bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of postoperative circulating tumour DNA to predict early recurrence in patients with stage I–III right-sided colon cancer: prospective observational study
Authors: Lygre Kristin B , Forthun Rakel B , Høysæter Trude , Hjelle Sigrun M , Eide Geir E , Gjertsen Bjørn T , Pfeffer Frank , Hovland Randi
Published: January 2024

Background

Right-sided colon cancer (RCC) differs in mutation profile and risk of recurrence compared to distal colon cancer. Circulating tumour DNA (ctDNA) present after surgery can identify patients with residual disease after curative surgery and predict risk of early recurrence.

Methods

This is a prospective observational biomarker trial with exploration of ctDNA in 50 non-metastatic RCC patients for which oncological right-sided colectomy was performed. Blood samples were collected preoperatively, within 1 month post surgery, 3 months (not mandatory), 6 months and every 6 months thereafter. Plasma cell free DNA and/or tumour was investigated for cancer-related mutations by the next-generation sequencing (NGS) panel AVENIO surveillance specifically designed for ctDNA analysis. Detected mutations were quantified using digital droplet PCR (ddPCR) for follow-up. Recurrence-free survival was explored.

Results

50 patients were recruited. Somatic cancer-related mutations were detected in 47/50 patients. ddPCR validated results from NGS for 27/34 (plasma) and 72/72 samples (tumour). Preoperative ctDNA was detected in 31/47 of the stage I/III patients and the majority of ctDNA positive patients showed reduction of ctDNA after surgery (27/31). ctDNA-positive patients at first postoperative sample had high recurrence risk compared to patients without measurable ctDNA (adjusted hazard ratio: 172.91; 95% c.i.: 8.70 to 3437.24; P: 0.001).

Conclusion

ctDNA was detectable in most patients with non-metastatic RCC before surgery. Positive postoperative ctDNA was strongly associated with early recurrence. Detectable postoperative ctDNA is a prognostic factor with high (100%) positive predictive value for recurrence in this cohort of non-metastatic RCC.

Clinical Trial Registration

ClinicalTrials.gov ID: NCT03776591
Impact of complexity in minimally invasive liver surgery on enhanced recovery measures: prospective study
Authors: Dahlke Paul M , Benzing Christian , Lurje Georg , Malinka Thomas , Raschzok Nathanael , Kamali Can , Gül-Klein Safak , Schöning Wenzel , Hillebrandt Karl H , Pratschke Johann , Neudecker Jens , Krenzien Felix
Published: January 2024

Background

Adherence to enhanced recovery after surgery (ERAS) protocols is crucial for successful liver surgery. The aim of this study was to assess the impact of minimally invasive liver surgery complexity on adherence after implementing an ERAS protocol.

Methods

Between July 2018 and August 2021, a prospective observational study involving minimally invasive liver surgery patients was conducted. Perioperative treatment followed ERAS guidelines and was recorded in the ERAS interactive audit system. Kruskal–Wallis and ANOVA tests were used for analysis, and pairwise comparisons utilized Wilcoxon rank sum and Welch's t-tests, adjusted using Bonferroni correction.

Results

A total of 243 patients were enrolled and categorized into four groups based on the Iwate criteria: low (n = 17), intermediate (n = 81), advanced (n = 74) and expert difficulty (n = 71). Complexity correlated with increased overall and major morbidity rate, as well as longer length of stay (all P < 0.001; standardized mean difference = 0.036, 0.451, 0.543 respectively). Adherence to ERAS measures decreased with higher complexity (P < 0.001). Overall adherence was 65.4%. Medical staff-centred adherence was 79.9%, while patient-centred adherence was 38.9% (P < 0.001). Complexity significantly affected patient-centred adherence (P < 0.001; standardized mean difference (SMD) = 0.420), but not medical staff-centred adherence (P = 0.098; SMD = 0.315). Postoperative phase adherence showed major differences among complexity groups (P < 0.001, SMD = 0.376), with mobilization measures adhered to less in higher complexity cases.

Conclusion

The complexity of minimally invasive liver surgery procedures impacts ERAS protocol adherence for each patient. This can be addressed using complexity-adjusted cut-offs and ‘gradual adherence’ based on the relative proportion of cut-off values achieved.
Neurodevelopmental and synaptic defects in DNAJC6 parkinsonism, amenable to gene therapy
Authors: Abela Lucia , Gianfrancesco Lorita , Tagliatti Erica , Rossignoli Giada , Barwick Katy , Zourray Clara , Reid Kimberley M , Budinger Dimitri , Ng Joanne , Counsell John , Simpson Arlo , Pearson Toni S , Edvardson Simon , Elpeleg Orly , Brodsky Frances M , Lignani Gabriele , Barral Serena , Kurian Manju A
Published: January 2024

DNAJC6 encodes auxilin, a co-chaperone protein involved in clathrin-mediated endocytosis (CME) at the presynaptic terminal. Biallelic mutations in DNAJC6 cause a complex, early-onset neurodegenerative disorder characterized by rapidly progressive parkinsonism-dystonia in childhood. The disease is commonly associated with additional neurodevelopmental, neurological and neuropsychiatric features. Currently, there are no disease-modifying treatments for this condition, resulting in significant morbidity and risk of premature mortality.

To investigate the underlying disease mechanisms in childhood-onset DNAJC6 parkinsonism, we generated induced pluripotent stem cells (iPSC) from three patients harbouring pathogenic loss-of-function DNAJC6 mutations and subsequently developed a midbrain dopaminergic neuronal model of disease.

When compared to age-matched and CRISPR-corrected isogenic controls, the neuronal cell model revealed disease-specific auxilin deficiency as well as disturbance of synaptic vesicle recycling and homeostasis. We also observed neurodevelopmental dysregulation affecting ventral midbrain patterning and neuronal maturation. To explore the feasibility of a viral vector-mediated gene therapy approach, iPSC-derived neuronal cultures were treated with lentiviral DNAJC6 gene transfer, which restored auxilin expression and rescued CME.

Our patient-derived neuronal model provides deeper insights into the molecular mechanisms of auxilin deficiency as well as a robust platform for the development of targeted precision therapy approaches.
In vivo calcium imaging shows that satellite glial cells have increased activity in painful states
Authors: Jager Sara E , Goodwin George , Chisholm Kim I , Denk Franziska
Published: January 2024

Satellite glial cells are important for proper neuronal function of primary sensory neurons for which they provide homeostatic support. Most research on satellite glial cell function has been performed with in vitro studies, but recent advances in calcium imaging and transgenic mouse models have enabled this first in vivo study of single-cell satellite glial cell function in mouse models of inflammation and neuropathic pain. We found that in naïve conditions, satellite glial cells do not respond in a time-locked fashion to neuronal firing. In painful inflammatory and neuropathic states, we detected time-locked signals in a subset of satellite glial cells, but only with suprathreshold stimulation of the sciatic nerve. Surprisingly, therefore, we conclude that most calcium signals in satellite glial cells seem to develop at arbitrary intervals not directly linked to neuronal activity patterns. More in line with expectations, our experiments also revealed that the number of active satellite glial cells was increased under conditions of inflammation or nerve injury. This could reflect the increased requirement for homeostatic support across dorsal root ganglion neuron populations, which are more active during such painful states.
General dermatology and dermatology in primary healthcare
Authors: Fleming Sarah , Kearney Nicola , Eustace Karen
Published: January 2024

A 24-year-old woman was seen in the dermatology clinic with a 5-month history of excessive wrinkling of the palmar aspects of both hands in response to contact with water.
Biologic agent patient screening and monitoring practices among Irish dermatologists, rheumatologists and gastroenterologists
Authors: Barry Rory , Watchorn Richard E
Published: January 2024

Separate clinical practice guidelines for the use of biologic therapies are published by national societies for dermatology, rheumatology and gastroenterology. As the same biologic agents may be indicated for multiple diseases, risk vs. benefit considerations, urgency of initiation and specialist comfort in prescribing biologics can vary substantially for different diseases and clinical scenarios. We undertook a survey to gain insight into biologic prescribing practices of dermatologists, rheumatologists and gastroenterologists practising in Ireland.
Structural Elucidation of Novel Degradation Impurities of Ibrutinib in Ibrutinib Tablets Using Preparative Chromatography, LCMS, HRMS and 2D NMR Techniques
Authors: Yerla Rajender Reddy , Manubolusurya Surendrababu , Meganathan Saravanakumar , Madalapu Veerababu , Vaidyanathan Gopal
Published: January 2024

Ibrutinib is an orally administered compound that functions as an irreversible covalent inhibitor of the Bruton tyrosine kinase, an essential element in multiple cellular processes including B-cell differentiation, proliferation, migration, survival and apoptosis. The compound has been found to demonstrate efficacy against a range of B-cell malignancies. The drug product is available in oral tablet and capsule formulations. The drug degradation profiles of tablets dosage form were assessed in accordance with regulatory guidelines. The results indicate that the drug substance is susceptible to alkaline and oxidative stress. The oxidation degradation led to the identification of three significant unknown degradation impurities. The three compounds were isolated through the application of preparative liquid chromatography, and their structures were determined using analytical techniques such as liquid chromatography–mass spectrometry, high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Utilizing structural elucidation data, predictions were made regarding the composition of impurities, revealing them to be novel degradation impurities that bear structural resemblance to ibrutinib. Additionally, potential pathways for the formation of the impurities were proposed.
Gold Rush vs. War: Keynes on reviving animal spirits in times of crisis
Authors: Bee Michele , Fèvre Raphaël
Published: January 2024

This paper aims to exploit fully the heuristic virtues of Keynes’ famous ‘old bottles’ story, deploying a multi-layered argument and drawing out its broadest implications. In essence, we show that through this story Keynes was making a very serious point about anti-crisis policies: the need for authorities to stimulate animal spirits by relying on people’s natural impulse to action. Rather than taking the place of entrepreneurs and paying people to dig holes, Keynes seems to be arguing that public authorities should put entrepreneurs in a situation where they are so enthusiastic that they go into debt to dig holes, just like during a gold rush. At the same time, it is a question of restoring the banks’ willingness to lend for these overoptimistic projects in a period of total depression. This article explores the conditions that make public intervention as effective as possible through the enthusiasm and individual initiative that can be generated by an artificial gold rush. Such intervention therefore can be as minimal as possible, without having to resort to the opposite authoritarian solution of war. Since the gold rush builds cities and war destroys them, Keynes spent considerable energy convincing his contemporaries that liberal-democratic countries would have to take the former path if they wanted to avoid the latter.
Conceptualizing embeddedness as a key dimension for analyzing journalistic cultures
Authors: Vos Tim P , Hanusch Folker
Published: January 2024

The study of journalistic cultures has a long history in communication research. Yet, much scholarship has been criticized for emanating too much from normative and—particularly in the case of comparative work—ethnocentric assumptions. While much progress has been made, the field arguably still suffers from these imbalances, restricting a more holistic understanding of journalistic cultures. This article aims to address this gap by proposing a repurposed concept for the study of journalistic cultures that focuses on the extent to which journalists are embedded in communities’ experiences, values, histories, places, and languages. Following an overview and explication of how embeddedness has been used in journalism scholarship, but also in other disciplines, we argue that the term provides an opportunity to better contextualize journalistic cultures, contributing to a less normatively dismissive and more explanatory approach to analyzing journalism and comparing journalistic cultures.
Vasostatins: new molecular targets for atherosclerosis, post-ischaemic angiogenesis, and arteriogenesis
Authors: Madonna Rosalinda , Barachini Serena , Ghelardoni Sandra , Lu Lin , Shen Wei-Feng , De Caterina Raffaele
Published: January 2024

The chromogranin–secretogranin secretory proteins—granins—are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage.
“Stuckness” and the Fraying Promise of Postfeminism in Contemporary Women’s Short Stories
Authors: Appleton Marni
Published: January 2024

While postfeminism is typically associated with upbeat feelings, such as confidence and resilience, scholars have begun to examine the emergence of less positive feelings alongside the compulsory outward presentation of enthusiasm. This essay examines feelings of “stuckness” in two short stories—“Would Like to Meet” (2014) by May-Lan Tan and “Los Angeles” (2020) by Emma Cline—and how these feelings illuminate the affective regulation of postfeminism. It also makes the case that the short story is an adept form through which to explore the contradictions of neoliberal femininity and that women short story writers are utilizing the tendencies of the form—particularly in regard to the short story’s ending—to re-create the lingering, non-cathartic feelings produced by the deteriorating promise of postfeminist culture.
DAPredict: a database for drug action phenotype prediction
Authors: Meng Qingkang , Cai Yiyang , Zhou Kun , Xu Fei , Huo Diwei , Xie Hongbo , Yu Meini , Zhang Denan , Chen Xiujie
Published: January 2024

The phenotypes of drug action, including therapeutic actions and adverse drug reactions (ADRs), are important indicators for evaluating the druggability of new drugs and repositioning the approved drugs. Here, we provide a user-friendly database, DAPredict (http://bio-bigdata.hrbmu.edu.cn/DAPredict), in which our novel original drug action phenotypes prediction algorithm (Yang,J., Zhang,D., Liu,L. et al. (2021) Computational drug repositioning based on the relationships between substructure-indication. Brief. Bioinformatics, 22, bbaa348) was embedded. Our algorithm integrates characteristics of chemical genomics and pharmacogenomics, breaking through the limitations that traditional drug development process based on phenotype cannot analyze the mechanism of drug action. Predicting phenotypes of drug action based on the local active structures of drugs and proteins can achieve more innovative drug discovery across drug categories and simultaneously evaluate drug efficacy and safety, rather than traditional one-by-one evaluation. DAPredict contains 305 981 predicted relationships between 1748 approved drugs and 454 ADRs, 83 117 predicted relationships between 1478 approved drugs and 178 Anatomical Therapeutic Chemicals (ATC). More importantly, DAPredict provides an online prediction tool, which researchers can use to predict the action phenotypic spectrum of more than 110 000 000 compounds (including about 168 000 natural products) and corresponding proteins to analyze their potential effect mechanisms. DAPredict can also help researchers obtain the phenotype-corresponding active structures for structural optimization of new drug candidates, making it easier to evaluate the druggability of new drug candidates and develop more innovative drugs across drug categories.

Database URL:  http://bio-bigdata.hrbmu.edu.cn/DAPredict/
Hospital Surgical Volume–Outcome Relationship of Postoperative Morbidity for Ileocolic Resection in Crohn’s Disease: A French Nationwide Study of 4205 Patients
Authors: Bitterlin Thibaut , Valibouze Caroline , Lenne Xavier , Bruandet Amélie , Desreumaux Pierre , Zerbib Philippe
Published: January 2024

Background and Aims

Despite the development of medical therapy, nearly 50% of patients with Crohn’s disease [CD] undergo surgery during their lifetime. Several studies have suggested some risk factors for postoperative morbidity [POM] after ileocolic resection [ICR]. However, the impact of surgical hospital volume on POM in CD has not been extensively studied. This study aimed to assess the impact of surgical hospital volume on POM after ICR for CD.

Methods

All patients with CD who underwent ICR in France between 2013 and 2022 were identified in the French Database, Programme de Médicalisation des Systèmes d’Information. Using the Chi-square automatic interaction detector, we determined the cut-off value to split high-surgical-volume [≥6 ICRs/year] and low-surgical-volume centres [<6 ICRs/year]. The primary outcome was the evaluation of major POM during hospitalization. POM was evaluated according to the surgical volume centre. The Elixhauser comorbidity index [ECI] was used to categorize the comorbidities of patients.

Results

A total of 4205 patients were identified, and the major POM during hospitalization was significantly [p = 0.0004] lower in the high-surgical-volume [6.2%] compared to low-surgical-volume centres [9.1%]. After multivariate analysis, independent factors associated with major POM were surgical hospital volume [p = 0.024], male sex [p = 0.029], ECI ≥ 1 [p < 0.001], and minor POM [p < 0.001].

Conclusion

Major POM after ICR for CD is closely associated with surgical hospital volume. Centralization of surgery for CD is desirable, especially in patients with major comorbidities.
Prophylactic Versus Endoscopy-driven Treatment of Crohn’s Postoperative Recurrence: A Retrospective, Multicentric, European Study [PORCSE Study]
Authors: Geldof Jeroen , Truyens Marie , Hanssens Michiel , Van Gucht Emily , Holvoet Tom , Elorza Ainara , Bouillon Vincent , Barros Sónia , Martins Viviana , Argyriou Konstantinos , Potamianos Spyridon , Diculescu Mircea , Stroie Tudor , Bossuyt Peter , Moens Annick , Theodoraki Eirini , Koutroubakis Ioannis E , Pedro Juliana , Fernandes Samuel , Nikolaou Pinelopi , Karmiris Konstantinos , Baert Filip J , Ferreiro-Iglesias Rocio , Peeters Harald , Claeys Sophie , Casanova Maria José , Eder Piotr , Porter Ross J , Arnott Ian , Karakan Tarkan , Mesonero Francisco , Revés Joana , Van Dyck Evi , Jauregui-Amezaga Aranzazu , Mañosa Míriam , Rivière Pauline , Marquez Mosquera Lucia , Portela Francisco , Pimentel Raquel , Lobaton Triana
Published: January 2024

Background and Aims

No consensus exists on optimal strategy to prevent postoperative recurrence [POR] after ileocaecal resection [ICR] for Crohn’s disease [CD]. We compared early medical prophylaxis versus expectant management with treatment driven by findings at elective endoscopy 6–12 months after ICR.

Methods

A retrospective, multicentric, observational study was performed. CD patients undergoing first ICR were assigned to Cohort 1 if a biologic or immunomodulator was [re]started prophylactically after ICR, or to Cohort 2 if no postoperative prophylaxis was given and treatment was started as reaction to elective endoscopic findings. Primary endpoint was rate of endoscopic POR [Rutgeerts >i1]. Secondary endpoints were severe endoscopic POR [Rutgeerts i3/i4], clinical POR, surgical POR, and treatment burden during follow-up.

Results

Of 346 included patients, 47.4% received prophylactic postoperative treatment [proactive/Cohort 1] and 52.6% did not [reactive/Cohort 2]. Endoscopic POR [Rutgeerts >i1] rate was significantly higher in Cohort 2 [41.5% vs 53.8%, OR 1.81, p = 0.039] at endoscopy 6–12 months after surgery. No significant difference in severe endoscopic POR was found [OR 1.29, p = 0.517]. Cohort 2 had significantly higher clinical POR rates [17.7% vs 35.7%, OR 3.05, p = 0.002] and numerically higher surgical recurrence rates [6.7% vs 13.2%, OR 2.59, p = 0.051]. Cox proportional hazards regression analysis showed no significant difference in time to surgical POR of proactive versus expectant/reactive approach [HR 2.50, p = 0.057]. Quasi-Poisson regression revealed a significantly lower treatment burden for immunomodulator use in Cohort 2 [mean ratio 0.53, p = 0.002], but no difference in burden of biologics or combination treatment.

Conclusions

The PORCSE study showed lower rates of endoscopic POR with early postoperative medical treatment compared with expectant management after first ileocaecal resection for Crohn’s disease.
Blocking GPR15 Counteracts Integrin-dependent T Cell Gut Homing in Vivo
Authors: Schramm Sebastian , Liu Li-Juan , Saad Marek , Dietz Lisa , Dedden Mark , Müller Tanja M , Atreya Imke , Voskens Caroline J , Atreya Raja , Neurath Markus F , Zundler Sebastian
Published: January 2024

Background and Aims

The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD].

Methods

We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally.

Results

GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7.

Conclusions

GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed.
Azathioprine Plus Exclusive Enteral Nutrition Versus Azathioprine Monotherapy for the Prevention of Postoperative Recurrence in Patients with Crohn’s Disease: An Open-Label, Single-Centre, Randomized Controlled Trial
Authors: Duan Ming , Lu Mengjie , Diao Yanqing , Cao Lei , Wu Qiong , Liu Yuxiu , Gong Jianfeng , Zhu Weiming , Li Yi
Published: January 2024

Background

Azathioprine [AZA] effectively prevents postoperative endoscopic recurrence [ER] in Crohn’s disease [CD]. However, the efficacy of AZA emerges after 3 months. Exclusive enteral nutrition [EEN] can maintain remission in CD. The present trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD.

Methods

In total, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus 3 months of EEN [AZA + EEN] postoperatively. The primary endpoint was the rate of ER at 12 months. Secondary endpoints included the rate of ER at 3 months, clinical recurrence [CR], CD activity index [CDAI] scores, faecal calprotectin [FC], and C-reactive protein [CRP]. Quality of life was assessed using Short Form-36 [SF-36] and the Inflammatory Bowel Disease Questionnaire [IBDQ].

Results

Patients in the AZA + EEN group exhibited significantly lower rates of ER compared to the AZA group at both 12 months (33.3% [13/39] vs 63.2% [24/38], P = 0.009) and 3 months (8.6% [3/35] vs 28.1% [9/32], P = 0.037) post-surgery. The rates of CR between the two groups at 3 and 12 months were similar. CDAI scores, FC, albumin level, and CRP were all comparable between the two groups. Quality of life was significantly higher in the AZA group than in the AZA + EEN group at 3 months but became comparable from 5 to 12 months postoperatively.

Conclusion

In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted.

Trial Number

NCT05214430.
Tritrophic effects mediate host suitability for two parasitoids of the carob moth (Lepidoptera: Pyralidae), infesting pistachio kernels
Authors: Baghery Fatemeh , Michaud J P , Dini Ali
Published: January 2024

The carob moth, Ectomyelois ceratoniae (Zeller) (Lepidoptera: Pyralidae), is an important pest of pistachio causing direct damage to nuts during ripening, and in storage. We examined the tritrophic effects of 5 pistachio cultivars, representing the full range of kernel suitability for E. ceratoniae, on 2 larval parasitoids, Habrobracon hebetor (Say) (Hymenoptera: Braconidae), a gregarious, synovigenic, idiobiont, ectoparasitoid, and Venturia canescens Gravenhorst (Hymenoptera: Ichneumonidae), a solitary, pro-ovigenic, koinobiont, endoparasitoid. The suitability of pistachio cultivars for development and reproduction of the 2 parasitoids was closely correlated, despite their divergent lifestyles and developmental patterns, and paralleled variation in kernel suitability for host larvae. Although kernels of the most resistant cultivar reduced demographic parameters of the parasitoids, the potential impact on numerical responses was minor. Successful biological control of carob moth within the vulnerable period of nut ripening will likely depend on the functional responses of earlier generations of adult parasitoids emerging from other fruit and nut crops, or those released in an augmentation program.
Normal values for left atrial strain, volume, and function derived from 3D echocardiography: the Copenhagen City Heart Study
Authors: Yafasov Marat , Olsen Flemming Javier , Skaarup Kristoffer Grundtvig , Lassen Mats Christian Højbjerg , Johansen Niklas Dyrby , Lindgren Filip Lyng , Jensen Gorm Boje , Schnohr Peter , Møgelvang Rasmus , Søgaard Peter , Biering-Sørensen Tor
Published: January 2024

Aims

3D echocardiographic (3DE) assessment of the left atrium (LA) is a new modality of potential clinical value. Age- and sex-based normative values are needed to benchmark these parameters for clinical use.

Methods and results

Of 4466 participants in the 5th Copenhagen City Heart Study, a prospective longitudinal cohort study on the general population, 2082 participants underwent 3DE of the LA. Healthy participants were included to establish normative values for LA strain, volume, and function by 3DE. The effects of age and sex were also evaluated. After excluding participants with comorbidities, 979 healthy participants (median age 44 years, 39.6% males) remained. The median and limits of normality (2.5th and 97.5th percentiles) for functional and volumetric measures were as follows: LA reservoir strain (LASr) 30.8% (18.4–44.2%), LA conduit strain (LAScd) 19.1% (6.8–32.0%), LA contractile strain 11.7% (4.3–22.2%), total LA emptying fraction (LAEF) 61.4% (47.8–71.0%), passive LAEF 37.7% (17.4–53.9%), active LAEF 37.4% (22.2–52.5%), LA minimum volume index (LAVimin) 10.2 (5.9–18.5) mL/m2, and LA maximum volume index (LAVimax) 26.8 (16.5–40.1) mL/m2. All parameters changed significantly with increasing age (P value for all <0.001). Significant sex-specific differences were observed for all parameters except active LAEF and LAVimax. Sex significantly modified the association between age and LASr (P for interaction < 0.001), LAScd (P for interaction < 0.001), LAVimin (P for interaction = 0.037), and total LAEF (P for interaction = 0.034) such that these parameters deteriorated faster with age in females than males.

Conclusion

We present age- and sex-specific reference material including limits of normality for LA strain, volume, and function by 3DE.
Early use of intrapartum intra-aortic balloon pump support for haemodynamic stabilization of peripartum and anthracycline-induced cardiomyopathy: a case report
Authors: Chandran Karthic , Quimby Donald , Bezerra Hiram G , Crousillat Daniela
Published: January 2024

Background

Prior exposure to cardiotoxic cancer therapies has been associated with an increased risk of peripartum cardiomyopathy (PPCM). The management of PPCM in this population remains a clinical challenge. Few studies have explored the use of mechanical circulatory support in PPCM. We present a case of early implementation of intra-aortic balloon pump (IABP) therapy for acute stabilization and intrapartum support of PPCM.

Case summary

A 36-year-old G4P2103 (4th pregnancy, two full-term, one premature birth, 0 abortions, and three living children) woman at 26 weeks and 5 days gestation with history of combined peripartum and anthracycline-induced cardiomyopathy [previously left ventricular ejection fraction (LVEF) 10–15% and recently 40–45%] presented with acute decompensated heart failure. Her clinical status deteriorated with a drop in LVEF to 15–20% with a significant increase in pulmonary pressures and worsening mitral regurgitation. A multidisciplinary decision with the cardio-obstetrics team was made to place a pulmonary artery catheter for invasive haemodynamic monitoring and IABP insertion prior to delivery. Intra-aortic balloon pump support had a profound immediate decrease in her systemic and pulmonary vascular resistance allowing for a successful repeat caesarean delivery. Her haemodynamics remained stable after IABP removal and pulmonary pressures improved. She was discharged one week following her delivery on guideline-directed medical therapy.

Discussion

Our case highlights the use of prophylactic intrapartum IABP in combined anthracycline-induced and PPCM and begins to explore its safety and efficacy in this high-risk patient population.
Innovation and disruptive science determine the future of cardiothoracic surgery
Authors: Beyersdorf Friedhelm
Published: January 2024

One of the currently most asked questions in the field of medicine is how any specialty in the future will evolve to ensure better health for the patients by using current, unparalleled developments in all areas of science. This article will give an overview of new and evolving strategies for cardiothoracic (CT) surgery that are available today and will become available in the future in order to achieve this goal. In the founding era of CT surgery in the 1950s and 1960s, there was tremendous excitement about innovation and disruptive science, which eventually resulted in a completely new medical specialty, i.e. CT surgery. Entirely new treatment strategies were introduced for many cardiovascular diseases that had been considered incurable until then. As expected, alternative techniques have evolved in all fields of science during the last few decades, allowing great improvements in diagnostics and treatment in all medical specialties. The future of CT surgery will be determined by an unrestricted and unconditional investment in innovation, disruptive science and our own transformation using current achievements from many other fields. From the multitude of current and future possibilities, I will highlight 4 in this review: improvements in our current techniques, bringing CT surgery to low- and middle-income countries, revolutionizing the perioperative period and treating as yet untreatable diseases. These developments will allow us a continuation of the previously unheard-of treatment possibilities provided by ingenious innovations based on the fundamentals of CT surgery.
Recovery of adrenal function after stopping mitotane in patients with adrenocortical carcinoma
Authors: Altieri Barbara , Kimpel Otilia , Megerle Felix , Detomas Mario , Chifu Irina , Fuss Carmina Teresa , Quinkler Marcus , Kroiss Matthias , Fassnacht Martin
Published: January 2024

Objective

Mitotane is the standard therapy of adrenocortical carcinoma (ACC) due to its relative selectivity of its cytotoxic effects toward adrenocortical cells. Therefore, it virtually always leads to adrenal insufficiency. Frequency and characteristics of hypothalamic–pituitary–adrenal axis recovery after discontinuation are ill-defined.

Methods

This was a retrospective study of patients with ACC adjuvantly treated with mitotane for ≥12 months who were disease-free at mitotane stop and had a minimum follow-up ≥1 year. Primary endpoint was adrenal recovery. Cox regression analyses were used to identify predictive factors. Moreover, mitotane plasma elimination rate and hormonal changes after mitotane stop were investigated.

Results

Fifty-six patients (36 women) treated with mitotane for a median time of 25 months and an average daily dose of 2.8 g were included. Median time after discontinuation until mitotane levels dropped below 5 and 2 mg/L, and the detection limit was 152 days (interquartile range: 114-202), 280 days (192-370), and 395 days (227-546), respectively. Full adrenal recovery was documented in 32 (57%) patients after a median time of 26 months (95% confidence interval [CI] = 19.6-32.4). In 4 patients (7.1%), adrenal insufficiency persisted >5 years after discontinuation. Mitotane peak ≥ 27 mg/L significantly correlated with longer time to adrenal recovery (hazard ratio [HR] = 0.2, 95% CI = 0.1-0.8, P = .03). Twenty-seven of 38 patients (71%) followed in reference centers achieved adrenal recovery compared with only 5/18 (28%) followed up in non-reference centers (HR = 4.51, 95% CI = 1.71-11.89, P = .002). Other investigated factors were not associated with adrenal function after discontinuation.

Conclusions

Our study demonstrates that adrenal recovery occurs in most patients after stopping mitotane, particularly when followed up in specialized centers, but not in all. Elimination time of mitotane after treatment discontinuation is very long but individually quite variable.
Reference intervals for serum 11-oxygenated androgens in children
Authors: Adriaansen Bas P H , Oude Alink Sandra E , Swinkels Dorine W , Schröder Mariska A M , Span Paul N , Sweep Fred C G J , Claahsen-van der Grinten Hedi L , van Herwaarden Antonius E
Published: January 2024

Objective

Classic androgens such as dehydroepiandrosterone, androstenedione, and testosterone are generally measured for diagnosis and treatment monitoring in children and adolescents with hyperandrogenism, as can occur in congenital adrenal hyperplasia, premature pubarche, or polycystic ovarian syndrome. However, adrenally-derived 11-oxygenated androgens also contribute to the androgen pool and should therefore be considered in clinical management. Nevertheless, paediatric reference intervals are lacking. Therefore, we developed a serum assay to establish reference intervals for four 11-oxygenated androgens in addition to four classic androgens.

Design

Reference interval study for serum 11-oxygenated androgens in children.

Methods

We developed and validated a sensitive liquid chromatography-tandem mass spectrometry assay and quantified eight serum androgens, including four 11-oxygenated androgens, in serum of 256 healthy children (aged 0-17 years old). An age-dependency for all androgens was observed, and therefore we divided the cohort based on age (prepubertal [n = 133; 94 boys, 39 girls] and pubertal [n = 123; 52 boys, 71 girls]) to compute reference intervals (2.5th-97.5th percentiles).

Results

In the prepubertal group, there was no significant sex-difference for any of the measured androgens. In the pubertal group, androstenedione, testosterone, and dihydrotestosterone showed a significant difference between boys and girls. In contrast, adrenal androgens dehydroepiandrosterone, 11-hydroxyandrostenedione, 11-ketoandrostenedione, 11-hydroxytestosterone, and 11-ketotestosterone did not.

Conclusions

We developed and validated an assay for 11-oxygenated androgens, in addition to four classic androgens and established reference intervals. This enables a comprehensive evaluation of serum androgen status in children with clinical symptoms of hyperandrogenism.
Cardiovascular disease risk communication and prevention: a meta-analysis
Authors: Bakhit Mina , Fien Samantha , Abukmail Eman , Jones Mark , Clark Justin , Scott Anna Mae , Glasziou Paul , Cardona Magnolia
Published: January 2024

Background and Aims

Knowledge of quantifiable cardiovascular disease (CVD) risk may improve health outcomes and trigger behavioural change in patients or clinicians. This review aimed to investigate the impact of CVD risk communication on patient-perceived CVD risk and changes in CVD risk factors.

Methods

PubMed, Embase, and PsycINFO databases were searched from inception to 6 June 2023, supplemented by citation analysis. Randomized trials that compared any CVD risk communication strategy versus usual care were included. Paired reviewers independently screened the identified records and extracted the data; disagreements were resolved by a third author. The primary outcome was the accuracy of risk perception. Secondary outcomes were clinician-reported changes in CVD risk, psychological responses, intention to modify lifestyle, and self-reported changes in risk factors and clinician prescribing of preventive medicines.

Results

Sixty-two trials were included. Accuracy of risk perception was higher among intervention participants (odds ratio = 2.31, 95% confidence interval = 1.63 to 3.27). A statistically significant improvement in overall CVD risk scores was found at 6–12 months (mean difference = −0.27, 95% confidence interval = −0.45 to −0.09). For primary prevention, risk communication significantly increased self-reported dietary modification (odds ratio = 1.50, 95% confidence interval = 1.21 to 1.86) with no increase in intention or actual changes in smoking cessation or physical activity. A significant impact on patients’ intention to start preventive medication was found for primary and secondary prevention, with changes at follow-up for the primary prevention group.

Conclusions

In this systematic review and meta-analysis, communicating CVD risk information, regardless of the method, reduced the overall risk factors and enhanced patients’ self-perceived risk. Communication of CVD risk to patients should be considered in routine consultations.
A polygenic risk score added to a QRISK®2 cardiovascular disease risk calculator demonstrated robust clinical acceptance and clinical utility in the primary care setting
Authors: Fuat Ahmet , Adlen Ella , Monane Mark , Coll Ruth , Groves Sarah , Little Elizabeth , Wild Jonathan , Kamali Farzan J , Soni Yusuf , Haining Shona , Riding Helen , Riveros-Mckay Fernando , Peneva Iliana , Lachapelle Alexander , Giner-Delgado Carla , Weale Michael E , Plagnol Vincent , Harrison Seamus , Donnelly Peter
Published: January 2024

Aims

The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service.

Methods and results

The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were ‘likely’ or ‘very likely’ to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%.

Conclusion

Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.
Environmental effects on genetic variance are likely to constrain adaptation in novel environments
Authors: Walter Greg M , Monro Keyne , Terranova Delia , la Spina Enrico , Majorana Maria , Pepe Giuseppe , Clark James , Cozzolino Salvatore , Cristaudo Antonia , Hiscock Simon J , Bridle Jon
Published: January 2024

Adaptive plasticity allows populations to cope with environmental variation but is expected to fail as conditions become unfamiliar. In novel conditions, populations may instead rely on rapid adaptation to increase fitness and avoid extinction. Adaptation should be fastest when both plasticity and selection occur in directions of the multivariate phenotype that contain abundant genetic variation. However, tests of this prediction from field experiments are rare. Here, we quantify how additive genetic variance in a multivariate phenotype changes across an elevational gradient, and test whether plasticity and selection align with genetic variation. We do so using two closely related, but ecologically distinct, sister species of Sicilian daisy (Senecio, Asteraceae) adapted to high and low elevations on Mt. Etna. Using a quantitative genetic breeding design, we generated and then reciprocally planted c. 19,000 seeds of both species, across an elevational gradient spanning each species’ native elevation, and then quantified mortality and five leaf traits of emergent seedlings. We found that genetic variance in leaf traits changed more across elevations than between species. The high-elevation species at novel lower elevations showed changes in the distribution of genetic variance among the leaf traits, which reduced the amount of genetic variance in the directions of selection and the native phenotype. By contrast, the low-elevation species mainly showed changes in the amount of genetic variance at the novel high elevation, and genetic variance was concentrated in the direction of the native phenotype. For both species, leaf trait plasticity across elevations was in a direction of the multivariate phenotype that contained a moderate amount of genetic variance. Together, these data suggest that where plasticity is adaptive, selection on genetic variance for an initially plastic response could promote adaptation. However, large environmental effects on genetic variance are likely to reduce adaptive potential in novel environments.
Characterization of a novel 4-guanidinobutyrase from Candida parapsilosis
Authors: Gaikwad Santoshkumar R , Punekar Narayan S , Pathan Ejaj K
Published: January 2024

Enzymes of the ureohydrolase superfamily are specific in recognizing their substrates. While looking to broaden the substrate specificity of 4-guanidinobutyrase (GBase), we isolated a yeast, typed as Candida parapsilosis (NCIM 3689), that efficiently utilized both 4-guanidinobutyrate (GB) and 3-guanidinopropionate (GP) as a sole source of nitrogen. A putative GBase sequence was identified from its genome upon pBLAST query using the GBase sequence from Aspergillus niger (AnGBase). The C. parapsilosis GBase (CpGBase) ORF was PCR amplified, cloned, and sequenced. Further, the functional CpGBase protein expressed in Saccharomyces cerevisiae functioned as GBase and 3-guanidinopropionase (GPase). S. cerevisiae cannot grow on GB or GP. However, the transformants expressing CpGBase acquired the ability to utilize and grow on both GB and GP. The expressed CpGBase protein was enriched and analyzed for substrate saturation and product inhibition by γ-aminobutyric acid and β-alanine. In contrast to the well-characterized AnGBase, CpGBase from C. parapsilosis is a novel ureohydrolase and showed hyperbolic saturation for GB and GP with comparable efficiency (Vmax/KM values of 3.4 and 2.0, respectively). With the paucity of structural information and limited active site data available on ureohydrolases, CpGBase offers an excellent paradigm to explore this class of enzymes.
More water, less light: how to improve silver fir seeding to convert Norway spruce monocultures into mixed stands in a drier region of Germany
Authors: Schattenberg Christian , Stritih Ana , Thom Dominik
Published: January 2024

Adaptive forest management gains importance as climate and disturbance regimes continue to change. Norway spruce monocultures are particularly vulnerable to those changes. Thus, there is a strong demand to convert pure spruce stands toward better adapted forest ecosystems. Silver fir has similar wood properties as Norway spruce, but is less vulnerable to droughts. Yet, little is known how to efficiently admix silver fir into Norway spruce monocultures. We analyzed seedling abundance in mature Norway spruce monocultures 1 year after soil scarification and silver fir seeding in a relatively dry region of southern Germany. Our objectives were to study the effect of soil scarification and seeding on regeneration density and to identify drivers of seedling abundance. We collected data on regeneration, forest structure, as well as soil and light conditions at 103 scarified and 25 untreated control plots. We used non-parametric independence tests to compare scarified and untreated plots. Subsequently, we used boosted regression trees to investigate the drivers of seedling abundance. Norway spruce strongly benefited from soil scarification (P < .001), with seedling numbers even exceeding those of silver fir. Both species thrived in soils with high plant available water capacity. In contrast, seedling numbers were overall negatively affected by light. Moreover, we found a higher density of silver fir regeneration at greater distance from neighboring trees and in soils devoid of carbonate. Our study indicates that water, not light, is the limiting factor for both Norway spruce and silver fir seedlings in the study region. Seeding silver fir will likely be most effective underneath an intact canopy on deep, fine-textured soils without carbonate, while maximizing the distance to Norway spruce trees. In conclusion, silver fir seeding can be optimized to become an effective adaptive measure to diversify Norway spruce monocultures, and thus to create more resistant and resilient forest ecosystems.