calls.

Results and conclusions

Pathway Elements include Thoracic aortic aneurysm – and dissection, Bicuspid Aortic Valve, Medium-sized artery aneurysms/dissection, Extravascular features and Family History. Recommendations for the evaluation of patients and family members are provided.

This pathway is advised to implement standardisation of diagnostic workup and follow-up of patients with suspected HTAD and the screening of their relatives and it focuses on patients with heritable aortic diseases whether syndromic or not. It is subject to adjustment with better recognition of new entities, and with the technical progress and increased availability of genetic testing.
Poster No. 135 Stroke risk of patients with new AF during ACS may depend on onset and duration
Authors: Bor Wilbert , Azzahhafi J , di Maio N , Van Der Sangen N M R , Rayhi S , Peper J , Ten Berg J M
Published: October 2022

Background/rationale

Newly diagnosed atrial fibrillation(AF) during acute coronary syndrome(ACS) is associated with worse outcomes. In this study we evaluated the associated stroke risk of newly diagnosed AF in ACS patients according to the onset and duration of the episode.

Results

Amongst 4433 patients presenting with ACS, 439(9.9%) had newly diagnosed AF and 396(8.9%) had known AF. Of the new AF cases, 27.5% occurred post-CABG. The onset was within 24 hours of ACS presentation in 70.1% of non-CABG cases. The new AF episodes lasted longer than 24 hours in42.9% of the non-CABG cases. At discharge 54.0% of patients with new AF was treated with OAC, in contrast to 89.2% with known AF.

The incidence of ischemic stroke at one year was 1.2% in patients without AF, 1.0% with known AF, and 3.6% with new AF(P < 0.001). Within patients developing AF post-CABG, the incidence was 4/120(3.3%). Within non-CABG patients, the incidence of ischemic stroke for patients with onset within 24 hours of presentation was 0/133(0.0%) for patients with an episode lasting < 24 hours, and 6/109(5.5%) for patients with an episode lasting > 24 hours. For patients with new AF onset after 24 hours the incidence was 5/120(5.5%) for patients with an episode lasting < 24 hours, and 5/92(5.4%) for patients with an episode lasting > 24 hours.

Conclusion

Patients with newly diagnosed AF during ACS seem undertreated with OAC. The associated risk of ischemic stroke with new AF during ACS may be lower in episodes that terminate within the first 24 hours of presentation.
Poster No. 137 A very evident pulmonary thrombus
Authors: Coelho Catarina Gonçalves , Saraiva Mariana , Luís Joana , Mendes Sofia Lázaro , Pitta Maria Luz , Martins Vítor Paulo
Published: October 2022

Clinical case

Female patient, 78 years-old, that complained of epigastric pain and intense fatigue for a week. While waiting in the urgency department, she became hypotensive, with refractory shock. Electrocardiogram showed sinus rhythm, 90 bpm, de novo right bundle block and infraST in the right precordial leads. The echocardiogram showed a dilated right ventricle (ratio RV/LV > 1), with depressed function and major tricuspid regurgitation, RV/RA gradient of at least 55 mmHg. Left ventricle presented “D-shape”, preserved function and no segmental kinetic changes. The pulmonary artery was dilated and a serpentiform mass was visible, protruding through the pulmonary valve; similar masses were also visible in its branches. The diagnosis of pulmonary embolism (PE) was assumed and fibrinolysis was started, given there were no contra-indications.

One year before, she had an intermediate-risk PE in the context of COVID-19, with a similar echocardiographic presentation. She recovered RV function in the following months and stopped anticoagulation 3 months after that episode.

Discussion

PE can present with varying degrees of severity. Bedside echocardiography can be of major help in its diagnosis, especially in critical patients. The visualization of a thrombus in the pulmonary artery is rare, particularly in transthoracic echocardiogram. Echocardiogram is also useful for risk stratification and prognostic evaluation. This patient developed obstructive shock due to massive PE and the fibrinolytic treatment was paramount for her survival. A good echocardiogram helped in the differential diagnosis and enabled the Cardiologist to assist the patient in the best way.
Clinical Case 20—Recurrent intracoronary in-stent restenosis in a young woman
Authors: Cabral Margarida , Carvalho Mariana , Fernandes Sara , Carvalho Rita , Teixeira Tiago , Ruivo Catarina , de Sousa Pedro Jerónimo , Antunes Alexandre , Morais João
Published: October 2022

Clinical case

A 39-year-old smoker woman underwent a percutaneous coronary intervention with two Zotarolimus-eluting stents implantation due to right coronary artery occlusion in the context of ST-elevation myocardial infarction (MI). She was medicated with dual antiplatelet therapy and high-intensity statin and stopped smoking.

Nine months later, due to angina symptoms, cardiac catheterization with intravascular ultrasound showed severe restenosis, treated with a drug-coated balloon (DCB).

Two months later, she was admitted due to non-ST elevation MI and the cardiac catheterization presented thrombotic occlusion of previously implanted stents, treated with balloon dilatation. After two months, she remained with angina and a dobutamine stress echocardiogram showed inferior wall ischemia. The angiographic revision revealed proximal in-stent restenosis, treated with DCB.

About a year later, a fifth coronary angiography was performed due to recurrence of angina. Diffuse in-stent restenosis by neo-atherosclerosis was identified by optical coherence tomography. The lesion was treated with a cutting balloon and Everolimus-eluting stent implantation. The cholesterol-lowering treatment was optimized and the patient remained stable for some months. However, she is currently reporting recurrence of angina. Clinical management and guidance await Heart Team discussion.

Learning points
When the patient is making the (wrong?) diagnosis: a biographical approach to patients consulting for presumed Lyme disease
Authors: Lutaud Romain , Verger Pierre , Peretti-Watel Patrick , Eldin Carole
Published: October 2022

Background

Media coverage of Lyme disease (LD) has led to an increase in consultations for presumed LD in Europe. However, LD is confirmed in only 10%–20% of patients, with a significant number remaining in a diagnostic dead-end.

Objectives

To reach a deeper understanding of how patients themselves contribute to the diagnostic process. To describe the genesis of the LD hypothesis in care pathways.

Methods

In 2019, 30 patients from a prospective cohort consulting in the infectious diseases department at University Hospital in Marseille for presumed LD were recruited for semistructured interviews. The inclusion criteria were: suffering from subjective symptoms for 6 months, no clinical or paraclinical argument suggesting current LD. The patients’ medical trajectories were collected using a biographical approach.

Results

The diagnosis of LD was primarily triggered by identification with personal testimonies found on the Internet. Most of patients were leading their own diagnostic investigation. The majority of participants were convinced they had LD despite the lack of medical evidence and the scepticism of their referring GP.

Conclusion

GPs should first systematically explore patients’ aetiologic representations in order to improve adherence to the diagnosis especially in the management of medically unexplained symptoms. Long COVID-19 syndrome challenge offers an opportunity to promote active patient involvement in diagnosis.
8. Infringement
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter considers the question of what amounts to copyright infringement, first by differentiating between ‘primary’ infringement and ‘secondary’ infringement. It then explains the three criteria used to determine whether copyright in a work has been infringed: whether the defendant carried out one of the activities that falls within the copyright owner’s rights; whether there is a causal link between the work used (that is, reproduced, issued, rented, performed, communicated, or adapted) by the defendant and the copyright work; and whether the restricted act has been committed in relation to the work or a substantial part thereof. It also looks at the European approach to finding infringement (following the Infopaq decision) and compares it with the British approach before concluding with a description of non-literal copying of such works.
11. Exploitation and Use of Copyright
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter examines the ways in which copyright can be exploited or transferred, with emphasis on the two most important forms of exploitation: assignment and licensing. It also discusses the transfer of copyright in the case of mortgages, bankruptcy, or death, as well as situations in which compulsory licences and voluntary licences are used to exploit copyright. In addition, the chapter considers testamentary dispositions, techniques for exploiting works that rely on the use of technological protection measures, and the role of collecting societies in copyright exploitation.
16. Procedure for Grant of a Patent
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter explains the processes involved in granting patents as well as the factors that applicants must take into account when deciding whether to patent an invention in the UK. The role of patent agents and the choice of route to take to secure grant of the patent are considered. The chapter then documents the procedures in the application for a patent, paying particular attention to some of the key features of the UK and European Patent Office patent application processes together with the Patent Cooperation Treaty. It also describes situations in which applicants and patentees are able to amend their applications and the restrictions under which such amendments operate. Finally, it looks at a number of proposals to reform the patent procedure.
26. Subject Matter: The Requirement that there be a Design
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter considers the requirements for a design to be protected, with particular reference to the requirement that there be a design. It begins by outlining the requirements for validity before turning to the definition of ‘design’ with respect to registered designs in the UK as well as unregistered designs, citing three key elements of this definition: appearance, features, and product. It also examines three types of design that are excluded from the very broad definition of design: designs dictated solely by technical function; designs for products that must be produced in a specific way to enable them to connect to another product; and designs that are contrary to morality or public policy.
31. Introduction to Passing Off and Trade Marks
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter introduces the common law of passing off and the statutory regime that protects registered trade marks found in the Trade Marks Act 1994. It commences with a brief history of trade marks and the development of their legal protection. This is followed by a discussion of the ways in which legal protection of signs and symbols are justified. It then considers the international and regional background that informs and constrains the law on trade marks in the UK, with particular reference to registration and the harmonization of standards. The chapter concludes by looking at challenges posed to trade marks by electronic commerce and the use of trade marks as domain names, as well as recent developments in artificial intelligence which will impact this field.
36. Subject Matter
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter discusses three requirements that a sign must satisfy to be validly registered or, if it is already registered, to ensure that it is not subsequently declared invalid: there is a sign; the sign can be represented adequately; and the sign must be capable of distinguishing the goods or services of one undertaking from those of other undertakings. The chapter also considers specific policy-based limits on the registration of shapes or other characteristics of products, in the form of three ‘functionality’ exclusions. It also briefly outlines certification and collective marks.
41. Trade Mark Defences
Authors: Bently L. , Sherman B. , Gangjee D. , Johnson P.
Published: October 2022

This chapter is about the various defences that are available to a person who has been accused of infringing a trade mark under the Trade Marks Act 1994. A prominent limitation on the scope of protection, which operates defensively, is whether the defendant has made a legally relevant use of the mark. Besides this, the defendant is excused if the mark has been used (i) as the defendant’s own personal name or address, (ii) for descriptive purposes, or (iii) to indicate the intended purpose of a product or service. These three uses are subject to a proviso testing for whether the use has been in accordance with honest practices in industrial and commercial matters. Additional defences facilitate comparative advertising and permit parallel importation via the exhaustion of the trade mark owner’s rights upon first sale. The chapter concludes by considering how expressive interests and the freedom of expression are balanced against trade mark rights. It also reviews the defence of honest concurrent use.
Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance
Authors: Copier Jaël S , Bootsma Marianne , Ng Chai A , Wilde Arthur A M , Bertels Robin A , Bikker Hennie , Christiaans Imke , van der Crabben Saskia N , Hol Janna A , Koopmann Tamara T , Knijnenburg Jeroen , Lommerse Aafke A J , van der Smagt Jasper J , Bezzina Connie R , Vandenberg Jamie I , Verkerk Arie O , Barge-Schaapveld Daniela Q C M , Lodder Elisabeth M
Published: October 2022

Background: Variants in KCNH2, encoding the human ether a-go-go (hERG) channel that is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to long QT syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods: A genotype–phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual-, and automated calibrated patch clamp. HEK293a cells expressing (i) wild-type (WT) KCNH2, (ii) KCNH2-p.S906L alone (homozygous, Hm) or (iii) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz) were used for manual patching. Automated patch clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. Results: Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2 or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch clamp showed a reduced current density by 69.8 and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared with KCNH2-WT. Assessment of KCNH2-p.S906L-Hz by calibrated automatic patch clamp assay showed a reduction in current density by 35.6%. Conclusion: The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.
Variability in straying behaviour among repeat spawning anadromous brown trout (Salmo trutta) followed over several years
Authors: Källo Kristi , Baktoft Henrik , Birnie-Gauvin Kim , Aarestrup Kim
Published: October 2022

Natal homing, a strategy in which individuals return to breed in the same river as they were born, is prevalent among salmonids. However, some individuals may not return to their natal river, and instead stray to non-natal rivers. To date, there is limited documentation on patterns of straying among iteroparous salmonids that have returned to spawn over multiple years. In this study, 21538 out-migrating juvenile anadromous brown trout (Salmo trutta L.) were tagged over two years with passive integrated transponder (PIT) tags, and followed as they returned to either their natal or three non-natal rivers in a fjord system, over multiple years. In total, 206 individuals were detected returning for more than one year, of which 43% were strayers. A divergence in migratory strategies among strayers was documented: a smaller proportion of strayers were only detected in non-natal rivers, while the majority (67%) displayed high variability in their migratory patterns as they were detected in both their natal and non-natal rivers, sometimes within the same reproductive season. This study documents high variability in the migratory patterns of repeat spawners and high probability for them to stray, and suggests that straying is an important life-history strategy possibly affecting individual fitness.
Retrograde type A aortic dissection: a different evil
Authors: Lopez-Marco Ana , Adams Benjamin , Oo Aung Ye
Published: October 2022

Retrograde type A aortic dissection (RTAAD) can be spontaneous or secondary to the instrumentation of the descending and thoraco-abdominal aorta. It has anatomical differences compared to antegrade type A aortic dissection that impact the management and prognosis. Treatment is not standardized. We report our approach to spontaneous RTAAD in our institution between 2018 and 2022 (n = 15). The mean age was 60.1 years and 93% were male. Aortic valve, coronary arteries and supra-aortic trunks were spared by the dissection in 80% of the cases; distal extension to iliacs was common and lower limb malperfusion was present in 4 cases (27%). The ascending aorta was dilated at presentation in 60% of the cases. Emergency surgery with arch/FET replacement was offered to 11 patients (73%); 3 patients (20%) received a limited proximal aortic repair; 1 patient was treated conservatively. Overall mortality was 47% (100% for limited proximal repair and 22% for those who received arch/FET). We advocate for aggressive treatment of RTAAD excluding the primary entry tear to prevent immediate- and mid-term complications.
The Stratified Homotopy Type of the Reductive Borel–Serre Compactification
Authors: Ørsnes Jansen Mikala
Published: October 2022

We identify the exit path $\infty $-category of the reductive Borel–Serre compactification as the nerve of a $1$-category defined purely in terms of rational parabolic subgroups and their unipotent radicals. As immediate consequences, we identify the fundamental group of the reductive Borel–Serre compactification, recovering a result of Ji–Murty–Saper–Scherk, and we obtain a combinatorial incarnation of constructible complexes of sheaves on the reductive Borel–Serre compactification as elements in a derived functor category.
The Future of Sino-Russian Relations in the Russian Far East: A Stable but Not Impervious Equilibrium
Authors: Stanko John C
Published: October 2022

This paper contributes to the ongoing debate on the nature of Sino-Russian relations by applying a multi-vector framework to examine the tenability of the so-called strategic partnership between Russia and China in the Russian Far East (RFE). Addressing a growing body of literature that seeks to move beyond single-factor evaluations of the dyadic relationship, I embrace the principles of analytic eclecticism, borrowing from Voskressenki's (Alexei D. Voskressenski, Russia and China: A Theory of Inter-State Relations [London, 2003]) multifactor framework to advance an argument for intertwining the three dominant international relations research traditions—realism, liberalism, and constructivism—to conduct a more comprehensive evaluation of the current equilibrium in the RFE, rather than assuming in advance the most pertinent lens. This in turn allows for more effective application of international relations theory to Sino-Russian studies. To accomplish my aim, I incorporate data pertaining to economic, geopolitical, and ideational factors. From these data, I find that the relationship in the RFE is in a state of stable equilibrium, with the most important vectors contributing to the balance for each side at present, geopolitical considerations for Moscow and ideational concerns for Beijing, being conducive to cooperation. The short-term potential for conflict is thus minimal, but a shock in the form of increasing Chinese nationalist hostility toward Russia or continued territorial belligerence by Russia internationally would severely endanger the status quo. By applying a similar approach to other dimensions of the Sino-Russian relationship, scholars can gain greater traction in assessing the robustness of the continually evolving bilateral partnership between these two large and important neighbors.
Climate change and health informatics: pilot survey of perspectives across the field
Authors: Sarabu Chethan , Deonarine Andrew , Leitner Stefano , Fayanju Oluseyi , Fisun Myroslava , Nadeau Kari
Published: October 2022

Objective

Establish a baseline of informatics professionals’ perspectives on climate change and health.

Materials and Methods

Anonymized survey sent to 9 informatics listservs March 31, 2022 to April 15, 2022.

Results

N = 85 participants completed part or all of survey. Majority of participants worked at hospitals with 1000+ employees (73%) in urban areas (60%) in the United States. Respondents broadly reported general understanding of climate change and health (51%), but 71% reported unfamiliarity with technologies that could help clinicians and informaticians address the impacts of climate change. Seventy-one percent of surveyed wanted climate-driven environmental health information included in EHRs. Seventy-six percent of respondents reported that informaticians should be involved in institutional decarbonization. Seventy-eight percent of respondents felt that it was extremely, very, or moderately important to receive education on climate change.

Discussion

General consensus on need to engage informaticians in climate change response, but gaps identified in knowledge dissemination and tools for adaptation and mitigation.

Conclusion

Informaticians broadly concerned about climate change and want to be engaged in efforts to combat it, but further education and tool development needed.
Determination of Ethanol Content in Water Kefir Using Headspace Gas Chromatography With Mass Spectrometry Detection: Matrix Extension and Methanol Characterization
Authors: Sy Hong , Chan Michael , Finley Jamie
Published: October 2022

Background

Water kefir is a fermented beverage using water, sugar, and cultured microorganism grains as the primary ingredients. Ethanol may be present at varying levels within the final product due to the fermentation process, so it is vital to have a validated method to meet regulatory, quality, and safety requirements.

Objective

This study describes using water kefir as a matrix for the evaluation of the previously validated method employing headspace gas chromatography mass spectrometry (HS-GCMS) detection for ethanol in kombucha. The study objective is to demonstrate the method originally using kombucha is also fit for the analysis of water kefir. This method will also evaluate the determination of methanol within the water kefir samples.

Method

The matrix extension study was performed as per the AOAC INTERNATIONAL guidance documents outlined in Appendix K: Guidelines for Dietary Supplements and Botanicals using HS-GCMS for ethanol determination. Ethanol determination in each water kefir sample is quantified against an external standard calibration curve. The same instrumentation is used for methanol characterization.

Results

RSDr and HorRat values obtained for from the study demonstrated acceptable precision with RSDr values of 1.03 to 6.68% and HorRat values determined to be between 0.23 and 1.52 for ethanol determination within kefir samples. Similarly, acceptable values of RSDr ranging from 1.45 to 3.39% and HorRat ranging from 0.25 to 0.49 were observed with methanol determination. For methanol determination, the limit of detection (LOD) and limit of quantification (LOQ) determined for the method in this study to be 16 and 21 ppm, respectively. The methanol spike recovery study gave overall recoveries ranging from 89 to 91%, demonstrating acceptable method accuracy.

Conclusions

The results of this study demonstrate the previously validated HS-GCMS method for ethanol determination in kombucha can also be used to quantify ethanol in water kefir samples. The method is also suitable for the determination of methanol within water kefir samples.

Highlights

A straightforward method has been adapted to include the the quantification of ethanol and methanol in fermented beverages such as Water Kefir samples.