bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between serum uric acid and coronary collateral circulation in patients with coronary chronic total occlusion
Authors: Li Jing , Pei Haifeng , Ye Xianglin , Tian Jing , Yang Haixia , Liu Qing , Wang Xiong , Wang Peng
Published: January 2023

Background and purpose:

Previous studies showed urate crystals in atherosclerotic plaques, suggesting that uric acid is involved in plaque formation, but whether it affects the formation of coronary collateral circulation (CCC) is unknown. This single-center retrospective study was conducted to investigate whether serum uric acid (SUA) level has an association with the CCC in patients with coronary chronic total occlusion (CTO).

Methods:

The final analysis included a total of 94 patients with CTO (defined as 100% stenosis in at least one of the left anterior descending artery, circumflex artery and right coronary artery with thrombolysis in myocardial infarction [TIMI] grade 0 of forward flow) for more than 3 months (66.03 ± 10.10 years of age; 54 men and 40 women). In the analysis, patients were divided into four groups of equal size based on the SUA level on admission (n = 32, 31, 31 for low, mid, and high SUA groups). Multivariate logistic regression was conducted to identify risk factors that were associated with poor CCC (as defined by Rentrop level ≤ 1).

Results:

The rate of poor CCC was 44.5% in the low SUA group, 54.8% in the mid-SUA group, and 77.4% in the high SUA group, respectively (P < 0.05 for all three pairwise comparisons). In multivariate regression analysis that treated SUA as a continuous variable, poorer CCC was associated with higher SUA (adjusted odds ratio [OR] = 1.011, 95% confidence interval [CI]: 1.005–1.017, P < 0.05). In comparison to the patients with lowest SUA in the regression analysis that treated SUA as a categorical variable, there was a statistically non-significant trend for increased risk of poor CCC (OR 2.277, 95% CI: 0.753–6.884) in the patient with mid-level SUA. The risk of poor CCC was significantly elevated in the patients with high SUA (OR 6.243, 95% CI: 1.872–20.828).

Conclusions:

Elevated SUA level was associated with poor CCC in patients with CTO.
Disparities in Benign Gynecologic Surgical Care
Authors: Laughman Kimberly , Ogu Nkechinyelum Q. , Warner Kristina J. , Traylor Jessica
Published: January 2023

A person’s health is not only affected by their disease states, but also the quality of care and posttreatment sequelae. Research shows that disparities exist in benign gynecologic surgery access to care, techniques, and perioperative outcomes. Surgical education, pathways that emphasize minimally invasive approaches, and patient-centered care that recognizes historical influences on patient perspectives are critical to dampening these disparities.
The Spectrum of Hepatic Critical Care During Pregnancy: A Clinical Review
Authors: Matos Lucía Rivera , Reau Nancy S.
Published: January 2023

Hepatic disease during pregnancy can result in the development of critical illness requiring special attention from a multidisciplinary team with a low threshold for tertiary care transfer to provide access to liver transplantation. Management of this population requires taking into consideration the benefit and risks of both mother and fetus. A myriad of diseases has been recognized, some being unique to pregnancy while others are common to the general population. We present a review of the literature on the diagnosis, management, and prognosis of these diseases to aid in the optimization of care in this special population.
Mitigating Misogynoir: Inclusive Professionalism as a Health Equity Strategy
Authors: Tucker Edmonds Brownsyne , Sharp Sacha , Walker Valencia P.
Published: January 2023

As Obstetrics and Gynecology begins to recognize how structural racism drives inequitable health outcomes, it must also acknowledge the effects of structural racism on its workforce and culture. Black physicians comprise ~5% of the United States physician population. Unique adversities affect Black women physicians, particularly during residency training, and contribute to the lack of equitable workforce representation. Eliminating racialized inequities in clinical care requires addressing these concerns. By applying historical context to present-day realities and harms experienced by Black women (ie, misogynoir), Obstetrics and Gynecology can identify interventions, such as equity-focused recruitment and retention strategies, that transform the profession.
Chronic heart failure management in adult patients with congenital heart disease
Authors: Dhingra Nitish K. , Mazer C. David , Connelly Kim A. , Verma Subodh
Published: January 2023

Purpose of review

A growing number of adult patients with congenital heart disease (ACHD) are entering the healthcare system as a result of advances in the diagnosis and management of congenital heart defects. Heart failure is a common final pathway for this diverse patient population, representing the leading cause of mortality in ACHD patients. Herein, we review present guideline-directed management of heart failure in ACHD patients.

Recent findings

There exists a dearth of data to guide management of ACHD-related heart failure. Given this gap, recent guidelines have been limited in the recommendations they can provide for this patient population, with practitioners being consequently forced to generalize findings from studies of acquired heart disease patients based on mechanistic plausibility. The small number of studies directly assessing ACHD patients have been largely limited in their clinical relevance through being negative, small, observational, limited to specific subsets of ACHD patients or assessing nonvalidated outcomes.

Despite the prevalence and impact of ACHD-related heart failure, there are limited evidence-based therapies for its management. Given the rising burden of this clinical problem, definitive trials assessing newer therapies are required to establish their potential role in heart failure amongst ACHD patients.
Describing The Location and Morphology of The Dots in White Dot Fovea Using Adaptive Optics
Authors: Salcedo-Ledesma; Gerardo Ledesma-Gil Alfredo , Spaide Richard F.
Published: January 2023

Purpose:

To characterize the white dots in white dot fovea, an entity chiefly described in Japan, using adaptive optics (AO) imaging and propose a hypothesis regarding their origin.

Method:

The patient underwent comprehensive ophthalmic examination, including color and green-monochromatic fundus photography, fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and AO imaging.

Results:

An asymptomatic 66-year-old Korean woman presented with bilateral white, glistening deposits in a ring pattern around the fovea of both eyes. The dots were highly reflective on green monochromatic images, were not visible on FA, and appeared hyperreflective in the inner retina using SD-OCT. AO showed polygonal granules ranging from 1-10 microns in size. The patient denied any systemic disorder or the use of any medications related to crystalline retinopathy. The patient had lived in Japan for 35 years prior to just moving to the United States.

Conclusion:

The location, small size, and polygonal shape of the dots in white dot fovea are suggestive of intraretinal deposition of crystals, and not cells on the surface of the fovea as has been previously proposed. Carotenoid deposition related to dietary habits is a plausible cause because of the similarity to other retinopathies associated to these compounds.
Fresh Versus Frozen Versus Lyophilized Fecal Microbiota Transplant for Recurrent Clostridium Difficile Infection
Authors: Gangwani Manesh Kumar , Aziz Muhammad , Aziz Abeer , Priyanka Fnu , Weissman Simcha , Phan Khiem , Dahiya Dushyant Singh , Ahmed Zohaib , Sohail Amir Humza , Lee-Smith Wade , Kamal Faisal , Javaid Toseef , Nawras Ali , Hart Benjamin
Published: January 2023

Introduction:

Clostridium difficile Infection is a significant source of morbidity and mortality, which is on the rise. Fecal Microbiota Transplantation (FMT) is an alternative therapy to antibiotics with a high success rate and low relapse rate. Current data regarding the efficacy of the types of FMT used, namely fresh, frozen, and lyophilized is conflicting. Our review attempts to consolidate this data and highlight the most efficacious treatment currently available.

Methodology:

MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, SciELO, the Korean Citation Index, and Global Index Medicus were systematically searched from inception through May 3, 2022. Studies in which patients are undergoing any form of FMT who had failed antibiotic treatment previously were included. Both pairwise (direct) and network (direct + indirect) meta-analysis were performed using a random effects model and DerSimonian-Laird approach. A frequentist approach was used for network meta-analysis. Risk differences with (RD) with 95% confidence interval (CI) were calculated.

Results:

A total of 8 studies, including 4 RCTs and 4 cohort studies, were included with a total of 616 patients. Fresh FMT was determined to be most successful with 93% efficacy 95% CI (0.913 to 0.999) followed by frozen with 88% efficacy 95% CI (0.857 to 0.947) and lyophilized with 83% efficacy 95% CI (0.745 to 0.910). The direct meta-analysis showed no statistically significant difference between fresh and frozen group. (RD −0.051 95% CI −0.116 to 0.014 P=0.178). No significant differences were noted in frozen versus lyophilized groups with an overall trend towards Fresh FM (RD −0.061 95% CI −0.038 to 0.160 P=0.617). On network meta-analysis, when compared with fresh group, a lower recovery rate was noted with both frozen group (RD −0.06 95% CI −0.11 to 0.00 P=0.05) and lyophilized group (RD −0.16 95% CI −0.27 to −0.05 P=0.01).

Conclusion:

We conclude the efficacy of Frozen and Lyophilized preparations is high with no difference in direct comparison, and the relative efficacy reduction based on network analysis is outweighed by the safety, accessibility, and practicality of Frozen or Lyophilized preparations.
Sexual and gender diversity in cancer care and survivorship
Authors: Schulz-Quach Christian , Kennedy Margo , Lyver Brendan
Published: January 2023

Purpose of the review

Sexual and gender diverse (SGD) cancer patients possess unique identities and needs that must be considered during their cancer care. This narrative review explores the current literature on sexual and gender diversity in cancer care and survivorship, in addition to providing recommendations encouraged by the current literature.

Recent findings

We performed a literature search for articles published in English between January 2021 and June 2022 in Medline ALL and Embase. Fifty-two studies were included in this review. The many identities encapsulated in 2SLGBTQIA+ (2 Spirited, Lesbian, Gay, Bisexual, Transgender, Queer, Intersexual, Asexual, Agender, Aromantic and all gender identities and sexual orientations that are not listed) communities each have their own unique backgrounds, needs and disparities in cancer care and survivorship. However, we also identified specific protective factors in the cancer experience of SGD patients such as reports of higher resiliency and stronger support networks. Much of the recent research features recommendations on improving cancer care by creating inclusive patient questionnaires, improving in-person and online resources, and educating healthcare providers and patient-facing staff on inclusive care.

SGD patients have their own specific challenges during and following their cancer care. As the research continues to grow, we gain a better understanding of the needs of these patients and future steps to take to improve SGD patients’ cancer experience.
Morphological profiling by Cell Painting in human neural progenitor cells classifies hit compounds in a pilot drug screen for Alzheimer’s disease
Authors: McDiarmid Amina H. , Gospodinova Katerina O. , Elliott Richard J.R. , Dawson John C. , Hughes Rebecca E. , Anderson Susan M. , Glen Sophie C. , Glerup Simon , Carragher Neil O. , Evans Kathryn L.
Published: January 2023

1

Alzheimer’s disease (AD) accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to AD drug discovery. We chose to develop a cell phenotype-based drug screen centred on the AD-risk gene,SORL1, which encodes the protein SORLA. Increased AD risk has been repeatedly linked to variants inSORL1, particularly those that confer loss of, or decreased, SORLA. This is consistent with the lowerSORL1levels observed in post-mortem brain samples from individuals with AD. Consistent with its role in the endolysosomal pathway, deletion ofSORL1is associated with enlarged endosomes in neural progenitor cells (NPCs) and neurons. We, therefore, hypothesised that multiparametric, image-based phenotyping would identify features characteristic ofSORL1deletion. An automated morphological profiling assay (known as Cell Painting) was adapted to wild-type andSORL1-/-NPCs. This methodology was used to determine the phenotypic response ofSORL1-/-NPCs to treatment with compounds from a small FDA/internationally-approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures forSORL1-/-NPCs compared to isogenic wild-type controls. Furthermore, we identified 16 approved drugs that reversed the mutant morphological signatures in NPCs derived from 3SORL1-/-subclonal iPSC lines. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis confirmed targeting to gene sets associated with these annotated targets, and to pathways/biological processes associated with DNA synthesis/damage/repair, Proteases/proteasome and metabolism._Prediction of novel targets for some compounds revealed enrichment in pathways associated with neural cell function and AD. The findings suggest that image-based phenotyping by morphological profiling distinguishesSORL1-/-NPCs from isogenic wild-type lines, and predicts treatment responses that rescueSORL1-/--associated cellular signatures that are relevant to both SORLA function and AD. Overall, this work suggests that i) a quantitative phenotypic metric can distinguish iPSC-derived SORL1-/-NPCs from isogenic wild-type control and ii) phenotypic screening combined with multiparametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer’s disease.
A Network-based Transcriptomic Landscape of HepG2 cells to Uncover Causal Gene Cytotoxicity Interactions Underlying Drug-Induced Liver Injury
Authors: Wijaya Lukas S. , Gabor Attila , Pot Iris E. , van de Have Luca , Saez-Rodriguez Julio , Stevens James L. , Le Dévédec Sylvia E. , Callegaro Giulia , van de Water Bob
Published: January 2023

Drug-induced liver injury (DILI) remains the main reason of drug development attritions largely due to poor mechanistic understanding. Toxicogenomics to interrogate the mechanism of DILI has been broadly performed. Gene network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improving mechanistic interpretation of toxicogenomics data. In this current study, we performed an extensive concentration time course response-toxicogenomics study in the HepG2 cell line exposed to various DILI compounds, reference compounds for stress response pathways, cytokine receptors, and growth factor receptors. We established > 500 conditions subjected to whole transcriptome targeted RNA sequences and applied weighted gene co-regulated network analysis (WGCNA) to the transcriptomics data followed by identification of gene networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress responses gene networks. We correlated gene network with cell death as the progressive cellular outcomes. Causality of the target genes of these modules was evaluated using RNA interference validation experiments. We identified thatGTPBP2, HSPA1B, IRF1, SIRT1andTSC22D3exhibited strong causality towards cell death. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI.
Developmental diet alters the fecundity-longevity relationship and age-related gene expression inDrosophila melanogaster
Authors: Collins David H. , Prince David C. , Donelan Jenny L. , Chapman Tracey , Bourke Andrew F. G.
Published: January 2023

The standard evolutionary theory of ageing predicts a negative relationship (trade-off) between fecundity and longevity. However, this relationship can become positive: (i) under the influence of longevity-enhancing mutations; (ii) when individuals have unequal resources; and (iii) in eusocial insects, in which reproductive queens outlive less- or non-reproductive workers. Developmental diet is likely to be central to determining trade-offs as it affects key fitness traits such as adult body size, but its exact role remains uncertain. For example, inDrosophila melanogasterfruit flies, changes in adult diet can affect fecundity, longevity, and gene expression throughout life, but it is unknown how changes in developmental (larval) diet affect fecundity-longevity relationships or gene expression in adults. UsingD. melanogaster, we therefore tested the hypothesis that variation in developmental diet alters the directionality of fecundity-longevity relationships in adults, and characterised associated gene expression changes. We rearedD. melanogasterlarvae on low (20%), medium (100%), and high (120%) SYA (Sugar Yeast Agar) diets, and transferred adult females developing from these larvae to a common (110% SYA) adult diet. We measured life-time fertility (realised fecundity) and longevity of individual adult females and, using mRNA-seq, profiled gene expression changes across two time-points. Adult females raised on the different larval diets exhibited fecundity-longevity relationships that were significantly different in directionality, i.e., varied from positive to negative, despite minimal differences in mean life-time fertility or longevity. Treatments also differed in age-related gene expression, including expression of genes known to be associated with ageing. Hence, this study shows that the sign of fecundity-longevity relationships in adult insects can be altered and even reversed by variation in larval diet quality. Furthermore, larval diet quality may be a key mechanistic factor underpinning positive fecundity-longevity relationships observed in species such as eusocial insects.
Oncogenic GNAS uses PKA-dependent and independent mechanisms to induce cell proliferation in human pancreatic ductal and acinar organoids
Authors: Desai Ridhdhi , Muthuswamy Senthil
Published: January 2023

Ductal and acinar pancreatic organoids generated from human pluripotent stem cells (hPSCs) are promising models to study pancreatic diseases, including precursor lesions of pancreatic cancer. Genome sequencing studies have revealed that mutations in a G-protein (GNASR201C) are exclusively observed in intraductal papillary mucinous neoplasms (IPMNs), one of the most common cystic pancreatic precancerous lesions. GNASR201Ccooperates with oncogenic KRASG12V/Dto produce IPMN lesions in mice; however, the biological mechanisms by which oncogenic GNAS affects the ductal and acinar exocrine pancreas are not understood. In this study, we use pancreatic ductal and acinar organoids generated from human embryonic stem cells to investigate mechanisms by which GNASR201Cfunctions. As expected, GNASR201C-induced cell proliferation in acinar organoids was PKA-dependent. Surprisingly, GNASR201C-induced cell proliferation independent of the canonical PKA signaling in short-term and stable, long-term cultures of GNAS-expressing ductal organoids and in an immortalized ductal epithelial cell line, demonstrating that GNASR201Cuses PKA-dependent and independent mechanisms to induce cell proliferation in the exocrine pancreas. Co-expression of oncogenic KRASG12V and GNASR201Cinduced cell proliferation in ductal and acini organoids in a PKA-independent and dependent manner, respectively. Thus, we identify cell lineage-specific roles for PKA signaling driving pre-cancerous lesions and report the development of a human pancreatic ductal organoid model system to investigate mechanisms regulating GNASR201C-induced IPMNs.
Self-supervised vision transformers accurately decode cellular state heterogeneity
Authors: Pfaendler Ramon , Hanimann Jacob , Lee Sohyon , Snijder Berend
Published: January 2023

Characterising cellular phenotypic heterogeneity is essential to understand the relationship between the molecular and morphological determinants of cellular state. Here we report that publicly available self-supervised vision transformers (ss-ViTs) accurately elucidate phenotypic stem cell heterogeneity out-of-the-box. Moreover, we introduce scDINO, an adapted ss-ViT trained on five-channel automated microscopy data, attaining excellent performance in delineating peripheral blood immune cell identity. Thus, ss-ViTs represent a leap forward in the unsupervised analysis of phenotypic heterogeneity.
PacBio Hi-Fi genome assembly of the Iberian dolphin freshwater musselUnio delphinusSpengler, 1793
Authors: André Gomes-dos-Santos , Manuel Lopes-Lima , André Machado M. , Amílcar Teixeira , Filipe C. Castro L. , Elsa Froufe
Published: January 2023

Mussels of order Unionida are a group of strictly freshwater bivalves with nearly 1,000 described species widely dispersed across world freshwater ecosystems. They are highly threatened showing the highest record of extinction events within faunal taxa. Conservation is particularly concerning in species occurring in the Mediterranean biodiversity hotspot that are exposed to multiple anthropogenic threats, possibly acting in synergy. That is the case of the dolphin freshwater musselUnio delphinusSpengler, 1793, endemic to the western Iberian Peninsula with recently strong population declines. To date, only four genome assemblies are available for the order Unionida and only one European species. We present the first genome assembly ofUnio delphinus. We used the PacBio HiFi to generate a highly contiguous genome assembly. The assembly is 2.5 Gb long, possessing 1254 contigs with a contig N50 length of 10 Mbp. This is the most contiguous freshwater mussel genome assembly to date and is an essential resource for investigating the species’ biology and evolutionary history that ultimately will help to support conservation strategies.
HepaRG cells undergo increased levels of post-differentiation patterning in physiologic conditions when maintained as 3D cultures in paper-based scaffolds
Authors: Diprospero Thomas J. , Brown Lauren G. , Fachko Trevor D. , Lockett Matthew R.
Published: January 2023

Monolayer cultures of hepatocytes lack many aspects of the liver sinusoid, including a tissue-level organization that results from extracellular matrix interactions and gradients of soluble molecules that span from the portal triad to the central vein. We measured the activity and transcript levels of drug-metabolizing enzymes in HepaRG cells maintained in three different culture configurations: as monolayers, seeded onto paper scaffolds that were pre-loaded with a collagen matrix, and when seeded directly into the paper scaffolds as a cell-laden gel. Drug metabolism was significantly decreased in the presence of the paper scaffolds compared to monolayer configurations when cells were exposed to standard culture conditions. Despite this decreased function, transcript levels suggest the cells undergo increased polarization and adopt a biliary-like character in the paper scaffolds, including the increased expression of transporter proteins (e.g.,ABCB11andSLOC1B1) and theKRT19cholangiocyte marker. When exposed to representative periportal or perivenous culture conditions, we observed in vivo zonal-like patterns, including increased cytochrome P450 (CYP) activity and transcript levels in the perivenous condition. This increased CYP activity is more pronounced in the laden configuration, supporting the need to include multiple aspects of the liver microenvironment to observe the post-differentiation processing of hepatocytes.

TOC Figure
Composite Deep Network with Feature Weighting for Improved Delineation of COVID Infection in Lung CT
Authors: Dutta Pallabi , Mitra Sushmita
Published: January 2023

An early effective screening and grading of COVID-19 has become imperative towards optimizing the limited available resources of the medical facilities. An automated segmentation of the infected volumes in lung CT is expected to significantly aid in the diagnosis and care of patients. However, an accurate demarcation of lesions remains problematic due to their irregular structure and location(s) within the lung.

A novel deep learning architecture, Composite Deep network with Feature Weighting(CDNetFW), is proposed for efficient delineation of infected regions from lung CT images. Initially a coarser-segmentation is performed directly at shallower levels, thereby facilitating discovery of robust and discriminatory characteristics in the hidden layers. The novel feature weighting module helps prioritise relevant feature maps to be probed, along with those regions containing crucial information within these maps. This is followed by estimating the severity of the disease.

The deep networkCDNetFWhas been shown to outperform several state-of-the-art architectures in the COVID-19 lesion segmentation task, as measured by experimental results on CT slices from publicly available datasets, especially when it comes to defining structures involving complex geometries.
Prevalence of adequately iodized salt and its determinants in Gambela district, Southwest Ethiopia
Authors: Tesfaye Getamesay Aynalem , Gemechu Ebissa Negera , Umer Abdella Yasin , Chanie Fentaneh Teshome
Published: January 2023

Background

Iodine deficiency disorders (IDDs) are among the major public health problems for populations all over the world. Even though the recommended strategy for IDD control is universal salt iodization, little was known about availability of adequately iodized salt in Gambela region.

Objective

This study was conducted to determine availability of adequately iodized salt and associated factors in Gambela district, Southwest Ethiopia.

Methods

A community-based cross-sectional study was conducted in July 2019 in Gambela district. Multistage sampling method was employed to select 422 households. A structured questionnaire and rapid test kits were data collection instruments. Multivariate logistic regression was used to identify association.

Results

About 52.8% (95% CI: 0.47, 0.57) of households had adequately iodized salt. College diploma and above educational status (AOR=4.27, 95% CI: 1.47, 12.44), favorable attitude (AOR=5.69, 95% CI: 2.83, 11.42), walking less than 30 minutes to get iodized salt (AOR=4.69, 95% CI: 2.56, 8.60), using packed salt (AOR=2.75, 95% CI: 1.54, 4.93) and using covered salt container (AOR=3.93, 95% CI: 2.21, 6.98) were factors positively associated with availability of adequately iodized salt.

Conclusions

The availability of adequately iodized salt in Gambela district is very low. Enhancing community awareness about the benefit and good practice of iodized salt should be emphasized besides improving accessibility.
Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 153,122 U.S. patients
Authors: Liu Ruishan , Wang Lisa , Rizzo Shemra , Garmhausen Marius Rene , Pal Navdeep , Waliany Sarah , McGough Sarah , Lin Yvonne G. , Huang Zhi , Neal Joel , Copping Ryan , Zou James
Published: January 2023

Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline) for multiple reasons including a lack of effective approved treatments. Here we present a systematic characterization of the patterns of off-label and off-guideline usage in 153,122 U.S. patients with 14 common cancer types using a large electronic health record (EHR)-derived de-identified database. We find that 18.3% and 3.9% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Out of the 14 malignancies investigated, advanced bladder cancer has the highest proportion with 8.1% of patients receiving off-guideline treatments, most of which are recommended for non-small cell lung cancer. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. Underrepresented minority patients are less likely to receive off-guideline treatments in several cancer types. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analysis of large real-world cohorts can identify interesting candidates for potential label expansion by identifying off-label treatments that demonstrate effectiveness in the real world setting. For example, we find that hormonal agents approved for breast cancer are used off-label in patients with ovarian cancer. Moreover, these hormonal agents show promising effectiveness in ovarian cancer with adjusted hazard ratio 0.53 (0.44, 0.65) compared to standard-of-care. This work demonstrates the power of large-scale computational analysis of real-world data for investigating non-standard cancer treatment usages.
N-terminal proteoforms may engage in different protein complexes
Authors: Bogaert Annelies , Fijalkowska Daria , Staes An , Van de Steene Tessa , Vuylsteke Marnik , Stadler Charlotte , Eyckerman Sven , Spirohn Kerstin , Hao Tong , Calderwood Michael A. , Gevaert Kris
Published: January 2023

Alternative translation initiation and alternative splicing may give rise to N-terminal proteoforms, proteins that differ at their N-terminus compared to their canonical counterparts. Such proteoforms can have altered localizations, stabilities and functions. While proteoforms generated from splice variants can be engaged in different protein complexes, it remained to be studied to what extent this applies to N-terminal proteoforms. To address this, we mapped the interactomes of several pairs of N-terminal proteoforms and their canonical counterparts. First, we generated a catalogue of N-terminal proteoforms found in the HEK293T cellular cytosol from which 22 pairs were selected for interactome profiling. Additionally, we provide evidence for the expression of several N-terminal proteoforms, identified in our catalogue, across different human tissues as well as tissue-specific expression, highlighting their biological relevance. Protein-protein interaction profiling revealed that the overlap of the interactomes for both proteoforms is generally high, showing their functional relation. We also showed that N-terminal proteoforms can be engaged in new interactions and/or lose several interactions compared to their canonical counterpart, thus further expanding the functional diversity of proteomes.
Probing the sub-cellular mechanisms of LCA5-Leber Congenital Amaurosis and associated gene therapy with expansion microscopy
Authors: Faber Siebren , Mercey Olivier , Junger Katrin , Garanto Alejandro , Ueffing Marius , Collin Rob W.J. , Boldt Karsten , Guichard Paul , Hamel Virginie , Roepman Ronald
Published: January 2023

Leber Congenital Amaurosis (LCA) is a group of Inherited Retinal Diseases (IRDs) characterized by the early onset and rapid loss of photoreceptor cells. Despite the discovery of a growing number of genes associated with this disease, the molecular mechanisms of photoreceptor cell degeneration of most LCA subtypes remain poorly understood. Here, using retina-specific affinity proteomics combined with Ultrastructure Expansion Microscopy (U-ExM), we revealed the structural and molecular defects underlying LCA type 5 (LCA5) with unprecedented resolution. We showed thatLCA5-encoded lebercilin, together with Retinitis Pigmentosa 1 protein (RP1) and the intraflagellar transport (IFT) proteins IFT81 and IFT88, localize at the bulge region of the photoreceptor outer segment (OS), a region crucial for OS membrane disc formation. Next, we demonstrated that mutant mice deficient for lebercilin exhibit early axonemal defects at the bulge region and the distal OS, accompanied by reduced level of RP1 and IFT proteins, affecting membrane disc formation and presumably leading to photoreceptor death. Finally, we probed theLCA5gene augmentation therapy strategy using U-ExM by monitoring its subcellular outcome. We found that, expression ofLCA5partially restores the bulge region, preserves OS axoneme structure and membrane disc formation, as well as photoreceptor survival.
HuR inhibition reduces post-ischemic cardiac remodeling by dampening acute inflammatory gene expression and the innate immune response
Authors: Slone Samuel , Anthony Sarah R. , Green Lisa C. , Nieman Michelle L. , Alam Perwez , Wu Xiaoqing , Roy Sudeshna , Aube Jeffrey , Xu Liang , Lorenz John N. , Owens A. Phillip , Kanisicak Onur , Tranter Michael
Published: January 2023

Myocardial ischemia/reperfusion (I/R) injury and the resulting cardiac remodeling is a common cause of heart failure. The RNA binding protein Human Antigen R (HuR) has been previously shown to reduce cardiac remodeling following both I/R and cardiac pressure overload, but the full extent of the HuR-dependent mechanisms within cells of the myocardium have yet to be elucidated. In this study, we applied a novel small molecule inhibitor of HuR to define the functional role of HuR in the acute response to I/R injury and gain a better understanding of the HuR-dependent mechanisms during post-ischemic myocardial remodeling. Our results show an early (two hours post-I/R) increase in HuR activity that is necessary for early inflammatory gene expression by cardiomyocytes in response to I/R. Surprisingly, despite the reductions in early inflammatory gene expression at two hours post-I/R, HuR inhibition has no effect on initial infarct size at 24-hours post-I/R. However, in agreement with previously published work, we do see a reduction in pathological remodeling and preserved cardiac function at two weeks post-I/R upon HuR inhibition. RNA-sequencing analysis of neonatal rat ventricular myocytes (NRVMs) at two hours post-LPS treatment to model damage associated molecular pattern (DAMP)-mediated activation of toll like receptors (TLRs) demonstrates a broad HuR-dependent regulation of pro-inflammatory chemokine and cytokine gene expression in cardiomyocytes. We show that conditioned media from NRVMs pre-treated with HuR inhibitor loses the ability to induce inflammatory gene expression in bone marrow derived macrophages (BMDMs) compared to NRVMs treated with LPS alone. Functionally, HuR inhibition in NRVMs also reduces their ability to induce endocrine migration of peripheral blood monocytesin vitroand reduces post-ischemic macrophage infiltration to the heartin vivo.In summary, these results suggest a HuR-dependent expression of pro-inflammatory gene expression by cardiomyocytes that leads to subsequent monocyte recruitment and macrophage activation in the post-ischemic myocardium.
Association Between Primary Tumour–Brain Metastasis Receptor Status Mismatch and Outcomes in Breast Cancer Brain Metastasis
Authors: Zheng Yilong , Low Chen Ee , Tan Sheryl Yen Pin , Hing Clarisse Wei Yen , Yau Chun En , Teo Kejia , Nga Vincent Diong Weng , Yeo Tseng Tsai , Wong Andrea Li-Ann , Lim Mervyn Jun Rui
Published: January 2023

Structured abstract

Objective

To evaluate the association between primary tumour–brain metastasis receptor status mismatch and outcomes in patients with breast cancer brain metastasis (BCBM).

Methods

Patients who (1) had a histologically verified breast-to-brain metastasis, (2) were 18 years old or above on the day of surgical resection, and (3) had the ER (estrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2) statuses of both the primary breast tumour and the secondary brain metastasis were retrospectively recruited. Univariate time-to-event analysis was performed using the Kaplan-Meier method. The exposures analysed were the various combinations of ER, PR, and HER2 statuses between the primary breast tumour and the secondary brain metastasis. The outcomes were overall mortality and recurrence.

Results

Of the 158 patients who underwent surgical resection of brain metastases during the study period, 31 were included in the analysis. The mean (SD) age of the study population was 56.7 (12.2), and most patients were Chinese (54.8%). On univariate analysis of the association between the various receptor status combinations and overall mortality, ER (p=0.920) and PR (p=0.390) status conversion were both found to not be associated with overall mortality. However, HER2 status conversion was found to be significantly associated with overall mortality (p=0.026). Specifically, patients whose primary tumour was HER2+ but whose secondary brain metastasis was HER2− had the poorest outcome, with a median overall survival of 3.4 months. On the other hand, the median overall survival of the other HER2 receptor status combinations ranged from 10.9 to 16.6 months. There were no statistically significant associations between status conversion of any of the receptors and recurrence.

Conclusions

Among patients who underwent surgical resection of BCBMs, patients with primary tumour HER2+ but secondary brain metastasis HER2− had a significantly higher risk of mortality. However, ER and PR status conversion was not significantly associated with outcomes.
A Cost-effective Purification Process for Erythropoietin Biosimilar through Downstream Process Engineering
Authors: Nag Kakon , Haq Sarker Md. Enamul , Kumar Samir , Chakraborty Sourav , Khan Habiba , Islam Md. Jikrul , Rahman Khan Md. Maksusdur , Rahman Chowdhury Md. Mashfiqur , Roy Rony , Roy Ratan , Biswas Bipul Kumar , Hasan Bappi Md. Emrul , Mohiuddin Mohammad , Sultana Naznin
Published: January 2023

Well-characterized and scalable downstream process for purification of biologics is extremely demanding for delivering quality therapeutics to patients at a reasonable price. Erythropoietin (EPO) is a blockbuster biologic with diverse clinical applications but its application is limited to financially well-off societies due to high price. The high price of EPO is associated with the technical difficulties related to the purification challenge to obtain qualified product with a cost-effective defined process. Though there are reports for purification of EPO but there is no report of well-characterized downstream process with critical process parameters (CPPs) that can deliver EPO consistently satisfying the quality target product profile (QTPP), which is a critical regulatory requirement. To advance the field, we applied quality by design (QbD) principle and design of experiment (DoE) protocol to establish an effective process, which is scalable up to 100× batch size satisfying QTPP. We have successfully transformed the process from static mode to dynamic mode and validated. Insignificant variation (p> 0.05) within and between 1×, 10× and 100× batches showed that the process is reproducible and seamlessly scalable. The biochemical analysis along with the biofunctionality data ensures that the products from different-scale batches were indifferent and comparable to a reference product. Our study thereby established a robust and scalable downstream process of EPO biosimilar satisfying QTPP. The technological scheme presented here can speed-up the production of not only EPO but many other life-saving biologics and make them available to mass population at a reduced cost.
Bacopa monnieriphytochemicals regulate fibroblast cell migration via modulation of focal adhesions
Authors: Zirmire Ravindra K. , Saha Dyuti , Tanimu Habibu , Zaarour Rania , Bird Deborah , Cherian Prakash , Misra Namita , Sanyal Aryasekhar , Roy Nita , Jamora Colin
Published: January 2023

TheBacopa monnieriplant contains a large repertoire of active phytochemicals that have been used extensively in traditional medicine for the treatment of various complex diseases. More recently it has been shown to increase the wound healing rate in rats, though its mechanism of action is largely unknown. Here we investigated the cellular pathways activated by a methanol extract ofBacopa monnieriin human dermal fibroblasts, which play many critical roles in the wound healing program. Gene expression analysis revealed thatBacopa monnieriextract can enhance tissue repair by modulating multiple processes involved in the wound healing program such as migration, proliferation, and angiogenesis. We discovered thatBacopa monnieriextract can increase migration of fibroblasts via modulating the size and number of focal adhesions.Bacopa monnieri-mediated changes in focal adhesions are dependent on α5β1 integrin activation and subsequent phosphorylation of Focal Adhesion Kinase (FAK). Altogether our results suggest thatBacopa monnieriextract could enhance the wound healing rate via modulating fibroblast migration in the wound bed.
Geographic migration and vaccine-induced fitness changes ofStreptococcus pneumoniae
Authors: Belman Sophie , Lefrancq Noémie , Nzenze Susan , Downs Sarah , du Plessis Mignon , Lo Stephanie ,   The Global Pneumococcal Sequencing Consortium, McGee Lesley , Madhi Shabir A. , von Gottberg Anne , Bentley Stephen D. , Salje Henrik
Published: January 2023

Streptococcus pneumoniaeis a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location. The extent and mechanisms of spread, and vaccine-driven changes in fitness and antimicrobial resistance (AMR), remain largely unquantified. Using geolocated genome sequences from South Africa (N=6910, 2000-2014) we developed models to reconstruct spread, pairing detailed human mobility data and genomic data. Separately we estimated the population level changes in fitness of strains that are (vaccine type, VT) and are not (non-vaccine type, NVT) included in the vaccine, first implemented in 2009, as well as differences in strain fitness between those that are and are not resistant to penicillin. We estimated that pneumococci only become homogenously mixed across South Africa after about 50 years of transmission, with the slow spread driven by the focal nature of human mobility. Further, in the years following vaccine implementation the relative fitness of NVT compared to VT strains increased (RR: 1.29 [95% CI 1.20-1.37]) – with an increasing proportion of these NVT strains becoming penicillin resistant. Our findings point to highly entrenched, slow transmission and indicate that initial vaccine-linked decreases in AMR may be transient.

One-Sentence Summary

We describe geographic migration, and fitness dynamics conferred by NVT strains and AMR, for the globally endemic pathogenStreptococcus pneumoniae.
SARS-CoV-2 Omicron XBB.1.5 May Be a Variant That Spreads More Widely and Faster Than Other Variants
Authors: Sugano Aki , Kataguchi Haruyuki , Ohta Mika , Someya Yoshiaki , Kimura Shigemi , Maniwa Yoshimasa , Tabata Toshihide , Takaoka Yutaka
Published: January 2023

In this research, we aimed to predict the relative risk of the recent new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the basis of our previous research. We first performed molecular docking simulation analyses of the spike proteins with human angiotensin-converting enzyme 2 (ACE2) to determine the binding affinities to human cells of three new variants of SARS-CoV-2: Omicron BQ.1, XBB, and XBB.1.5 We then investigated the three variants to discover the evolutionary distance of the spike protein gene (S gene) from the Wuhan, Omicron BA.1, and Omicron BA.4/5 variants, to understand the changes in the S gene.

The results indicated that the XBB.1.5 variant had the highest binding affinity of the spike protein with ACE2 and the longest evolutionary distance of the S gene. Thisin silicoevidence suggested that the XBB.1.5 variant may produce infections that spread more widely and faster than can infections of preexisting variants.
X-ray methods for strain energy evaluation of dislocated crystals
Authors: Borbély András , Aoufi Asdin , Becht Dunstan
Published: January 2023

Two X-ray methods are applied to estimate the strain energy of crystals containing dislocations, a simpler method based on the full width at half-maximum (FWHM) of the diffraction peaks, and asymptotic line profile analysis (LPA), which exploits the functional form of the Fourier transform corresponding to small Fourier parameters. It is shown analytically that, in the single-defect approximation, the modified Williamson–Hall (mWH) plot of the FWHMs is linear and the slope of the line is directly related to the strain energy of the dislocation system. Evaluation of the numerically generated peaks for randomly arranged edge dislocation dipoles shows that the method based on the mWH plot gives accurate strain energy, while asymptotic LPA overestimates it by about 50%. The accurate result given by the mWH plot is explained by the long correlation distance associated with the FWHM, which better captures the dislocation arrangement over large distances. By contrast, asymptotic LPA is related to atomic correlations over distances smaller than the mean dislocation–dislocation spacing, where the displacement gradient is mainly determined by the field of single dislocations. Therefore, asymptotic LPA leads to a very accurate dislocation density (with error less than 1%) and the result is independent of the dislocation arrangement. However, these short-range correlations overestimate the outer cut-off radius by one order of magnitude.
Application of gamification for sustainable construction: an evaluation of the challenges
Authors: Oke Ayodeji Emmanuel , Aliu John , Tunji-Olayeni Patience , Abayomi Timilehin
Published: January 2023

Purpose

This paper aims to identify and evaluate the challenges affecting the adoption of gamification practices in developing countries through the lens of the Nigerian construction industry.

Design/methodology/approach

A scoping literature review was conducted through which challenges to the adoption of gamification practices were identified, which helped in the formulation of a questionnaire survey. Data was obtained from construction professionals including architects, builders, engineers and quantity surveyors. Retrieved data were analyzed using several statistical tools such as percentages, frequencies, mean item scores (MIS) and exploratory factor analyses.

Findings

Based on the MIS ranking results, the top five significant challenges to the adoption of gamification were lack of capacity and expertise, lack of budgeting for innovation, lack of technical infrastructure, hesitation to adopt and limited internet connectivity. Through factor analysis, the challenges identified were categorized into five principal clusters, namely, organizational challenges, technical-related challenges, human-related challenges, data security challenges and economic challenges.

Practical implications

The identification and evaluation of the key challenges hindering the adoption of gamification practices would help construction organizations and stakeholders to understand the need to embrace and implement the concept into their activities, operations and processes to improve the engagement and motivation levels of employees.

Originality/value

To the best of the authors’ knowledge, this study is the first of its kind in the study area to identify and evaluate the challenges affecting the adoption of gamification practices using a structured quantitative approach.