bluuebunny/crossref_metadata_2025 huggingface dataset:
DrTransformer: heuristic cotranscriptional RNA folding using the nearest neighbor energy model
Authors: Badelt Stefan , Lorenz Ronny , Hofacker Ivo L
Published: January 2023

Motivation

Folding during transcription can have an important influence on the structure and function of RNA molecules, as regions closer to the 5′ end can fold into metastable structures before potentially stronger interactions with the 3′ end become available. Thermodynamic RNA folding models are not suitable to predict structures that result from cotranscriptional folding, as they can only calculate properties of the equilibrium distribution. Other software packages that simulate the kinetic process of RNA folding during transcription exist, but they are mostly applicable for short sequences.

Results

We present a new algorithm that tracks changes to the RNA secondary structure ensemble during transcription. At every transcription step, new representative local minima are identified, a neighborhood relation is defined and transition rates are estimated for kinetic simulations. After every simulation, a part of the ensemble is removed and the remainder is used to search for new representative structures. The presented algorithm is deterministic (up to numeric instabilities of simulations), fast (in comparison with existing methods), and it is capable of folding RNAs much longer than 200 nucleotides.

Availability and implementation

This software is open-source and available at https://github.com/ViennaRNA/drtransformer.

Supplementary information

Supplementary data are available at Bioinformatics online.
DiffCircaPipeline: a framework for multifaceted characterization of differential rhythmicity
Authors: Xue Xiangning , Zong Wei , Huo Zhiguang , Ketchesin Kyle D , Scott Madeline R , Petersen Kaitlyn A , Logan Ryan W , Seney Marianne L , McClung Colleen , Tseng George
Published: January 2023

Circadian oscillations of gene expression regulate daily physiological processes, and their disruption is linked to many diseases. Circadian rhythms can be disrupted in a variety of ways, including differential phase, amplitude and rhythm fitness. Although many differential circadian biomarker detection methods have been proposed, a workflow for systematic detection of multifaceted differential circadian characteristics with accurate false positive control is not currently available. We propose a comprehensive and interactive pipeline to capture the multifaceted characteristics of differentially rhythmic biomarkers. Analysis outputs are accompanied by informative visualization and interactive exploration. The workflow is demonstrated in multiple case studies and is extensible to general omics applications.

Availability and implementation

R package, Shiny app and source code are available in GitHub (https://github.com/DiffCircaPipeline) and Zenodo (https://doi.org/10.5281/zenodo.7507989)

Supplementary information

Supplementary data are available at Bioinformatics online.
FungiExp: a user-friendly database and analysis platform for exploring fungal gene expression and alternative splicing
Authors: Liu Jinding , Zhang Yaru , Shi Yapin , Zheng Yiqing , Zhu Yali , Guan Zhuoran , Shen Danyu , Dou Daolong
Published: January 2023

Fungi form a large and heterogeneous group of eukaryotic organisms with diverse ecological niches. The high importance of fungi contrasts with our limited understanding of fungal lifestyle and adaptability to environment. Over the last decade, the high-throughput sequencing technology produced tremendous RNA-sequencing (RNA-seq) data. However, there is no comprehensive database for mycologists to conveniently explore fungal gene expression and alternative splicing. Here, we have developed FungiExp, an online database including 35 821 curated RNA-seq samples derived from 220 fungal species, together with gene expression and alternative splicing profiles. It allows users to query and visualize gene expression and alternative splicing in the collected RNA-seq samples. Furthermore, FungiExp contains several online analysis tools, such as differential/specific, co-expression network and cross-species gene expression conservation analysis. Through these tools, users can obtain new insights by re-analyzing public RNA-seq data or upload personal data to co-analyze with public RNA-seq data.

Availability and implementation

The FungiExp is freely available at https://bioinfo.njau.edu.cn/fungiExp.

Supplementary information

Supplementary data are available at Bioinformatics online.
Adversarial dense graph convolutional networks for single-cell classification
Authors: Wang Kangwei , Li Zhengwei , You Zhu-Hong , Han Pengyong , Nie Ru
Published: January 2023

Motivation

In single-cell transcriptomics applications, effective identification of cell types in multicellular organisms and in-depth study of the relationships between genes has become one of the main goals of bioinformatics research. However, data heterogeneity and random noise pose significant difficulties for scRNA-seq data analysis.

Results

We have proposed an adversarial dense graph convolutional network architecture for single-cell classification. Specifically, to enhance the representation of higher-order features and the organic combination between features, dense connectivity mechanism and attention-based feature aggregation are introduced for feature learning in convolutional neural networks. To preserve the features of the original data, we use a feature reconstruction module to assist the goal of single-cell classification. In addition, HNNVAT uses virtual adversarial training to improve the generalization and robustness. Experimental results show that our model outperforms the existing classical methods in terms of classification accuracy on benchmark datasets.

Availability and implementation

The source code of HNNVAT is available at https://github.com/DisscLab/HNNVAT.

Supplementary information

Supplementary data are available at Bioinformatics online.
Anti-amyloid antibody therapies in Alzheimer’s disease
Authors: Perneczky Robert , Jessen Frank , Grimmer Timo , Levin Johannes , Flöel Agnes , Peters Oliver , Froelich Lutz
Published: January 2023

After years of failed attempts to develop a disease-modifying therapy for Alzheimer’s disease, consistent evidence in support of clinical efficacy was finally presented for a monoclonal antibody targeting the amyloid-β protofibrils. In addition to meeting the primary outcome of slowing clinical disease progression over 18 months, secondary clinical outcomes and amyloid-β lowering on PET also underpin the positive results of the trial.

In this opinion piece, we highlight the key characteristics of the previous unsuccessful trials and analyse the potential reasons why those attempts to develop a treatment for early Alzheimer’s disease failed. We compare the safety profiles of the different antibodies and highlight cautionary measures for their routine clinical use. Last, we discuss the role of blood-based biomarkers in transforming the clinical care pathway to facilitate the uptake of antibody treatments, proposing an integrated case-finding and treatment model crossing the different healthcare sectors.

Taken together, a real breakthrough may have been achieved by proving that amyloid-β reduction results in clinical benefits, rather than just biomarker changes. At the same time, routine use of the new generation of drugs will show if statistical efficacy translates into clinically meaningful change. This may just be the beginning of a new era of Alzheimer’s disease drug development.
Interleukin-18 as a severity marker and novel potential therapeutic target for epidermolytic ichthyosis
Authors: Ansai Osamu , Miyauchi Toshinari , Hayashi Ryota , Katsumi Tatsuya , Nishiguchi Tomoki , Hasegawa Akito , Shinkuma Satoru , Natsuga Ken , Nomura Toshifumi , Shimomura Yutaka , Abe Riichiro
Published: January 2023

Background

Epidermolytic ichthyosis (EI) is a major form of nonsyndromic inherited ichthyosis, characterized by erythroderma, marked hyperkeratosis and scale, bulla and erosion at birth, associated with KRT1/KRT10 mutations. The cytokine and chemokine profiles in EI are poorly understood, and specific treatment options have not been established.

Aim

To explore novel biomarkers and therapeutic targets in patients with EI.

Methods

We analysed cytokine levels in serum and skin samples from 10 patients with inherited ichthyosis, including seven patients with EI. Wild-type and mutant KRT1 constructs were established and transfected into HaCaT cells, an immortalized keratinocyte cell line, for in vitro immunoblotting and immunocytochemistry analyses.

Results

Multiplex cytokine/chemokine analysis revealed that 10 cytokines/chemokines [interleukin (IL)-1β, IL-4, IL-17A, IL-16, IL-18, IL-1 receptor-α, macrophage colony-stimulating factor, interferon-α2, basic fibroblast growth factor and monocyte chemotactic protein-3] were significantly increased in patients with EI. Furthermore, IL-18 levels were significantly higher in patients with EI [n = 7; 2714.1 (1438.0) pg mL−1] than in healthy controls [n = 11; 218.4 (28.4) pg mL−1, P < 0.01]. Immunohistochemical analyses showed that IL-18 expression was elevated in skin samples from patients with EI. Serum IL-18 levels correlated with the severity of ichthyosis, as measured by the Ichthyosis Scoring System. Immunoblotting analysis revealed that mature IL-18 levels were increased in the supernatant of mutant KRT1 expressing HaCaT cells. Additionally, these cells showed NLRP3 aggregation in the cytoplasm and ASC clustered around mutant keratin aggregations. These findings suggest that mutant keratin might promote the activation of the NLRP3 inflammasome and its downstream caspase-1-mediated IL-18 release in keratinocytes from patients with EI.

Conclusions

Our results suggest that serum IL-18 is a severity marker released from the skin of patients with EI. Blockade of IL-18 may be a useful novel therapeutic option for patients with EI.
Effects of metformin on clinical, hormonal and relevant gene expression parameters in patients with acne: an observational study
Authors: Kamboj Parul , Kaushik Akanksha , Handa Sanjeev , Dutta Pinaki , Saikia Uma Nahar , Pal Arnab , De Dipankar
Published: January 2023

Background

Acne vulgaris is associated with insulin resistance and elevated insulin-like growth factor-1 (IGF-1). Metformin is commonly used for treatment of acne in patients with polycystic ovarian syndrome (PCOS). However, the benefits of metformin in patients with acne in general are not well established.

Aim

To study the effectiveness of metformin treatment in patients with acne but who do not have PCOS and to understand the mechanisms of action of metformin in acne not related to PCOS.

Method

In this observational study, 30 patients with clinically confirmed acne vulgaris were treated with metformin (1000 mg daily) for 3 months without any other topical or systemic active intervention for their acne. The effect of metformin at the clinical, hormonal and genetic level was assessed.

Results

Metformin monotherapy significantly (P < 0.001) decreased the global acne grading score for acne followed by a marginal increase in insulin; with a significant (P = 0.03) increase in insulin-like growth factor-1 (IGF-1). A significant (P < 0.001) decrease in free androgen index resulting from a significant (P < 0.001) increase in sex hormone-binding globulin (SHBG) with decrease in testosterone was observed. Homeostasis model assessment insulin resistance (HOMA-IR) was not significantly changed. Forkhead box protein O1 (FOXO1) expression was significantly (P = 0.006) downregulated with metformin treatment at the mRNA level without any significant changes at protein level. Expression of lipogenic genes, namely HMGCR, SQLE and ACSL5 (P = 0.001, P = 0.03, P = 0.03, respectively) were also downregulated.

Conclusion

Metformin monotherapy led to significant clinical improvement in acne, possibly by reducing testosterone, inhibiting FOXO1 and reducing lipid synthesis by decreasing the expression of lipogenic genes.
Implementation of a novel palliative care curriculum for dermatology residents
Authors: Zhong Connie S , Goldman Nathaniel , Afvari Shawn , Chen Steven T , Lawton Andrew J , Charrow Alexandra P
Published: January 2023

Increasing literature suggests that palliative care and dermatology are closely intertwined; however, there are no documented palliative care curricula in dermatology residency. In this study, we developed a palliative care curriculum for Harvard dermatology residents, and assessed residents’ knowledge, skills and attitudes towards palliative care before and after the curriculum. We found that a palliative care curriculum increases residents’ knowledge and confidence in goals of care discussions and palliative care referrals, and that a palliative care curriculum is well received among dermatology residents.
Multiple waxy papules in a woman in her fifties
Authors: Mustari Akash P , Parkhi Mayur , Vinay Keshavamurthy
Published: January 2023

A woman in her 50 s presented with progressive asymptomatic papules on her face, trunk and extremities of 2 years duration. She had dysphagia, significant weight loss and had been operated on for carpal tunnel syndrome. Biopsy showed deposition of amorphous eosinophilic material in the dermis that was highlighted by Congo red stain.
Chloroquine reduces neutrophil extracellular trap (NET) formation through inhibition of peptidyl arginine deiminase 4 (PAD4)
Authors: Ivey Abby D , Matthew Fagan B , Murthy Pranav , Lotze Michael T , Zeh Herbert J , Hazlehurst Lori A , Geldenhuys Werner J , Boone Brian A
Published: January 2023

Neutrophil extracellular traps (NETs) occur when chromatin is decondensed and extruded from the cell, generating a web-like structure. NETs have been implicated in the pathogenesis of several sterile disease states and thus are a potential therapeutic target. Various pathways have been shown to induce NETs, including autophagy, with several key enzymes being activated like peptidyl arginine deiminase 4 (PAD4), an enzyme responsible for citrullination of histones, allowing for DNA unwinding and subsequent release from the cell. Pre-clinical studies have already demonstrated that chloroquine (CQ) and hydroxychloroquine (HCQ) are able to reduce NETs and slow disease progression. The exact mechanism as to how these drugs reduce NETs has yet to be elucidated. CQ and HCQ decrease NET formation from various NET activators, independent of their autophagy inhibitory function. CQ and HCQ were found to inhibit PAD4 exclusively, in a dose-dependent manner, confirmed with reduced CitH3+ NETs after CQ or HCQ treatment. Circulating CitH3 levels were reduced in pancreatic cancer patients after HCQ treatment. In silico screening of PAD4 protein structure identified a likely binding site interaction at Arg639 for CQ and Trp347, Ser468, and Glu580 for HCQ. SPR analysis confirmed the binding of HCQ and CQ with PAD4 with KD values of 54.1 µM (CQ) and 88.1 µM (HCQ). This data provide evidence of direct PAD4 inhibition as a mechanism for CQ/HCQ inhibition of NETs. We propose that these drugs likely reduce NET formation through multiple mechanisms; the previously established TLR9 and autophagy inhibitory mechanism and the novel PAD4 inhibitory mechanism.
Activation of brain arousal networks coincident with eye blinks during resting state
Authors: Demiral Şükrü Barış , Kure Liu Christopher , Benveniste Helene , Tomasi Dardo , Volkow Nora D
Published: January 2023

Eye-blinking has been implicated in arousal and attention. Here we test the hypothesis that blinking-moments represent arousal surges associated with activation of the ascending arousal network (AAN) and its thalamic projections. For this purpose, we explored the temporal relationship between eye-blinks and fMRI BOLD activity in AAN and thalamic nuclei, as well as whole brain cluster corrected activations during eyes-open, resting-state fMRI scanning. We show that BOLD activations in the AAN nuclei peaked prior to the eye blinks and in thalamic nuclei peaked prior to and during the blink, consistent with the role of eye blinking in arousal surges. Additionally, we showed visual cortex peak activation prior to the eye blinks, providing further evidence of the visual cortex’s role in arousal, and document cerebellar peak activation post eye blinks, which might reflect downstream engagement from arousal surges.
Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities
Authors: Mitroulis Ioannis , Hajishengallis George , Chavakis Triantafyllos
Published: January 2023

Cardiometabolic disorders are chief causes of morbidity and mortality, with chronic inflammation playing a crucial role in their pathogenesis. The release of differentiated myeloid cells with elevated pro-inflammatory potential, as a result of maladaptively trained myelopoiesis may be a crucial factor for the perpetuation of inflammation. Several cardiovascular risk factors, including sedentary lifestyle, unhealthy diet, hypercholesterolemia, and hyperglycemia, may modulate bone marrow hematopoietic progenitors, causing sustained functional changes that favour chronic metabolic and vascular inflammation. In the present review, we summarize recent studies that support the function of long-term inflammatory memory in progenitors of the bone marrow for the development and progression of cardiometabolic disease and related inflammatory comorbidities, including periodontitis and arthritis. We also discuss how maladaptive myelopoiesis associated with the presence of mutated hematopoietic clones, as present in clonal hematopoiesis, may accelerate atherosclerosis via increased inflammation.
Risk factors and consequences of post-esophagectomy delirium: a systematic review and meta-analysis
Authors: Papaconstantinou Dimitrios , Frountzas Maximos , Ruurda Jelle P , Mantziari Stella , Tsilimigras Diamantis I , Koliakos Nikolaos , Tsivgoulis Georgios , Schizas Dimitrios
Published: January 2023

Post-operative delirium (POD) is a state of mental and neurocognitive impairment characterized by disorientation and fluctuating levels of consciousness. POD in the context of esophageal surgery may herald serious and potentially life-threatening post-operative complications, or conversely be a symptom of severe underlying pathophysiologic disturbances. The aim of the present systematic review and meta-analysis is to explore risk factors associated with the development of POD and assess its impact on post-operative outcomes. A systematic literature search of the MedLine, Web of Science, Embase and Cochrane CENTRAL databases and the clinicaltrials.gov registry was undertaken. A random-effects model was used for data synthesis with pooled outcomes expressed as Odds Ratios (OR), or standardized mean differences (WMD) with corresponding 95% Confidence Intervals. Seven studies incorporating 2449 patients (556 with POD and 1893 without POD) were identified. Patients experiencing POD were older (WMD 0.29 ± 0.13 years, P < 0.001), with higher Charlson’s Comorbidity Index (CCI; WMD 0.31 ± 0.23, P = 0.007) and were significantly more likely to be smokers (OR 1.38, 95% CI 1.07–1.77, P = 0.01). Additionally, POD was associated with blood transfusions (OR 2.08, 95% CI 1.56–2.77, P < 0.001), and a significantly increased likelihood to develop anastomotic leak (OR 2.03, 95% CI 1.25–3.29, P = 0.004). Finally, POD was associated with increased mortality (OR 2.71, 95% CI 1.24–5.93, P = 0.01) and longer hospital stay (WMD 0.4 ± 0.24, P = 0.001). These findings highlight the clinical relevance and possible economic impact of POD after esophagectomy for malignant disease and emphasize the need of developing effective preventive strategies.
GATA6-AS1 Regulates Intestinal Epithelial Mitochondrial Functions, and its Reduced Expression is Linked to Intestinal Inflammation and Less Favourable Disease Course in Ulcerative Colitis
Authors: Sosnovski Katya E , Braun Tzipi , Amir Amnon , Moshel Danielle , BenShoshan Marina , VanDussen Kelli L , Levhar Nina , Abbas-Egbariya Haya , Beider Katia , Ben-Yishay Rakefet , Asad Ali Syed , Moore Sean R , Kugathasan Subra , Abramovich Ifat , Glick Saar Efrat , Weiss Batya , Barshack Iris , Gottlieb Eyal , Geiger Tamar , Ben-Horin Shomron , Ulitsky Igor , Hyams Jeffrey S , Denson Lee A , Haberman Yael
Published: January 2023

Background and Aims

Widespread dysregulation of long non-coding RNAs [lncRNAs] including a reduction in GATA6-AS1 was noted in inflammatory bowel disease [IBD]. We previously reported a prominent inhibition of epithelial mitochondrial functions in ulcerative colitis [UC]. However, the connection between reduction of GATA6-AS1 expression and attenuated epithelial mitochondrial functions was not defined.

Methods

Mucosal transcriptomics was used to conform GATA6-AS1 reduction in several treatment-naïve independent human cohorts [n=673]. RNA pull-down followed by mass spectrometry was used to determine the GATA6-AS1 interactome. Metabolomics and mitochondrial respiration following GATA6-AS1 silencing in Caco-2 cells were used to elaborate on GATA6-AS1 functions.

Results

GATA6-AS1 showed predominant expression in gut epithelia using single cell datasets. GATA6-AS1 levels were reduced in Crohn’s disease [CD] ileum and UC rectum in independent cohorts. Reduced GATA6-AS1 lncRNA was further linked to a more severe UC form, and to a less favourable UC course. The GATA6-AS1 interactome showed robust enrichment for mitochondrial proteins, and included TGM2, an autoantigen in coeliac disease that is induced in UC, CD and coeliac disease, in contrast to GATA6-AS1 reduction in these cohorts. GATA6-AS1 silencing resulted in induction of TGM2, and this was coupled with a reduction in mitochondrial membrane potential and mitochondrial respiration, as well as in a reduction of metabolites linked to aerobic respiration relevant to mucosal inflammation. TGM2 knockdown in GATA6-AS1-deficient cells rescued mitochondrial respiration.

Conclusions

GATA6-AS1 levels are reduced in UC, CD and coeliac disease, and in more severe UC forms. We highlight GATA6-AS1 as a target regulating epithelial mitochondrial functions, potentially through controlling TGM2 levels.
Dialysis catheter-related sepsis resulted in infective endocarditis, septic pulmonary embolism and acute inferolateral STEMI: a case report
Authors: Ahmed Islam Abdelmoneim , Asiri Abdullah Ali , Attia Mohamed , Alshehri Saleh
Published: January 2023

Background

Embolic myocardial infarction is an uncommon but increasingly recognized complication of infective endocarditis (IE). Although the incidence is low and ranges from 1% to 10%, the mortality rate is high (64%). The characteristics of septic embolism on presentation are nonspecific and usually are unrecognized by clinicians. This case report aims to build a high index of suspicion among clinicians for IE presenting with the complication of embolic myocardial infarction especially in patients with indwelling venous catheters.

Case Summary

A 62-year-old woman with end-stage renal disease on haemodialysis presented with shortness of breath and desaturation. Her history was significant for end-stage renal disease managed with regular haemodialysis by a right-sided double-lumen tunnelled catheter. An initial diagnosis was made of pulmonary embolism, and management with intravenous heparin was initiated. She subsequently developed inferolateral ST-elevation myocardial infarction, and treatment with percutaneous coronary intervention to the posterior descending artery failed. Then, the patient developed complete heart block, aortic valve vegetation, acute severe aortic regurgitation, and shock.

Discussion

Acute coronary syndrome is usually an early and uncommon complication of IE and the risk of embolism decreases after antibiotic therapy is initiated. Due to the low incidence of coronary events in IE, only case reports have been published. Most patients with septic pulmonary embolism have a presentation similar to that for pneumonia. The diagnosis is therefore often delayed, which consequently influences prognosis. Our case report presents an example of IE-related multiple systemic embolization with poor patient outcome due to delayed diagnosis.
Cardiac rehabilitation, physical activity, and the effectiveness of activity monitoring devices on cardiovascular patients: an umbrella review of systematic reviews
Authors: Dafny Hila Ariela , Champion Stephanie , Gebremichael Lemlem G , Pearson Vincent , Hendriks Jeroen M , Clark Robyn A , Pinero de Plaza Maria Alejandra , Gulyani Aarti , Hines Sonia , Beleigoli Alline
Published: January 2023

Aims

To consolidate the evidence on the effectiveness of activity-monitoring devices and mobile applications on physical activity and health outcomes of patients with cardiovascular disease who attended cardiac rehabilitation (CR) programmes.

Methods and results

An umbrella review of published randomized controlled trials, systematic reviews, and meta-analyses was conducted. Nine databases were searched from inception to 9 February 2022. Search and data extraction followed the JBI methodology for umbrella reviews and PRISMA guidelines. Nine systematic reviews met the inclusion criteria, comparing outcomes of participants in CR programmes utilizing devices/applications, to patients without access to CR with devices/applications. A wide range of physical, clinical, and behavioural outcomes were reported, with results from 18 712 participants. Meta-analyses reported improvements in physical activity, minutes/week [standardized mean difference (SMD) 0.23, 95% confidence interval (CI) 0.10–0.35] and activity levels (SMD 0.29, 95% CI 0.07–0.51), and a reduction in sedentariness [risk ratio (RR) 0.54, 95% CI 0.39–0.75] in CR participants, compared with usual care. Of clinical outcomes, the risk of re-hospitalization reduced significantly (RR 0.49, 95% CI 0.27–0.89), and there was reduction (non-significant) in mortality (RR 0.27, 95% CI 0.05–1.54). From the behavioural outcomes, reviews reported improvements in smoking behaviour (RR 0.87, 95% CI 0.67–1.13) and total diet quality intake (RR 0.79, 95% CI 0.66–0.94) among CR patients.

Conclusions

The use of devices/applications was associated with increase in activity, healthy behaviours, and reductions in clinical indicators. Although most effect sizes indicate limited clinical benefits, the broad consistency of the narrative suggests devices/applications are effective at improving CR patients’ outcomes.
Recombinant or endogenous thyroid-stimulating hormone for radioactive iodine therapy in thyroid cancer: state of knowledge and current controversies
Authors: Coerts Hannelore I , de Keizer Bart , Marlowe Robert J , Verburg Frederik A
Published: January 2023

For patients undergoing radioiodine therapy (RIT) of differentiated thyroid carcinoma (DTC), thyroid-stimulating hormone (TSH) stimulation prior to RIT can be achieved using thyroid hormone withdrawal (THW) or administration of recombinant human TSH (rhTSH). As THW can lead to nausea, headaches, vomiting, fatigue, and dizziness secondary to transient acute hypothyroidism, rhTSH could be a good alternative. Recombinant human TSH has been administered in patients in order to stimulate TSH for RIT since 2005. According to the Martinique criteria formulated by the leading professional societies involved in care of patients with DTC, rhTSH can be applied in 3 settings: for remnant ablation, adjuvant treatment, and treatment of known disease. Numerous studies have investigated the effects of rhTSH as a method of TSH stimulation on the thyroid cell, the systemic effects, biokinetics, and clinical outcomes; however, no consensus has been reached about many aspects of its potential use. Recombinant human TSH is able to stimulate sufficient TSH levels (>30 mIU L–1) and is hypothesized to decrease risks of tumor cell proliferation. As rhTSH-use avoids the transiently impaired renal function associated with THW, radioiodine excretion is faster with the former, leading to a lower iodine-131 uptake and a difference in fractional remnant uptake, effective half-life, mean residence time, and dose to the blood. Differences between rhTSH and THW were observed in radioiodine genotoxic effects and endothelial-dependent vasodilation and inflammation. For thyroid remnant ablation, THW and rhTSH lead to similar remnant ablation rates. For adjuvant therapy and treatment of known disease, insufficient trials have been conducted and future prospective studies are recommended. The current review provides a state-of-the-science overview on the issues and debates surrounding TSH stimulation through either rhTSH adminsitration orendogenous TSH production after levothyroxin withdrawal.
What do spontaneous coronary artery dissection survivors want to support their recovery? a qualitative study
Authors: Binnie Kirsten , Neubeck Lis , McHale Sheona , Hanson Coral L
Published: January 2023

Aims

Spontaneous coronary artery dissection (SCAD) is increasingly recognized as an important cause of myocardial infarction predominantly affecting women aged younger than 50 years. There is limited research addressing female and male SCAD survivors’ experience of, or requirements for, support post-SCAD. This study explored what SCAD survivors wanted to support recovery.

Methods and results

A qualitative study using semi-structured video and telephone interviews. Data were analysed through thematic analysis using the framework approach. We interviewed 20 participants (19 females) with a mean age of 54.6 (+/-SD 8.5 years). Three overarching themes encapsulated participants’ views about support requirements. (i) Education and information. Participants thought healthcare professionals involved in diagnosis and supporting recovery required greater awareness of SCAD and the psychological effect of SCAD. They wanted accessible SCAD information immediately post-event and during the educational component of cardiac rehabilitation. (ii) Physical activity. Requirements were for advice tailored to individuals’ specific needs, physical capabilities, and physical activity preferences. Participants suggested that utilizing wearable technology was helpful to encourage a safe return to activity. (iii) Psychosocial support. Participants wanted formal psychosocial support immediately post-event, during cardiac rehabilitation and in the longer term.

Conclusion

Better healthcare professional training may improve diagnosis, and increase support and awareness of SCAD. SCAD support programmes should provide early SCAD specific education utilizing online sources, individually tailor physical activity prescription, offer wearable technology to support a return to being active, and provide short- and long-term psychosocial support. As SCAD is predominately a female condition, programmes should consider female physical activity preferences.
Effects of the dual inoculation of dark septate endophytes and Trichoderma koningiopsis on blueberry growth and rhizosphere soil microorganisms
Authors: Li Si , Shang Xiao-Jing , Luo Qi-Xing , Yan Qian , Hou Rui
Published: January 2023

Blueberry is a shallow root plant in which the absorption of nutrients is inefficient, resulting in slow growth under artificial cultivation conditions. Endophytes play an important role in promoting plant growth; however, the effects of Trichoderma spp. and dark septate endophytes (DSEs) on host plant growth and soil microorganisms are still debatable. We isolated two endophytic fungal species, Trichoderma koningiopsis (TK) and a DSE (Amesia nigricolor; AN), from blueberry roots, which can solubilize insoluble phosphorus and produce amylase and cellulase to promote plant growth. We found that under dual inoculation, the colonization rate and colonization intensity of TK were higher than they were under single inoculation with TK, while the colonization rate and colonization intensity of AN were lower under dual inoculation than under single inoculation with AN. The plant nutrients, root activity, available potassium, and parts of soil phosphatase activities were highest under dual inoculation. TK inoculation resulted in the highest diversity and richness in the soil fungi and bacteria, followed by dual inoculation. The abundance of Ascomycota, Acidobacteriae, Firmicutes, and Actinobacteriota increased significantly, resulting in Trichoderma and Vicinamibacteria inoculated with TK, Chaetomium and Alicyclobacillales inoculated with AN, and Hypocreales and Burkholderiaceae with dual inoculation enriched in the soil.
Revealing the Permanent and Transient Plant Understory in Gallery Forests in the Cerrado of Central Brazil
Authors: Tavora Ana Carolina , Carvalho-Silva Micheline , Amaral Eliel de Jesus , Cupertino-Eisenlohr Mônica A , Nogueira Eloisa V , Munhoz Cássia Beatriz R
Published: January 2023

The understories of tropical forests comprise complex communities and can be divided into permanent understory, where the generally shade-tolerant plant growth forms are less developed in height, and transient understory, where young tree individuals are only temporarily present. Despite a high contribution to species richness in tropical forests, the understory is poorly studied. Here, we examined the species composition, richness, structure, diversity, and the relative contribution of growth forms in permanent and transient understories of gallery forests in the Brazilian Cerrado. A total of 211 species distributed into sixty-seven families and 153 genera were sampled. The most species-rich family was Rubiaceae, and Miconia was the genus with the highest species richness. The species Hildaea pallens had the highest importance in the forests. The best-represented growth forms were tree seedlings, followed by shrubs and lianas. The transient component of the understory in gallery forests was the most diverse. However, in terms of species relative cover, both transient and permanent understory species contributed equally to the understory structure, mainly due to the high cover of Poaceae species. Our study is the first to examine composition, structure, diversity, and growth forms in the permanent and transient understories of gallery forests.

Study Implications: Our study is innovative in describing the plant community attributes of gallery forest understories in the Brazilian Cerrado. The understories of tropical forests comprise complex communities and can be divided into permanent and transient understory. The transient component of the understory in gallery forests was the most diverse, represented by seedlings and young tree specimens. However, in terms of species relative cover, both transient and permanent understory species contributed equally to the understory structure. Here, we provide evidence that may be useful to initiatives seeking to conduct ecological restoration and conservation of gallery forests in the Cerrado.
SPR-1/CoREST facilitates the maternal epigenetic reprogramming of the histone demethylase SPR-5/LSD1
Authors: Carpenter Brandon S , Scott Alyssa , Goldin Robert , Chavez Sindy R , Rodriguez Juan D , Myrick Dexter A , Curlee Marcus , Schmeichel Karen L , Katz David J
Published: January 2023

Maternal reprogramming of histone methylation is critical for reestablishing totipotency in the zygote, but how histone-modifying enzymes are regulated during maternal reprogramming is not well characterized. To address this gap, we asked whether maternal reprogramming by the H3K4me1/2 demethylase SPR-5/LSD1/KDM1A, is regulated by the chromatin co-repressor protein, SPR-1/CoREST, in Caenorhabditis elegans and mice. In C. elegans, SPR-5 functions as part of a reprogramming switch together with the H3K9 methyltransferase MET-2. By examining germline development, fertility, and gene expression in double mutants between spr-1 and met-2, as well as fertility in double mutants between spr-1 and spr-5, we find that loss of SPR-1 results in a partial loss of SPR-5 maternal reprogramming function. In mice, we generated a separation of function Lsd1 M448V point mutation that compromises CoREST binding, but only slightly affects LSD1 demethylase activity. When maternal LSD1 in the oocyte is derived exclusively from this allele, the progeny phenocopy the increased perinatal lethality that we previously observed when LSD1 was reduced maternally. Together, these data are consistent with CoREST having a conserved function in facilitating maternal LSD1 epigenetic reprogramming.
Theorizing “Place” in Aging in Place: The Need for Territorial and Relational Perspectives
Authors: Yarker Sophie , Doran Patty , Buffel Tine
Published: January 2023

This paper argues for a greater theorization of “place” within aging-in-place research. It extends calls for a relational conceptualization of place by demonstrating the need for aging-in-place researchers to also pay greater attention to territorial aspects of place. This complementary understanding will help establish a new spatial grammar within aging-in-place research, that not only would improve conceptual clarity to aging in place, but would also support a more critical engagement of aging in place in questions of inequality. The paper demonstrates this through a discussion of 2 forms of inequality pertinent to older people: the uneven capacity of places to support older people and experiences of social exclusion in relation to place attachment for older people from marginalized groups.
A Cautionary Tale: examples of the mis-location of small earthquakes beneath the Tibetan plateau by routine approaches
Authors: Craig Timothy J , Jackson James , Priestley Keith , Ekström Göran
Published: January 2023

Earthquake moment tensors and centroid locations in the catalogue of the Global CMT (gCMT) project, formerly the Harvard CMT project, have become an essential resource for studying active global tectonics, used by many solid-Earth researchers. The catalogue’s quality, long duration (1976–present), ease of access and global coverage of earthquakes larger than about Mw 5.5 have transformed our ability to study regional patterns of earthquake locations and focal mechanisms. It also allows researchers to easily identify earthquakes with anomalous mechanisms and depths that stand out from the global or regional patterns, some of which require us to look more closely at accepted interpretations of geodynamics, tectonics or rheology. But, as in all catalogues that are, to some extent and necessarily, produced in a semi-routine fashion, the catalogue may contain anomalies that are in fact errors. Thus, before re-assessing geodynamic, tectonic or rheological understanding on the basis of anomalous earthquake locations or mechanisms in the gCMT catalogue, it is first prudent to check those anomalies are real. The purpose of this paper is to illustrate that necessity in the eastern Himalayas and SE Tibet, where two earthquakes that would otherwise require a radical revision of current geodynamic understanding are shown, in fact, to have gCMT depths (and, in one case, also focal mechanism) that are incorrect.
Review of surgical experience in 188 infants and young children with Ebstein anomaly
Authors: Liu Wei , Wen Chen , Shentu Jin , Ma Ruixiang , Zhang Hao , Zhu Zhongqun , Shi Guocheng , Chen Huiwen
Published: January 2023

OBJECTIVES

This study sought to review our single-institutional surgical experience in paediatric Ebstein anomaly (EA).

METHODS

We retrospectively reviewed the paediatric patients with EA undergoing operation between 2004 and 2020. The time-to-event analysis was studied using Kaplan–Meier estimates. Cox regression model was used to identify risk factors for recurrent moderate–severe or greater tricuspid regurgitation (TR).

RESULTS

A total of 188 patients at a median age of 3.0 [interquartile range (IQR), 1.6–5.6] years were included, among whom 108 (57.4%) underwent cone reconstruction (CR). Bidirectional cavopulmonary shunt was required in 53 patients (28.2%). There were no in-hospital deaths. The median follow-up time was 5.6 (IQR, 2.9–8.9) years. Twenty-three (12.2%) developed recurrent moderate–severe or greater TR, among whom 9 required reoperation and 1 had late death. There was a lower incidence of recurrent TR (P = 0.006) and reoperation for TR (P = 0.037) in the CR group compared with the non-CR group. There was no difference in the incidence of recurrent TR (P = 0.61), reoperation (P = 0.9) and death (P = 0.48) among patients aged <1, 1–4 and 4–18 years.

CONCLUSIONS

Acceptable outcomes can be anticipated in paediatric EA undergoing CR in terms of freedom from TR of > moderate degree at a mid-term follow-up.
Genetic Landscape of Major Depressive Disorder: Assessment of Potential Diagnostic and Antidepressant Response Markers
Authors: Singh Priyanka , Srivastava Ankit , Guin Debleena , Thakran Sarita , Yadav Jyoti , Chandna Puneet , Sood Mamta , Chadda Rakesh Kumar , Kukreti Ritushree
Published: January 2023

Background

The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation.

Methods

We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values.

Results

A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response.

Conclusions

The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.
Error estimates for physics-informed neural networks approximating the Navier–Stokes equations
Authors: De Ryck Tim , Jagtap Ameya D , Mishra Siddhartha
Published: January 2023

We prove rigorous bounds on the errors resulting from the approximation of the incompressible Navier–Stokes equations with (extended) physics-informed neural networks. We show that the underlying partial differential equation residual can be made arbitrarily small for tanh neural networks with two hidden layers. Moreover, the total error can be estimated in terms of the training error, network size and number of quadrature points. The theory is illustrated with numerical experiments.
P22 Patient-level meta-analysis of efficacy and safety from STRIVE and ReSTORE: randomized, double-blinded, multicentre Phase 2 and Phase 3 trials of rezafungin in the treatment of candidaemia and/or invasive candidiasis
Authors: Soriano A , Thompson G R , Cornely O A , Kullberg B J , Kollef M , Vazquez J , Honore P M , Bassetti M , Pullman J , Dignani C , Das A F , Sandison T , Pappas P G
Published: January 2023

Background

Rezafungin is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus and Pneumocystis spp. in blood and marrow transplantation. Rezafungin once-weekly (QWk) was compared to caspofungin once-daily (QD) in two double-blind, randomized, controlled trials in patients with candidaemia and/or IC: STRIVE (Phase 2; NCT02734862) and the recently completed ReSTORE (Phase 3; NCT03667690). STRIVE demonstrated the efficacy and safety profile of rezafungin. ReSTORE showed rezafungin noninferiority to caspofungin for 30 day all-cause mortality (ACM) and global response at Day 14 with comparable safety. Patient-level meta-analyses of efficacy and safety from both trials are presented.

Methods

Details of STRIVE and ReSTORE were previously described. In this analysis of data from both trials, patients who received rezafungin QWk (400 mg in Week 1, then 200 mg) were compared with those who received caspofungin QD (70 mg on Day 1 followed by 50 mg) for ≥14 days (up to 4 weeks). Efficacy endpoints included 30 day ACM (primary US FDA), mycological response at Day 5 (secondary), and time to first negative blood culture (TTNBC) (exploratory). Safety was evaluated by adverse events (AEs).

Results

Groups were well matched (Table 1). Figure 1 shows 30 day ACM (overall and by final diagnosis). Mycological response at Day 5 was 73.4% (102/139) and 64.5% (100/155) in rezafungin and caspofungin groups, respectively (difference=9.5, 95% CI=−0.9, 19.9). In patients with positive blood culture before randomization, median TTNBC was 22.3 h in rezafungin-treated versus 26.3 h in caspofungin-treated patients (stratified log rank p=0.0034, not adjusted for multiplicity). The summary of AEs (Table 2) demonstrates similar outcomes for rezafungin and caspofungin groups.

Conclusions

In the Phase 2/3 patient-level meta-analysis, rezafungin QWk demonstrated efficacy with a similar 30 day ACM rate and safety comparable to that of caspofungin QD. Data for mycological eradication at Day 5 and TTNBC support results from the primary efficacy endpoint and provide initial evidence for the theory that high, front-loaded drug exposure leads to faster fungal clearance. Further analysis of this integrated dataset may provide additional insights on rezafungin efficacy and safety.
The PhenX Toolkit: standard measurement resources for cancer outcomes and survivorship research
Authors: Nekhlyudov Larissa , Bellizzi Keith , Galligan Andrew , King-Kallimanis Bellinda , Mayer Deborah K , Miaskowski Christine , Salz Talya , McCarty Catherine , Cox Lisa , Hill Christine , Hendershot Tabitha P , Maiese Deborah R , Hamilton Carol M
Published: January 2023

This brief report introduces the Cancer Outcomes and Survivorship domain in the PhenX Toolkit (consensus measures for Phenotypes and eXposures), which includes 15 validated measurement protocols for cancer survivorship research that were recommended for inclusion in this publicly available resource. Developed with input from the scientific community, the domain provides researchers with well-established measurement protocols for evaluating physical and psychological effects, financial toxicity, and patient experiences with cancer care. The PhenX Toolkit, funded by the National Human Genome Research Institute since 2007, is an online resource that provides high-quality standard measurement protocols for a wide range of research areas (eg, smoking cessation, harm reduction and biomarkers, and social determinants of health). Use of the PhenX Cancer Survivorship Outcomes and Survivorship domain can simplify the selection of measurement protocols, data sharing, and comparisons across studies investigating the cancer survivorship experience.