bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood-based transcriptomic signature panel identification for cancer diagnosis: benchmarking of feature extraction methods
Authors: Vijayan Abhishek , Fatima Shadma , Sowmya Arcot , Vafaee Fatemeh
Published: August 2022

Liquid biopsy has shown promise for cancer diagnosis due to its minimally invasive nature and the potential for novel biomarker discovery. However, the low concentration of relevant blood-based biosources and the heterogeneity of samples (i.e. the variability of relative abundance of molecules identified), pose major challenges to biomarker discovery. Moreover, the number of molecular measurements or features (e.g. transcript read counts) per sample could be in the order of several thousand, whereas the number of samples is often substantially lower, leading to the curse of dimensionality. These challenges, among others, elucidate the importance of a robust biomarker panel identification or feature extraction step wherein relevant molecular measurements are identified prior to classification for cancer detection. In this work, we performed a benchmarking study on 12 feature extraction methods using transcriptomic profiles derived from different blood-based biosources. The methods were assessed both in terms of their predictive performance and the robustness of the biomarker panels in diagnosing cancer or stratifying cancer subtypes. While performing the comparison, the feature extraction methods are categorized into feature subset selection methods and transformation methods. A transformation feature extraction method, namely partial least square discriminant analysis, was found to perform consistently superior in terms of classification performance. As part of the benchmarking study, a generic pipeline has been created and made available as an R package to ensure reproducibility of the results and allow for easy extension of this study to other datasets (https://github.com/VafaeeLab/bloodbased-pancancer-diagnosis).
Scalable batch-correction approach for integrating large-scale single-cell transcriptomes
Authors: Shen Xilin , Shen Hongru , Wu Dan , Feng Mengyao , Hu Jiani , Liu Jilei , Yang Yichen , Yang Meng , Li Yang , Shi Lei , Chen Kexin , Li Xiangchun
Published: August 2022

Integration of accumulative large-scale single-cell transcriptomes requires scalable batch-correction approaches. Here we propose Fugue, a simple and efficient batch-correction method that is scalable for integrating super large-scale single-cell transcriptomes from diverse sources. The core idea of the method is to encode batch information as trainable parameters and add it to single-cell expression profile; subsequently, a contrastive learning approach is used to learn feature representation of the additive expression profile. We demonstrate the scalability of Fugue by integrating all single cells obtained from the Human Cell Atlas. We benchmark Fugue against current state-of-the-art methods and show that Fugue consistently achieves improved performance in terms of data alignment and clustering preservation. Our study will facilitate the integration of single-cell transcriptomes at increasingly large scale.
Peripheral tau as a biomarker for neurodegenerative diseases: is life on Earth, life on Mars?
Authors: Dugger Brittany N , Harvey Danielle , Beach Thomas G , Adler Charles H
Published: August 2022

This scientific commentary refers to ‘Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies’ by Vacchi et al. (https://doi.org/10.1093/brain/awac161).
The influence of imagery vividness and internally-directed attention on the neural mechanisms underlying the encoding of visual mental images into episodic memory
Authors: Gjorgieva Eva , Geib Benjamin R , Cabeza Roberto , Woldorff Marty G
Published: August 2022

Attention can be directed externally toward sensory information or internally toward self-generated information. Using electroencephalography (EEG), we investigated the attentional processes underlying the formation and encoding of self-generated mental images into episodic memory. Participants viewed flickering words referring to common objects and were tasked with forming visual mental images of the objects and rating their vividness. Subsequent memory for the presented object words was assessed using an old–new recognition task. Internally-directed attention during image generation was indexed as a reduction in steady-state visual evoked potentials (SSVEPs), oscillatory EEG responses at the frequency of a flickering stimulus. The results yielded 3 main findings. First, SSVEP power driven by the flickering word stimuli decreased as subjects directed attention internally to form the corresponding mental image. Second, SSVEP power returned to pre-imagery baseline more slowly for low- than high-vividness later remembered items, suggesting that longer internally-directed attention is required to generate subsequently remembered low-vividness images. Finally, the event-related-potential difference due to memory was more sustained for subsequently remembered low- versus high-vividness items, suggesting that additional conceptual processing may have been needed to remember the low-vividness visual images. Taken together, the results clarify the neural mechanisms supporting the encoding of self-generated information.
Delay-related activity in marmoset prefrontal cortex
Authors: Wong Raymond K , Selvanayagam Janahan , Johnston Kevin D , Everling Stefan
Published: August 2022

Persistent delay-period activity in prefrontal cortex (PFC) has long been regarded as a neural signature of working memory (WM). Electrophysiological investigations in macaque PFC have provided much insight into WM mechanisms; however, a barrier to understanding is the fact that a portion of PFC lies buried within the principal sulcus in this species and is inaccessible for laminar electrophysiology or optical imaging. The relatively lissencephalic cortex of the New World common marmoset (Callithrix jacchus) circumvents such limitations. It remains unknown, however, whether marmoset PFC neurons exhibit persistent activity. Here, we addressed this gap by conducting wireless electrophysiological recordings in PFC of marmosets performing a delayed-match-to-location task on a home cage-based touchscreen system. As in macaques, marmoset PFC neurons exhibited sample-, delay-, and response-related activity that was directionally tuned and linked to correct task performance. Models constructed from population activity consistently and accurately predicted stimulus location throughout the delay period, supporting a framework of delay activity in which mnemonic representations are relatively stable in time. Taken together, our findings support the existence of common neural mechanisms underlying WM performance in PFC of macaques and marmosets and thus validate the marmoset as a suitable model animal for investigating the microcircuitry underlying WM.
Normative quantitative relaxation atlases for characterization of cortical regions using magnetic resonance fingerprinting
Authors: Choi Joon Yul , Hu Siyuan , Su Ting-Yu , Murakami Hiroatsu , Tang Yingying , Blümcke Ingmar , Najm Imad , Sakaie Ken , Jones Stephen , Griswold Mark , Wang Zhong Irene , Ma Dan
Published: August 2022

Quantitative magnetic resonance (MR) has been used to study cyto- and myelo-architecture of the human brain non-invasively. However, analyzing brain cortex using high-resolution quantitative MR acquisition can be challenging to perform using 3T clinical scanners. MR fingerprinting (MRF) is a highly efficient and clinically feasible quantitative MR technique that simultaneously provides T1 and T2 relaxation maps. Using 3D MRF from 40 healthy subjects (mean age = 25.6 ± 4.3 years) scanned on 3T magnetic resonance imaging, we generated whole-brain gyral-based normative MR relaxation atlases and investigated cortical-region-based T1 and T2 variations. Gender and age dependency of T1 and T2 variations were additionally analyzed. The coefficient of variation of T1 and T2 for each cortical-region was 3.5% and 7.3%, respectively, supporting low variability of MRF measurements across subjects. Significant differences in T1 and T2 were identified among 34 brain regions (P < 0.001), lower in the precentral, postcentral, paracentral lobule, transverse temporal, lateral occipital, and cingulate areas, which contain sensorimotor, auditory, visual, and limbic functions. Significant correlations were identified between age and T1 and T2 values. This study established whole-brain MRF T1 and T2 atlases of healthy subjects using a clinical 3T scanner, which can provide a quantitative and region-specific baseline for future brain studies and pathology detection.
Coronary physiology to guide treatment of coronary artery disease in a patient with severe aortic valve stenosis: friend or foe? A case report
Authors: Minten Lennert , McCutcheon Keir , Bennett Johan , Dubois Christophe
Published: August 2022

Background

Severe aortic valve stenosis (AS) is the most frequent valve pathology in the developed world requiring intervention. Due to common factors in pathogenesis, patients with AS frequently have concomitant coronary artery disease (CAD). Determining the relative contribution of each component to the disease state is not easy as there is much overlap in complaints. Moreover, severe AS interferes with the haemodynamic assessment of intermediate coronary lesions.

Case summary

In this case report we describe the presentation and management of an 84-year-old patient, with a severely degenerated aortic valve bioprosthesis and an intermediate coronary artery lesion, presenting with acute decompensated heart failure and chest pain. Initial invasive haemodynamic assessment of the coronary lesion provided challenging findings and a second catheterization and intervention was needed to free the patient from his chest pain.

Discussion

Optimal assessment and treatment of CAD before valve replacement are controversial. Aortic valve stenosis on itself can lead to subendocardial ischaemia with subsequent angina pectoris. Simultaneously, AS can significantly affect coronary haemodynamics, hereby interfering with intra-coronary haemodynamic assessment of co-existing coronary lesions. Currently used coronary physiological indices are not validated in the AS population and valve replacement has variable effects on the fractional flow reserve and commonly used resting indices, such as the resting full-cycle ratio. Further research on this topic is needed and an overview of currently running studies that will advance this field significantly is provided.
Unilateral left-sided thoracoscopic ablation of atrial fibrillation concomitant to minimally invasive bypass grafting of the left anterior descending artery
Authors: van der Heijden Claudia A J , Segers Patrique , Masud Anna , Weberndörfer Vanessa , Chaldoupi Sevasti-Marisevi , Luermans Justin G L M , Bijvoet Geertruida P , Kietselaer Bas L J H , van Kuijk Sander M J , Barenbrug Paul J C , Maessen Jos G , Bidar Elham , Maesen Bart
Published: August 2022

OBJECTIVES

Thoracoscopic ablation for atrial fibrillation (AF) and minimally invasive direct coronary artery bypass (MIDCAB) with robot-assisted left internal mammary artery (LIMA) harvesting may represent a safe and effective alternative to more invasive surgical approaches via sternotomy. The aim of our study was to describe the feasibility, safety and efficacy of a unilateral left-sided thoracoscopic AF ablation and concomitant MIDCAB surgery.

METHODS

Retrospective analysis of a prospectively gathered cohort was performed of all consecutive patients with AF and at least a critical left anterior descending artery (LAD) stenosis that underwent unilateral left-sided thoracoscopic AF ablation and concomitant off-pump MIDCAB surgery in the Maastricht University Medical Centre between 2017 and 2021.

RESULTS

Twenty-three patients were included [age 69 years (standard deviation = 8), paroxysmal AF 61%, left atrial volume index 42 ml/m2 (standard deviation = 11)]. Unilateral left-sided thoracoscopic isolation of the left (n = 23) and right (n = 22) pulmonary veins and box (n = 21) by radiofrequency ablation was succeeded by epicardial validation of exit- and entrance block (n = 22). All patients received robot-assisted LIMA harvesting and off-pump LIMA-LAD anastomosis through a left mini-thoracotomy. The perioperative complications consisted of one bleeding of the thoracotomy wound and one aborted myocardial infarction not requiring intervention. The mean duration of hospital stay was 6 days (standard deviation = 2). After discharge, cardiac hospital readmission occurred in 4 patients (AF n = 1; pleural- and pericardial effusion n = 2, myocardial infarction requiring the percutaneous intervention of the LIMA-LAD n = 1) within 1 year. After 12 months, 17/21 (81%) patients were in sinus rhythm when allowing anti-arrhythmic drugs. Finally, the left atrial ejection fraction improved postoperatively [26% (standard deviation = 11) to 38% (standard deviation = 7), P = 0.01].

CONCLUSIONS

In this initial feasibility and early safety study, unilateral left-sided thoracoscopic AF ablation and concomitant MIDCAB for LIMA-LAD grafting is a feasible, safe and efficacious for patients with AF and a critical LAD stenosis.
Biosynthesis of insect sex pheromone precursors via engineered β-oxidation in yeast
Authors: Petkevicius Karolis , Wenning Leonie , Kildegaard Kanchana R , Sinkwitz Christina , Smedegaard Rune , Holkenbrink Carina , Borodina Irina
Published: August 2022

Mating disruption with insect sex pheromones is an attractive and environmentally friendly technique for pest management. Several Lepidoptera sex pheromones have been produced in yeast, where biosynthesis could be accomplished by the expression of fatty acyl-CoA desaturases and fatty acyl-CoA reductases. In this study, we aimed to develop yeast Yarrowia lipolytica cell factories for producing Lepidoptera pheromones which biosynthesis additionally requires β-oxidation, such as (Z)-7-dodecenol (Z7-12:OH), (Z)-9-dodecenol (Z9-12:OH), and (Z)-7-tetradecenol (Z7-14:OH). We expressed fatty acyl-CoA desaturases from Drosophila melanogaster (Dmd9) or Lobesia botrana (Lbo_PPTQ) and fatty acyl-CoA reductase from Helicoverpa armigera (HarFAR) in combinations with 11 peroxisomal oxidases of different origins. Yeast cultivations were performed with supplementation of methyl myristate (14:Me). The oxidase Lbo_31670 from L. botrana provided the highest titers of (Z)-7-dodecenoate, (Z)-9-dodecenoate, and (Z)-7-tetradecenoate. However, no chain-shortened fatty alcohols were produced. The mutation of fatty acid synthase (Fas2pI1220F) to increase myristate production did not lead to targeted fatty alcohol production. The problem was solved by directing the reductase into peroxisomes, where the strain with Dmd9 produced 0.10 ± 0.02 mg/l of Z7-12:OH and 0.48 ± 0.03 mg/l of Z7-14:OH, while the strain with Lbo_PPTQ produced 0.21 ± 0.03 mg/l of Z9-12:OH and 0.40 ± 0.07 mg/l of Z7-14:OH. In summary, the engineering of β-oxidation in Y. lipolytica allowed expanding the portfolio of microbially produced insect sex pheromones.
Functional Compensation of Mouse Duplicates by their Paralogs Expressed in the Same Tissues
Authors: Luzuriaga-Neira Agusto , Subramanian Krishnamurthy , Alvarez-Ponce David
Published: August 2022

Analyses in a number of organisms have shown that duplicated genes are less likely to be essential than singletons. This implies that genes can often compensate for the loss of their paralogs. However, it is unclear why the loss of some duplicates can be compensated by their paralogs, whereas the loss of other duplicates cannot. Surprisingly, initial analyses in mice did not detect differences in the essentiality of duplicates and singletons. Only subsequent analyses, using larger gene knockout data sets and controlling for a number of confounding factors, did detect significant differences. Previous studies have not taken into account the tissues in which duplicates are expressed. We hypothesized that in complex organisms, in order for a gene’s loss to be compensated by one or more of its paralogs, such paralogs need to be expressed in at least the same set of tissues as the lost gene. To test our hypothesis, we classified mouse duplicates into two categories based on the expression patterns of their paralogs: “compensable duplicates” (those with paralogs expressed in all the tissues in which the gene is expressed) and “noncompensable duplicates” (those whose paralogs are not expressed in all the tissues where the gene is expressed). In agreement with our hypothesis, the essentiality of noncompensable duplicates is similar to that of singletons, whereas compensable duplicates exhibit a substantially lower essentiality. Our results imply that duplicates can often compensate for the loss of their paralogs, but only if they are expressed in the same tissues. Indeed, the compensation ability is more dependent on expression patterns than on protein sequence similarity. The existence of these two kinds of duplicates with different essentialities, which has been overlooked by prior studies, may have hindered the detection of differences between singletons and duplicates.
Genomic Insights into Genetic Diploidization in the Homosporous Fern Adiantum nelumboides
Authors: Zhong Yan , Liu Yongbo , Wu Wei , Chen Jingfang , Sun Chenyu , Liu Hongmei , Shu Jiangping , Ebihara Atsushi , Yan Yuehong , Zhou Renchao , Schneider Harald
Published: August 2022

Whole-genome duplication has been recognized as a major process in speciation of land plants, especially in ferns. Whereas genome downsizing contributes greatly to the post-genome shock responses of polyploid flowering plants, diploidization of polyploid ferns diverges by maintaining most of the duplicated DNA and is thus expected to be dominated by genic processes. As a consequence, fern genomes provide excellent opportunities to study ecological speciation enforced by expansion of protein families via polyploidy. To test the key predictions of this hypothesis, we reported the de novo genome sequence of Adiantum nelumboides, a tetraploid homosporous fern. The obtained draft genome had a size of 6.27 Gb assembled into 11,767 scaffolds with the contig N50 of 1.37 Mb. Repetitive DNA sequences contributed with about 81.7%, a remarkably high proportion of the genome. With 69,568, the number of predicted protein-coding genes exceeded those reported in most other land plant genomes. Intragenomic synteny analyses recovered 443 blocks with the average block size of 1.29 Mb and the average gene content of 16 genes. The results are consistent with the hypothesis of high ancestral chromosome number, lack of substantial genome downsizing, and dominance of genic diploidization. As expected in the calciphilous plants, a notable number of detected genes were involved in calcium uptake and transport. In summary, the genome sequence of a tetraploid homosporous fern not only provides access to a genomic resource of a derived fern, but also supports the hypothesis of maintenance of high chromosome numbers and duplicated DNA in young polyploid ferns.
Diploid-associated adaptation to chronic low-dose UV irradiation requires homologous recombination in Saccharomyces cerevisiae
Authors: Shibata Mana , Keyamura Kenji , Shioiri Takuya , Noda Shunsuke , Akanuma Genki , Hishida Takashi
Published: August 2022

Ultraviolet-induced DNA lesions impede DNA replication and transcription and are therefore a potential source of genome instability. Here, we performed serial transfer experiments on nucleotide excision repair-deficient (rad14Δ) yeast cells in the presence of chronic low-dose ultraviolet irradiation, focusing on the mechanisms underlying adaptive responses to chronic low-dose ultraviolet irradiation. Our results show that the entire haploid rad14Δ population rapidly becomes diploid during chronic low-dose ultraviolet exposure, and the evolved diploid rad14Δ cells were more chronic low-dose ultraviolet-resistant than haploid cells. Strikingly, single-stranded DNA, but not pyrimidine dimer, accumulation is associated with diploid-dependent fitness in response to chronic low-dose ultraviolet stress, suggesting that efficient repair of single-stranded DNA tracts is beneficial for chronic low-dose ultraviolet tolerance. Consistent with this hypothesis, homologous recombination is essential for the rapid evolutionary adaptation of diploidy, and rad14Δ cells lacking Rad51 recombinase, a key player in homologous recombination, exhibited abnormal cell morphology characterized by multiple RPA–yellow fluorescent protein foci after chronic low-dose ultraviolet exposure. Furthermore, interhomolog recombination is increased in chronic low-dose ultraviolet-exposed rad14Δ diploids, which causes frequent loss of heterozygosity. Thus, our results highlight the importance of homologous recombination in the survival and genomic stability of cells with unrepaired lesions.
Benchmarking ultra-high molecular weight DNA preservation methods for long-read and long-range sequencing
Authors: Dahn Hollis A , Mountcastle Jacquelyn , Balacco Jennifer , Winkler Sylke , Bista Iliana , Schmitt Anthony D , Pettersson Olga Vinnere , Formenti Giulio , Oliver Karen , Smith Michelle , Tan Wenhua , Kraus Anne , Mac Stephen , Komoroske Lisa M , Lama Tanya , Crawford Andrew J , Murphy Robert W , Brown Samara , Scott Alan F , Morin Phillip A , Jarvis Erich D , Fedrigo Olivier
Published: August 2022

Background

Studies in vertebrate genomics require sampling from a broad range of tissue types, taxa, and localities. Recent advancements in long-read and long-range genome sequencing have made it possible to produce high-quality chromosome-level genome assemblies for almost any organism. However, adequate tissue preservation for the requisite ultra-high molecular weight DNA (uHMW DNA) remains a major challenge. Here we present a comparative study of preservation methods for field and laboratory tissue sampling, across vertebrate classes and different tissue types.

Results

We find that storage temperature was the strongest predictor of uHMW fragment lengths. While immediate flash-freezing remains the sample preservation gold standard, samples preserved in 95% EtOH or 20–25% DMSO-EDTA showed little fragment length degradation when stored at 4°C for 6 hours. Samples in 95% EtOH or 20–25% DMSO-EDTA kept at 4°C for 1 week after dissection still yielded adequate amounts of uHMW DNA for most applications. Tissue type was a significant predictor of total DNA yield but not fragment length. Preservation solution had a smaller but significant influence on both fragment length and DNA yield.

Conclusion

We provide sample preservation guidelines that ensure sufficient DNA integrity and amount required for use with long-read and long-range sequencing technologies across vertebrates. Our best practices generated the uHMW DNA needed for the high-quality reference genomes for phase 1 of the Vertebrate Genomes Project, whose ultimate mission is to generate chromosome-level reference genome assemblies of all ∼70,000 extant vertebrate species.
Stardust: improving spatial transcriptomics data analysis through space-aware modularity optimization-based clustering
Authors: Avesani Simone , Viesi Eva , Alessandrì Luca , Motterle Giovanni , Bonnici Vincenzo , Beccuti Marco , Calogero Raffaele , Giugno Rosalba
Published: August 2022

Background

Spatial transcriptomics (ST) combines stained tissue images with spatially resolved high-throughput RNA sequencing. The spatial transcriptomic analysis includes challenging tasks like clustering, where a partition among data points (spots) is defined by means of a similarity measure. Improving clustering results is a key factor as clustering affects subsequent downstream analysis. State-of-the-art approaches group data by taking into account transcriptional similarity and some by exploiting spatial information as well. However, it is not yet clear how much the spatial information combined with transcriptomics improves the clustering result.

Results

We propose a new clustering method, Stardust, that easily exploits the combination of space and transcriptomic information in the clustering procedure through a manual or fully automatic tuning of algorithm parameters. Moreover, a parameter-free version of the method is also provided where the spatial contribution depends dynamically on the expression distances distribution in the space. We evaluated the proposed methods results by analyzing ST data sets available on the 10x Genomics website and comparing clustering performances with state-of-the-art approaches by measuring the spots' stability in the clusters and their biological coherence. Stability is defined by the tendency of each point to remain clustered with the same neighbors when perturbations are applied.

Conclusions

Stardust is an easy-to-use methodology allowing to define how much spatial information should influence clustering on different tissues and achieving more stable results than state-of-the-art approaches.
Thoracoscopic resection of pulmonary sequestration with carbon dioxide insufflation and indocyanine green
Authors: Koike Sachie , Miyazawa Masahisa , Kobayashi Nobutaka
Published: August 2022

We encountered a rare case of pulmonary sequestration supplied from the right renal artery, which was resected by video-assisted thoracic surgery with carbon dioxide insufflation and indocyanine green-guided technique. A 41-year-old woman with intralobar pulmonary sequestration supplied from the right renal artery was referred to our department. At the time of surgery, we used carbon dioxide insufflation to improve the manoeuvrable workspace for shutting off aberrant arteries and indocyanine green fluorescence guidance to differentiate the boundary of the sequestered lung from the normal lung. These procedures helped in the efficient resection of the lesion.
Comparison of intergenerational instrumental variable analyses of body mass index and mortality in UK Biobank
Authors: Barry Ciarrah-Jane , Carslake David , Wade Kaitlin H , Sanderson Eleanor , Davey Smith George
Published: August 2022

Background

An increasing proportion of people have a body mass index (BMI) classified as overweight or obese and published studies disagree whether this will be beneficial or detrimental to health. We applied and evaluated two intergenerational instrumental variable methods to estimate the average causal effect of BMI on mortality in a cohort with many deaths: the parents of UK Biobank participants.

Methods

In Cox regression models, parental BMI was instrumented by offspring BMI using an ‘offspring as instrument’ (OAI) estimation and by offspring BMI-related genetic variants in a ‘proxy-genotype Mendelian randomization’ (PGMR) estimation.

Results

Complete-case analyses were performed in parents of 233 361 UK Biobank participants with full phenotypic, genotypic and covariate data. The PGMR method suggested that higher BMI increased mortality with hazard ratios per kg/m2 of 1.02 (95% CI: 1.01, 1.04) for mothers and 1.04 (95% CI: 1.02, 1.05) for fathers. The OAI method gave considerably higher estimates, which varied according to the parent–offspring pairing between 1.08 (95% CI: 1.06, 1.10; mother–son) and 1.23 (95% CI: 1.16, 1.29; father–daughter).

Conclusion

Both methods supported a causal role of higher BMI increasing mortality, although caution is required regarding the immediate causal interpretation of these exact values. Evidence of instrument invalidity from measured covariates was limited for the OAI method and minimal for the PGMR method. The methods are complementary for interrogating the average putative causal effects because the biases are expected to differ between them.
Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker
Authors: Weigand Anne , Gärtner Matti , Scheidegger Milan , Wyss Patrik O , Henning Anke , Seifritz Erich , Stippl Anna , Herrera-Melendez Ana , Bajbouj Malek , Aust Sabine , Grimm Simone
Published: August 2022

Background

Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy.

Methods

We here explored the potential of pregenual anterior cingulate cortex (pgACC) activity to predict antidepressant effects of ketamine in relation to ketamine-induced changes in glutamatergic metabolism. Prior to a single i.v. infusion of ketamine, 24 patients with MDD underwent functional magnetic resonance imaging during an emotional picture-viewing task and magnetic resonance spectroscopy. Changes in depressive symptoms were evaluated using the Beck Depression Inventory measured 24 hours pre- and post-intervention. A subsample of 17 patients underwent a follow-up magnetic resonance spectroscopy scan.

Results

Antidepressant efficacy of ketamine was predicted by pgACC activity during emotional stimulation. In addition, pgACC activity was associated with glutamate increase 24 hours after the ketamine infusion, which was in turn related to better clinical outcome.

Conclusions

Our results add to the growing literature implicating a key role of the pgACC in mediating antidepressant effects and highlighting its potential as a multimodal neuroimaging biomarker of early treatment response to ketamine.
Expired medications and disposal practices in Arab households
Authors: Ghemrawi Rose , Kharaba Zelal , Aldulaymi Raghad , AlBataineh Nezar , Alghaly Fady , Qasem Naji , Khair Mostafa
Published: August 2022

Objectives

Over the past few decades, the accumulation of expired and unused medications in households has become a concern. Most people are unaware of how to properly dispose of unused and/or expired medicines. Our objective was to inspect the extent of expired medications within Arab households in United Arab Emirates (UAE), to determine which therapeutic groups yield greater amounts of unused medications, and evaluate drugs’ disposal practices.

Methods

This descriptive study was written in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for cross-sectional studies. It was conducted among Arab households in UAE (n = 503) using an online questionnaire between November 2020 and January 2021. Questions were related to participants’ socio-demographics, the prevalence of expired medications in households and their disposal.

Key findings

Around 58% of the respondents had expired medications in their houses and 74% had drugs that were never used. The most common medicines left unused were analgesics (34%) followed by cosmetics (27%) and antibiotics (26%). More than 42% of expired medications were in solid dosage forms, 28% were semisolid and 24% were liquid dosage forms. The predominant disposal method among the surveyed participants was throwing medications into the garbage (86%).

Conclusions

Large quantities of expired medications in Arab households exist with a high prevalence of analgesics, antibiotics and cosmetics. Arab households are unaware of the proper drug disposal procedures. Therefore, community pharmacists are recommended to offer training on proper medication disposal practices and to encourage the public to return medications to pharmacies.
Describing the impact of community pharmacy organisation type on emergency hormonal contraception services in England
Authors: Thayer Nick , White Simon , Frisher Martin
Published: August 2022

Objectives

In England, non-dispensing pharmacy services are commissioned either nationally or locally. For the national service Medicines Use Reviews (MURs), large multiple/chain pharmacies provide more consultations than independents. This study aimed to examine the relationship between community pharmacy organisation type and a local service, Emergency Hormonal Contraception (EHC). It also aimed to explore the influence of deprivation.

Methods

Freedom of information requests was sent to all 147 local authorities in England. Data included the number of EHC consultations by individual pharmacies across England (2017/18). Public data were used to identify pharmacies, match with MUR data, and group by organisation type. Bivariate correlations and ANOVA described the relationship between service provision, organisation type and deprivation.

Key findings

Pharmacy data were obtained from 76 (52%) local authorities. Following removal of unidentifiable pharmacies, 3069 were analysed – 56% of the estimated 5461 commissioned pharmacies in England. Bivariate correlations indicated a significant negative correlation between EHC provision and Index of Multiple Deprivation score. Greater deprivation correlated to greater EHC provision. A One-way ANOVA demonstrated significant differences between organisation types for MUR provision (larger organisations providing greater volumes). EHC provision demonstrated significant differences between groups and a U-shaped association; large multiple and independent organisations had higher levels than medium and small chains. A two-way ANOVA showed no significant interaction between deprivation and organisation type.

Conclusions

EHC provision does not increase linearly with organisation type. Deprivation appears a more reliable indicator of EHC provision. Provision is likely influenced by local factors but could increase with a nationally commissioned service.
Risk factors associated with cardiovascular mortality among gastric cancer patients: a population-based analysis
Authors: Wang Jing , Wang Qi , Du Xinyu , Zhu Xiaojie , Nie Chuang , Han Xu , Tian Wenjing , Li He , Zhou Haibo
Published: August 2022

Background

Cancer patients were found at a high risk of death from cardiovascular disease. This study aims to assess cardiovascular mortality risk and identify the potential risk factors associated with cardiovascular mortality among gastric cancer patients.

Methods

Gastric cancer patients were collected from the Surveillance Epidemiology and End Results database during 1975–2016. Standardized mortality ratios were calculated to compare cardiovascular mortality rates between gastric cancer patients and the general US population. Univariable Cox analysis and multivariable stepwise Cox analysis were adopted to identify the potential risk factors for cardiovascular disease death after gastric cancer diagnosis.

Results

There were 10 886 cardiovascular disease deaths identified among 165 433 individuals with gastric cancer observed for 410207.20 person-years. Gastric cancer patients were at a higher cardiovascular disease mortality risk (standardized mortality ratio = 3.35, 95% confidence interval: 3.24–3.47, P < 0.05). The study showed that older age at diagnosis (>80 years vs. 0–69 years, hazard ratio = 7.05, 95% confidence interval: 6.66–7.46, P < 0.001; 70–80 years vs. 0–69 years, hazard ratio = 3.35, 95% confidence interval: 3.19–3.53, P < 0.001), male sex (vs. female, hazard ratio = 1.39, 95% confidence interval: 1.33–1.45, P < 0.001), black race (vs. white, hazard ratio = 1.31, 95% confidence interval: 1.24–1.38, P < 0.001), without a partner (divorced/separated vs. married/partnered, hazard ratio = 1.35, 95% confidence interval: 1.25–1.45, P < 0.001; single vs. married/partnered, hazard ratio = 1.20, 95% confidence interval: 1.12–1.29, P < 0.001; widowed vs. married/partnered, hazard ratio = 1.41, 95% confidence interval: 1.34–1.48, P < 0.001), living in the northern plains (vs. pacific coast, hazard ratio = 1.23, 95% confidence interval: 1.16–1.29, P < 0.001) and surgery not performed (vs. performed, hazard ratio = 1.70, 95% confidence interval: 1.61–1.79, P < 0.001) were significantly associated with increased risk of cardiovascular disease death. Compared with patients with localized stage, distant staged patients were less likely to die of cardiovascular disease (hazard ratio = 0.88, 95% confidence interval: 0.83–0.94, P < 0.001).

Conclusions

Gastric cancer patients were at an increased risk of cardiovascular disease death. Older age at diagnosis, male sex, black race, without a partner, living in the northern plains and surgery not performed were significantly associated with cardiovascular disease death after gastric cancer diagnosis.
Transoral Robotic Surgery for Recurrent Tumors of the Upper Aerodigestive Tract (RECUT): An International Cohort Study
Authors: Hardman John C , Holsinger F Chris , Brady Grainne C , Beharry Avinash , Bonifer Alec T , D’Andréa Gregoire , Dabas Surender K , de Almeida John R , Duvvuri Umamaheswar , Floros Peter , Ghanem Tamer A , Gorphe Philippe , Gross Neil D , Hamilton David , Kurukulasuriya Chareeni , Larsen Mikkel Hjordt Holm , Lin Daniel J , Magnuson J Scott , Meulemans Jeroen , Miles Brett A , Moore Eric J , Pantvaidya Gouri , Roof Scott , Rubek Niclas , Simon Christian , Subash Anand , Topf Michael C , Van Abel Kathryn M , Vander Poorten Vincent , Walgama Evan S , Greenlay Emily , Potts Laura , Balaji Arun , Starmer Heather M , Stephen Sarah , Roe Justin , Harrington Kevin , Paleri Vinidh
Published: August 2022

Background

Transoral robotic surgery (TORS) is an emerging minimally invasive surgical treatment for residual, recurrent, and new primary head and neck cancers in previously irradiated fields, with limited evidence for its oncological effectiveness.

Methods

A retrospective observational cohort study of consecutive cases performed in 16 high-volume international centers before August 2018 was conducted (registered at clinicaltrials.gov [NCT04673929] as the RECUT study). Overall survival (OS), disease-free survival, disease-specific survivals (DSS), and local control (LC) were calculated using Kaplan-Meier estimates, with subgroups compared using log-rank tests and Cox proportional hazards modeling for multivariable analysis. Maximally selected rank statistics determined the cut point for closest surgical resection margin based on LC.

Results

Data for 278 eligible patients were analyzed, with median follow-up of 38.5 months. Two-year and 5-year outcomes were 69.0% and 62.2% for LC, 71.8% and 49.8% for OS, 47.2% and 35.7% for disease-free survival, and 78.7% and 59.1% for disease-specific survivals. The most discriminating margin cut point was 1.0 mm; the 2-year LC was 80.9% above and 54.2% below or equal to 1.0 mm. Increasing age, current smoking, primary tumor classification, and narrow surgical margins (≤1.0 mm) were statistically significantly associated with lower OS. Hemorrhage with return to theater was seen in 8.1% (n = 22 of 272), and 30-day mortality was 1.8% (n = 5 of 272). At 1 year, 10.8% (n = 21 of 195) used tracheostomies, 33.8% (n = 66 of 195) used gastrostomies, and 66.3% (n = 53 of 80) had maintained or improved normalcy of diet scores.

Conclusions

Data from international centers show TORS to treat head and neck cancers in previously irradiated fields yields favorable outcomes for LC and survival. Where feasible, TORS should be considered the preferred surgical treatment in the salvage setting.
Chronic Traumatic Encephalopathy in a Routine Neuropathology Service in Australia
Authors: Suter Catherine M , Affleck Andrew J , Lee Maggie , Davies Danielle , Burns Arran L , Sy Joanne , I’Ons Bernard , Buckland Michael E
Published: August 2022

Chronic traumatic encephalopathy (CTE) is a neuropathological diagnosis defined by a unique pattern of hyperphosphorylated tau (p-tau) accumulation that begins in neocortical regions of the brain. It is associated with a range of neuropsychological symptoms, but a definitive diagnosis can only be made by postmortem brain examination. In 2018, we instituted CTE screening for all autopsy brains as part of our routine departmental protocol by performing p-tau immunohistochemistry on a restricted set of 3 neocortical blocks (frontal, temporal, and parietal). This strategy allowed us to identify 4 cases of low-stage CTE from 180 consecutive autopsies. Two of the 4 cases had a documented history of brain injury; for the remaining 2 cases, there was a long history of treatment-resistant tonic/clonic epilepsy suggesting that undocumented brain injuries may have occurred. Our experience indicates that 3-block CTE screening is useful in identifying CTE in routine practice. The results of this study further support the association between prior head injuries and CTE and demonstrate that, albeit uncommon, CTE does occur in the general population. Our findings suggest that p-tau screening should be routinely pursued in brain autopsy, particularly where there is a documented or likely history of traumatic brain injury.
Yellow fever vaccine safety in immunocompromised individuals: a systematic review and meta-analysis
Authors: Wigg de Araújo Lagos Letícia , de Jesus Lopes de Abreu Ariane , Caetano Rosângela , Braga José Ueleres
Published: August 2022

Background

Yellow fever (YF) is an arbovirus with variable severity, including severe forms with high mortality. The vaccination is the most effective measure to protect against the disease. Non-serious and serious adverse events have been described in immunocompromised individuals, but previous studies have failed to demonstrate this association. This systematic review assessed the risk of adverse events after YF vaccination in immunocompromised individuals compared with its use in non-immunocompromised individuals.

Methods

A search was conducted in the MEDLINE, LILACS, EMBASE, SCOPUS, DARE, Toxiline, Web of Science and grey literature databases for publications until February 2021. Randomized and quasi-randomized clinical trials and observational studies that included immunocompromised participants (individuals with HIV infection, organ transplants, with cancer, who used immunosuppressive drugs for rheumatologic diseases and those on immunosuppressive therapy for other diseases) were selected. The methodological quality of observational or non-randomized studies was assessed by the ROBINS-I tool. Two meta-analyses were performed, proportion and risk factor analyses, to identify the summary measure of relative risk (RR) in the studies that had variables suitable for combination.

Results

Twenty-five studies were included, most with risk of bias classified as critical. Thirteen studies had enough data to carry out the proposed meta-analyses. Seven studies without a comparator group had their results aggregated in the proportion meta-analysis, identifying an 8.5% [95% confidence interval (CI) 0.07–21.8] risk of immunocompromised individuals presenting adverse events after vaccination. Six cohort studies were combined, with an RR of 1.00 (95% CI 0.78–1.29). Subgroup analysis was performed according to the aetiology of immunosuppression and was also unable to identify an increased risk of adverse events following vaccination.

Conclusions

It is not possible to affirm that immunocompromised individuals, regardless of aetiology, have a higher risk of adverse events after receiving the YF vaccine.
X-ray properties of early-type stars in the Tarantula Nebula from T-ReX
Authors: Crowther Paul A , Broos Patrick S , Townsley Leisa K , Pollock Andy M T , Tehrani Katie A , Gagné Marc
Published: August 2022

We reassess the historical LX/LBol relation for early-type stars from a comparison between T-ReX, the Chandra ACIS X-ray survey of the Tarantula Nebula in the Large Magellanic Cloud (LMC), and contemporary spectroscopic analysis of massive stars obtained primarily from VLT/FLAMES, VLT/MUSE, and HST/STIS surveys. For 107 sources in common (some host to multiple stars), the majority of which are bolometrically luminous (40 per cent exceed 106L⊙), we find an average log LX/LBol = −6.90 ± 0.65. Excluding extreme systems Mk 34 (WN5h+WN5h), R140a (WC4+WN6+), and VFTS 399 (O9 IIIn+?), plus four WR sources with anomalously hard X-ray components (R130, R134, R135, Mk 53) and 10 multiple sources within the spatially crowded core of R136a, log LX/LBol = −7.00 ± 0.49, in good agreement with Galactic OB stars. No difference is found between single and binary systems, nor between O, Of/WN, and WR stars, although there does appear to be a trend towards harder X-ray emission from O dwarfs, through O (super)giants, Of/WN stars, and WR stars. The majority of known OB stars in the Tarantula are not detected in the T-ReX point source catalogue, so we have derived upper limits for all undetected OB stars for which log LBol/L⊙ ≥ 5.0. A survival analysis using detected and upper limit log LX/LBol values indicates no significant difference between luminous O stars in the LMC and the Carina Nebula. This analysis suggests that metallicity does not strongly influence LX/LBol. Plasma temperatures for single, luminous O stars in the Tarantula ($\overline{kT_{m}}=1.0$ keV) are higher than counterparts in Carina ($\overline{kT_{m}}=0.5$ keV).
Reddening and the shape of the variable component of the continua of active galactic nuclei from the optical to the far-ultraviolet – I
Authors: Heard Clio Z P , Gaskell C Martin
Published: August 2022

We analyse the photometric variability of 4611 active galactic nuclei (AGNs) from the Sloan Digital Sky Survey (SDSS) Stripe 82. We recover the spectral energy distribution (SED) of the variable flux as a function of wavelength. For rest wavelengths longer than ∼2200 Å, we find that the SED of the variable component of the bluest AGNs is consistent with the Fν ∝ ν+1/3 spectrum predicted for an externally illuminated accretion disc. We confirm there is some residual variable emission corresponding to the ‘small blue bump’ and other broad-line region variability. We interpret steeper optical spectra of the variable component as being due to intrinsic reddening. This is supported by the correlation of the Balmer decrement with the colour excess of the variable component. We find the median internal reddening of SDSS AGNs in Stripe 82 with z < 0.4 to be E(B − V) ≈ 0.10 in agreement with the reddening derived from the Balmer decrement. Individual AGNs in the sample can have E(B − V) > 0.4.
Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice
Authors: Desjardins Cody A , Yao Monica , Hall John , O’Donnell Emma , Venkatesan Reshmii , Spring Sean , Wen Aiyun , Hsia Nelson , Shen Peiyi , Russo Ryan , Lan Bo , Picariello Tyler , Tang Kim , Weeden Timothy , Zanotti Stefano , Subramanian Romesh , Ibraghimov-Beskrovnaya Oxana
Published: August 2022

Current therapies for Duchenne muscular dystrophy (DMD) use phosphorodiamidate morpholino oligomers (PMO) to induce exon skipping in the dystrophin pre-mRNA, enabling the translation of a shortened but functional dystrophin protein. This strategy has been hampered by insufficient delivery of PMO to cardiac and skeletal muscle. To overcome these limitations, we developed the FORCETM platform consisting of an antigen-binding fragment, which binds the transferrin receptor 1, conjugated to an oligonucleotide. We demonstrate that a single dose of the mouse-specific FORCE–M23D conjugate enhances muscle delivery of exon skipping PMO (M23D) in mdx mice, achieving dose-dependent and robust exon skipping and durable dystrophin restoration. FORCE–M23D-induced dystrophin expression reached peaks of 51%, 72%, 62%, 90% and 77%, of wild-type levels in quadriceps, tibialis anterior, gastrocnemius, diaphragm, and heart, respectively, with a single 30 mg/kg PMO-equivalent dose. The shortened dystrophin localized to the sarcolemma, indicating expression of a functional protein. Conversely, a single 30 mg/kg dose of unconjugated M23D displayed poor muscle delivery resulting in marginal levels of exon skipping and dystrophin expression. Importantly, FORCE–M23D treatment resulted in improved functional outcomes compared with administration of unconjugated M23D. Our results suggest that FORCE conjugates are a potentially effective approach for the treatment of DMD.