bluuebunny/crossref_metadata_2025 huggingface dataset:
Bardet–Biedl syndrome with unique manifestations of congenital giant nevi and refractory anemia: a case report from Palestine
Authors: Milhem Mohammad , Shehadeh Daleen , Abu Nawa Yasmeen , Arman Roa , Masri Lara , Salman Zeena , Najajreh Mohammad
Published: March 2024

Introduction and importance:

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive disorder impacting multiple organs. Characterized by renal dysfunction, retinal dystrophy, obesity, polydactyly, intellectual disability, and hypogonadism, it lacks targeted treatment. Diagnosis relies on clinical criteria, and management emphasizes early detection, complication screening, and genetic counselling.

Case presentation:

A 4-year-old boy, born to first-cousin parents, presented with refractory iron-deficiency anaemia (IDA) and recurrent respiratory infections. Prenatal ultrasound revealed renal and limb anomalies. Physical examination showed dysmorphic features, polydactyly, and a giant-congenital naevus. Genetic testing revealed a homozygous MKKS variant. Despite oral iron, severe IDA persisted. Intravenous iron therapy yielded significant improvement.

Clinical discussion:

BBS, an autosomal recessive ciliopathy, involves various genes. In this case, the MKKS gene variant contributed to the syndrome. The incidence of BBS in the Arab population is discussed, emphasizing its rarity and varied clinical presentations. Incidence in the Arab population, including Palestine, is 1 in 13 500. Diagnostic criteria, encompassing major and minor features, highlight BBS complexity. Renal anomalies, visual disturbances, and cutaneous manifestations are common. Multidisciplinary care addresses systemic involvement with emerging treatments like setmelanotide.

Conclusion:

This case underscores BBS's rarity and complexity, featuring unique aspects like giant nevi and refractory IDA. Comprehensive management addresses renal, visual, cardiac, and neurologic aspects. Genetic counselling, prenatal testing, and preimplantation genetic diagnosis prevent transmission. Limitations include lacking local epidemiological data and prior studies in Palestine. This case contributes insights, stressing multidisciplinary management and prompting further research in underexplored populations.
A rare case of retained metallic foreign body in liver: case report and review of literature
Authors: Dev Santosh , Yadav Manish , Shah Newton Ashish , Dev Barsha , Devkota Shishir , Khadka Laxman , Das Dhiraj Kumar , Yadav Samridhi , Sah Jayant Kumar , Ghimire Bikal
Published: March 2024

Introduction and importance:

Foreign bodies in the liver are uncommon but can lead to severe conditions like liver abscess and sepsis. They typically enter through direct penetration, migration from the gastrointestinal tract, or through the blood. Common foreign objects include metal pins, or sewing needles swallowed accidentally.

Case presentation:

A 25-year-old male presented to our OPD with pain over the right abdomen with a prior history of projectile injury causing laceration over the right anterior abdomen with primary suturing. On radiological investigation, a retained foreign body was revealed. The metallic foreign body was embedded in the liver for 5 months. Removal of the foreign body was performed without any complications.

Clinical discussion:

Intrahepatic foreign bodies (FBs) in the liver can result from penetrating injuries, iatrogenic causes, or ingestion, particularly in children. Clinical presentations vary, and complications such as abscess formation may occur. Diagnosis involves imaging modalities like X-rays, ultrasonography, and computed tomography (CT) scans. The presented case highlights the importance of meticulous follow-up, as chronic pain manifested despite conservative management. The management of intrahepatic FBs depends on factors like size, location, and symptoms, with conservative approaches for stable patients. Surgical removal remains the mainstay of the treatment. Long-term monitoring is crucial to detect potential complications, and imaging studies play a key role in regular follow-up.

Conclusion:

Hepatic foreign bodies are rare, and symptoms vary based on size, type, and location, ranging from asymptomatic to complications such as abscess formation. Surgical removal is the main treatment, but in cases of noncomplicated hepatic foreign bodies, close follow-up is necessary.
Trends in Blood Mosaicism and Clinical Phenotype Score in Patients with Beckwith–Wiedemann Syndrome Evaluated for Tongue Reduction Surgery
Authors: Romeo Dominic J. , Wagner Connor S. , Massenburg Benjamin B. , Reddy Neil , Wu Meagan , Ng Jinggang J. , DeMarchis Madison , Liao Eric C. , Kalish Jennifer M. , Taylor Jesse A.
Published: March 2024

Background:

Most patients with Beckwith–Wiedemann syndrome (BWS) have macroglossia, with some requiring tongue reduction surgery (TRS). This study reports correlations between levels of affected cells (mosaicism) and BWS clinical score in patients evaluated for TRS. The authors also show correlations of clinical score and mosaicism with obstructive sleep apnea (OSA) severity.

Methods:

Blood mosaicism levels and BWS clinical score were recorded in patients with macroglossia referred to plastic surgery for evaluation. Associations among blood mosaicism, BWS clinical score, TRS, and OSA were assessed with appropriate statistics.

Results:

Of the 225 patients included, BWS blood testing was available in 128 (56.9%). Mosaicism levels were higher in those who underwent TRS compared with those who did not (85.9% [56.5 to 95.9] versus 29.7% [2.8 to 73.1]; P < 0.001). BWS clinical score was also higher in those requiring TRS (9.0 [8.0 to 11.0] versus 7.0 [6.0 to 9.0]; P < 0.001). There was a positive correlation between clinical score and obstructive apnea-hypopnea index (r = 0.320, P = 0.011). Receiver operating characteristic curve analysis showed that a clinical score of 11 or greater had 100% specificity and 36.4% sensitivity for detecting patients requiring TRS. Blood mosaicism of 80% or greater had 63.6% sensitivity and 83.6% specificity for predicting surgery. A combined criteria of BWS clinical score of 11 or greater or mosaicism of 80% or greater had 72.7% sensitivity and 83.6% specificity for predicting TRS.

Conclusions:

Blood mosaicism levels and higher BWS clinical scores seem to be associated with a greater frequency of having surgery in patients with macroglossia referred for surgical evaluation. Elevations in BWS clinical scoring are associated with increased OSA severity; increased blood mosaicism is not.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Stanley Falkow. 24 January 1934—5 May 2018
Authors: Ramakrishnan FRS Lalita , Cormack Brendan P.
Published: March 2024

Our understanding of infectious disease and disease-causing organisms has been broadly shaped by two revolutions. The first was the advent of clinical microbiology of the nineteenth and early twentieth centuries, which saw the isolation, identification and classification of disease-causing organisms. In the middle of the twentieth century, the emerging field of molecular biology transformed our understanding of genes and their regulation. Starting in 1960, Stanley Falkow fused clinical microbiology with molecular biology, founding the new discipline of molecular microbial pathogenesis. Over the next half century, he led and shaped this new discipline, revolutionizing our understanding of how pathogenic bacteria cause disease and become resistant to antibiotics.
On the Kermack–McKendrick with Weibull residence times
Authors: Cruz–López M. , Murillo-Salas A. , Velasco-Hernández J.X.
Published: March 2024

In this paper we develop a generalization of the Kermack-McKendrick SIR model where the time of infectiousness follows the Weibull distribution. We compute the equivalent classical results available for the classical SIR model, particularly a general expression for the basic reproduction number. We comment about the implications of this generalization in epidemic and metapopulation dynamics and illustrate our findings with some numerical simulations.
Optimisation strategies for directed evolution without sequencing
Authors: James Jess , Towers Sebastian , Foerster Jakob , Steel Harrison
Published: March 2024

Directed evolution can enable engineering of biological systems with minimal knowledge of their underlying sequence-to-function relationships. A typical directed evolution process consists of iterative rounds of mutagenesis and selection that are designed to steer changes in a biological system (e.g. a protein) towards some functional goal. Much work has been done, particularly leveraging advancements in machine learning, to optimise the process of directed evolution. Many of these methods, however, require DNA sequencing and synthesis, making them resource-intensive and incompatible with developments in targetedin vivomutagenesis. Operating within the experimental constraints of established sorting-based directed evolution techniques (e.g. Fluorescence-Activated Cell Sorting, FACS), we explore approaches for optimisation of directed evolution that do not require sequencing information. We then expand our methods to the context of emerging experimental techniques in directed evolution, which allow for single-cell selection based on fitness objectives defined from any combination measurable traits. Finally, we validate the developed selection strategies on the GB1 empirical landscape, demonstrating that they can lead to up to a 7.5 fold increase in the probability of attaining the global fitness peak.

Author summary

The standard approach to sorting-based selection in directed evolution is to take forward only the top-performing variants from each generation of a single population. In this work, we begin to explore alternative selection strategies within a simulated directed evolution framework. We propose “selection functions”, which allow us to tune the balance of exploration and exploitation of a fitness landscape, and we demonstrate that splitting a population into sub-populations can improve both the likelihood and magnitude of a successful outcome. We also propose strategies to leverage emerging selection methods that can implement single-cell selection based on any combination of measurable traits. We validate our optimised directed evolution approaches on the empirical fitness landscape of the GB1 immunoglobulin protein.
Sexual dimorphism and allometry in human scapular morphology
Authors: Lee Erin C.S. , Lawrence Rebekah L. , Rainbow Michael J.
Published: March 2024

Scapular morphology is highly variable across the human population and appears to be sexually dimorphic – differing significantly between males and females. However, previous investigations of sexual dimorphism in scapula shape have not considered the effects of allometry (the relationship between size and shape). Disentangling allometry from sexual dimorphism is necessary because apparent sex-based differences in morphology could be due to inherent differences in body size. This study aimed to investigate sexual dimorphism in scapula shape and examine the role of allometry in sex-based variation. We used three-dimensional geometric morphometrics with Procrustes ANOVA to quantify scapula shape variation associated with sex and size in 125 scapulae. Scapular morphology significantly differed between males and females, and males tended to have larger scapulae than females for the same body height. We found that males and females exhibited distinct allometric relationships, and sexually dimorphic shape changes did not align with male- or female-specific allometry. A secondary test revealed that sexual dimorphism in scapula shape persisted between males and females of similar body heights. Overall, our findings indicate that sex-based differences in scapular shape are independent of size-shape relationships. Our results shed light on the potential role of sexual selection in human shoulder evolution, present new hypotheses for biomechanical differences in shoulder function between sexes, and identify relevant traits for improving sex classification accuracy in forensic analyses.
PIPETS: A statistically informed, gene-annotation agnostic analysis method to study bacterial termination using 3’-end sequencing
Authors: Furumo Quinlan , Meyer Michelle
Published: March 2024

Background

Over the last decade the drop in short-read sequencing costs has allowed experimental techniques utilizing sequencing to address specific biological questions to proliferate, oftentimes outpacing standardized or effiective analysis approaches for the data generated. There are growing amounts of bacterial 3’-end sequencing data, yet there is currently no commonly accepted analysis methodology for this datatype. Most data analysis approaches are somewhatad hocand, despite the presence of substantial signal within annotated genes, focus on genomic regions outside the annotated genes (e.g. 3’ or 5’ UTRs). Furthermore, the lack of consistent systematic analysis approaches, as well as the absence of genome-wide ground truth data, make it impossible to compare conclusions generated by diffierent labs, using diffierent organisms.

Results

We present PIPETS, (PoissonIdentification ofPEaks fromTerm-Seq data), an R package available on Bioconductor that provides a novel analysis method for 3’-end sequencing data. PIPETS is a statistically informed, gene-annotation agnostic methodology. Across two diffierent datasets from two diffierent organisms, PIPETS identified significant 3’-end termination signal across a wider range of annotated genomic contexts than existing analysis approaches, suggesting that existing approaches may miss biologically relevant signal. Furthermore, assessment of the previously called 3’-end positions not captured by PIPETS showed that they were uniformly very low coverage.

Conclusions

PIPETS provides a broadly applicable platform to explore and analyze 3’-end sequencing data sets from across diffierent organisms. It requires only the 3’-end sequencing data, and is broadly accessible to non-expert users.
Identification of a Conserved B-Cell Epitope on the Capsid Protein of Porcine Circovirus Type 4
Authors: Fang Zheng , Sun Mingxia , Cai Xuehui , An Tongqing , Tu Yabin , Wang Haiwei
Published: March 2024

Porcine circovirus type 4 (PCV4), a recently identified circovirus, is prevalent in numerous provinces in China, as well as in South Korea, Thailand, and Europe. PCV4 virus rescued from an infectious clone showed pathogenicity, suggesting the economic impact of PCV4. However, there remains a lack of understanding regarding the immunogenicity and epitopes of PCV4. This study generated a monoclonal antibody (MAb) 1D8 by immunizing mice with PCV4 virus-like particles (VLPs). Subsequently, the epitope recognized by the MAb 1D8 was identified by truncated protein expression and alanine scanning mutagenesis analysis. Results showed that the225PKQG228located at the C-terminus of the PCV4 Cap protein is the minimal motif binding to the MAb. Homology modeling analysis and immunoelectron microscopy revealed that the epitope extends beyond the outer surface of the PCV4 VLP. Moreover, the epitope is highly conserved among PCV4 strains and does not react with other PCVs. Together, the MAb 1D8 recognized epitope shows potential for detecting PCV4. These findings significantly contribute to the design of antigens for PCV4 detection and control strategies.

IMPORTANCE

Porcine circovirus type 4 (PCV4) is a novel circovirus. Although PCV4 has been identified in several countries, including China, Korea, Thailand, and Spain, no vaccine is available. Given the potential pathogenic effects of PCV4 on pigs, PCV4 could threaten the global pig farming industry, highlighting the urgency for further investigation. Thus, epitopes of PCV4 remain to be determined. Our finding of a conserved epitope significantly advances vaccine development and pathogen detection.
Anion exchange regulates intestinal mucus expansion while Cftr regulatesde novomucus secretion
Authors: Ljungholm Penny L , Ermund Anna , Garsveden Molly M Söderlund , Pettersson Victor L , Gustafsson Jenny K
Published: March 2024

The intestinal epithelium is covered by mucus that protects the tissue from the luminal content. Studies have shown that anion secretion via the cystic fibrosis conductance regulator (Cftr) regulates mucus formation in the small intestine. However, mechanisms regulating mucus formation in the colon are less understood. The aim of this study was to explore the role of anion transport in regulation of mucus formation during steady state, and in response to carbamylcholine (CCh) and prostaglandin E2(PGE2). CftrΔF508 (CF) mice were used to assess the role of Cftr, and 4,4′-diisothiocyanatostilbene-2,2′-disulfonate (DIDS) was used to inhibit anion exchange. In the distal colon, steady state mucus expansion was reduced by apical DIDS, and normal in CF mice. PGE2stimulated mucus expansion withoutde novomucus secretion in wild type (WT) and CF distal colon via DIDS sensitive mechanisms, while CCh inducedde novomucus secretion in WT but not in CF colon. However, when added simultaneously, CCh and PGE2, stimulatedde novomucus secretion in CF colon via DIDS sensitive pathways. A similar response was observed in CF ileum that responded to CCh and PGE2with DIDS sensitivede novomucus secretion. In conclusion, this study suggests that apical anion exchange regulates intestinal mucus expansion, while Cftr regulatesde novomucus secretion from ileal and distal colon crypts. Furthermore, these findings demonstrate that in the absence of a functional Cftr channel, activation of anion exchange can help release mucus from intestinal goblet cells.
Presence of Ecuador in the Web of Science from open access in post-pandemic period 2019-2021: A multivariate analysis
Authors: Álvarez Muñoz Patricio , Pacheco Olea Fernando Erasmo , Peralta Gamboa Dennis Alfredo , Angelo Marcos Aviles Valenzuela
Published: March 2024

The study analyzed the presence of Ecuador in the post-pandemic Web of Science (WoS) from a multivariate dynamic, highlighting a significant transformation in scientific communication towards open access (OA). The methodology integrated multivariate statistical techniques, using R and specialized tools, to process 9,085 relevant articles. Between 2019 and 2021, 52% of Ecuadorian publications in WoS were open access. This movement reflects a commitment to quality research and accessibility, evidencing an increase in publications and citations under OA. The research highlights the importance of establishing robust national OA policies in Ecuador to promote scientific collaboration and an equitable distribution of knowledge. The dynamic biplot showed how universities in the post-pandemic period had stable and erratic behaviors towards open access. Of all the universities, the State University of Cuenca stands out in terms of quantity of production and migration to open access.
Molecular Phylogeny and Cryptic Morphology: A Combined Approach to Taxonomic Novelties inPolycarpaea(Caryophyllaceae) from Vietnam
Authors: Truong Thanh Hoang , Le Le Ba , Thi Kim Ngan Le , Thi Ai Minh Nguyen , Thi Lan Anh Truong , Thi Nhung Tran , Thai Vinh Tran , Van Son Le , Thi Kim Duong , Viet Bach Khoa Hoang , Ngoc Tieu Le , Van Binh Nguyen , Van Tien Tran
Published: March 2024

Three new species ofPolycarpaeafrom Vietnam,P. vanana,P. chungana,P. duonganaare described and illustrated based on evidence of molecular sequence data from two markers (ITS1-5.8S-ITS2 andrps16) and combined morphological characteristics.Polycarpaea vananais closely related toPolycarpaea gaudichaudi,P. arenaria,P. duonganabut differs by its stem glabrous, leaf ovate to elliptic, glabrous, ovary oblong ovoid, base obtuse, apex attenuate, capsule oblong void, 3.8 mm long.P. duonganadiffers from the three species mentioned above by its stem being densely villous, leaf spathulate, ciliate, ovary ovoid, base acute, apex obtuse, capsule ovoid, 1.2 mm long.Polycarpaea chunganais most similar toP. lignosabut differs in having leaf oblong or linear, sparse ciliate, sepal and petal apex deeply concaved or slightly bifid, ovary ovoid, ovoid, 0.8–1.0 mm long. Furthermore, the achievements of analysis using molecular data on the systematic positions of 7 other species are results that have not been in previous molecular analyses.
Distinct Functional Roles of Narrow and Broadband High-Gamma Activities in Human Primary Somatosensory Cortex
Authors: Ryun Seokyun , Chung Chun Kee
Published: March 2024

In previous studies, higher (broadband) and lower (narrowband) components of high-gamma (HG) activity (approximately from 50 to 150 Hz) have different functions and origins in the primary visual cortex (V1). However, in the primary somatosensory cortex (S1), it is unknown whether those are similarly segregated. Furthermore, the origin and functional role of S1 HG activity still remain unclear. Here, we investigate their roles by measuring neural activity during vibrotactile and texture stimuli in humans. Also, to estimate their origins, S1 layer-specific HG activity was measured in rats during somatosensory stimulation. In the human experiment, with texture stimulation, the lower HG activity (LHG, 50-70 Hz) in S1 represents the intensity of the sustained mechanical stimulus. In the vibrotactile experiment, the higher HG (HHG, 70 -150 Hz) activity in S1 depended on the ratio of low and high mechanical frequencies with its pattern being a mixture of neural activity for low and high mechanical frequencies. Furthermore, 8 texture types could be classified using power values of HHG activity, while the classification using LHG activity showed poor performance. In the rat experiment, we found that both HHG and LHG activities are highest in the somatosensory input layer (layer IV), similar to previous visual cortex studies. Interestingly, analysis of spike-triggered LFP (stLFP) revealed significant HG oscillations during pressure stimulation with the stLFP HG power most significant in layer IV, suggesting that both LHG and HHG activities are closely related to the neuronal firing in layer IV. In summary, LHG activity represents the intensity of tactile sensation, while HHG activity represents the detail of the surface geometry of objects interacting with skin. Additionally, low and high mechanical frequencies are processed in parallel in S1. Finally, both HHG and LHG originated in layer IV of S1.
Multi-omics Identify Serotonin Transporter as a Promising Therapeutic Target for Essential Tremor
Authors: Wang Lingbing , Li Yanjing , Lin Suzhen , Zhou Zhuofan , Zhang Shaoyi , Xu Tian-Le , Song Xing-Lei , Wu Yiwen
Published: March 2024

Essential tremor (ET) stands as one of the most prevalent cerebellar movement disorders. However, effective treatment remains elusive, largely due to a limited understanding of its molecular pathology. Harmaline-induced tremor in mouse is a well-established animal model for ET, while with enigmatic mechanism. The aim of this study was to get insight into the molecular intricacies underlying cerebellar dysfunction in harmaline-induced tremor. Combining LC-MS/MS and RNA-Seq analysis, we delved into the variation of the cerebellum between harmaline-induced tremor and the control ones. This comprehensive investigation revealed a profile of this mouse model from mRNA and protein level, highlighting 5194 correlated coding molecules, with 19 proving to be significant. Further KEGG enrichment analysis identified cerebellar serotonin transporter (SERT) as the key molecule in harmaline-induced tremor. The implications of this transcriptomic and proteomic exploration underscore the potential therapeutic value of targeting SERT as a novel treatment approach for ET. In general, our study unveils crucial insights that could pave the way for molecular target identification and effective therapeutic interventions for ET.
A Systematic Examination of Generative Artificial Intelligence (GAI) Usage Guidelines for Scholarly Publishing in Medical Journals
Authors: Yin Shuhui , Lu Peiyi , Xu Zhuoran , Lian Zi , Ye Chenfei , Li Chihua
Published: March 2024

Background

A thorough and in-depth examination of generative artificial intelligence (GAI) usage guidelines in medical journals will inform potential gaps and promote proper GAI usage in scholarly publishing. This study aims to examine the provision and specificity of GAI usage guidelines and their relationships with journal characteristics.

Methods

From the SCImago Journal Rank (SJR) list for medicine in 2022, we selected 98 journals as top journals to represent highly indexed journals and 144 as whole-spectrum sample journals to represent all medical journals. We examined their GAI usage guidelines for scholarly publishing between December 2023 and January 2024.

Results

Compared to whole-spectrum sample journals, the top journals were more likely to provide author guidelines (64.3% vs. 27.8%) and reviewer guidelines (11.2% vs. 0.0%) as well as refer to external guidelines (85.7% vs 74.3%). Probit models showed that SJR score or region was not associated with the provision of these guidelines among top journals. However, among whole-spectrum sample journals, SJR score was positively associated with the provision of author guidelines (0.85, 95% CI 0.49 to 1.25) and references to external guidelines (2.01, 95% CI 1.24 to 3.65). Liner models showed that SJR score was positively associated with the specificity level of author and reviewer guidelines among whole-spectrum sample journals (1.21, 95% CI 0.72 to 1.70), and no such pattern was observed among top journals.

Conclusions

The provision of GAI usage guidelines is limited across medical journals, especially for reviewer guidelines. The lack of specificity and consistency in existing guidelines highlights areas deserving improvement. These findings suggest that immediate attention is needed to guide GAI usage in scholarly publishing in medical journals.

Key points

Question

What are the provision and specificity of generative artificial intelligence (GAI) usage guidelines for scholarly publishing in top and whole-spectrum medical journals and their relationships with journal characteristics?

Findings

Author guidelines were more abundant and specific in top journals than in whole-spectrum journals. However, reviewer guidelines were extremely scarce in both groups of journals. Journal ranking score was associated with both provision and specificity of GAI usage guidelines in whole-spectrum journals while no significant relationship was found in top journals.

Meaning

The lack of provision and specificity as well as the inconsistencies in existing guidelines suggest that immediate attention is needed to guide GAI usage in scholarly publishing and safeguard integrity and trust in medical research.
CHARACTERIZATION OF ACROMEGALY ACCORDING TO TUMOR SIZE AT DIAGNOSIS
Authors: Del Corso Leticia Marinho , Andrade Vicente Florentino Castaldo , Fidalski Solena Ziemer Kusma , Boguszewski Cesar Luiz
Published: March 2024

Purpose

To evaluate the clinical, laboratory, radiological, therapeutic, and prognostic characteristics of patients with acromegaly according to the size of the growth hormone (GH)-secreting pituitary adenoma at diagnosis.

Patients and Methods

Observational, retrospective, single-center study of patients with acromegaly followed at a tertiary center. Data from medical records were evaluated regarding age, symptoms, presence of arterial hypertension, type 2 diabetes mellitus, hypopituitarism, size of the initial lesion, invasiveness (cavernous sinus invasion), T2-weighted magnetic resonance imaging signal intensity, GH and insulin-like growth factor type 1 (IGF-1) levels, treatment performed [surgery, use of somatostatin receptor ligands (SRL), pegvisomant, cabergoline and bromocriptine and radiotherapy] and response to surgical or adjuvant treatment (normal levels of GH and/or IGF-1 after each treatment instituted).Patients were divided into groups according to the size of the adenoma at diagnosis (group I = ≤ 10 mm, II = 10-19 mm, III = 20-29 mm, IV = 30-39 mm and V = ≥ 40 mm), and comparisons were made between the 5 groups and two-by-two comparisons.

Results

117 patients were studied (59 women, age at diagnosis 43 ± 13 years). Group I consisted of 11 patients (9%), group II of 54 (46%), group III of 34 (29%), group IV of 10 (9%) and group V of 8 patients (7%). The prevalence of hypertension, diabetes mellitus and hypopituitarism were 49%, 25% and 28%, respectively. Hypopituitarism, invasiveness, and the use of SRL had their prevalence increased according to the size of the adenoma, as well as GH levels. Age, on the other hand, showed a negative correlation with tumor size, and group I was older when compared to the group with macroadenoma. The ROC curves showed that in relation to the size of the adenoma at diagnosis, most of the outcomes evaluated (hypopituitarism, invasiveness, radiotherapy, use of SRL, use of medications other than SRL, disease control after surgery) occurred with a tumor diameter of around 20 mm.

Conclusion

Our study demonstrated that microadenomas and macroadenomas < 20 mm are associated with lower morbidity and better therapeutic response in acromegaly. From a tumor diameter of 20 mm, there was no significant difference in the clinical, therapeutic and prognostic behavior of GH-secreting pituitary adenomas.

Trial Registration number (Plataforma Brasil)

CAAE 30066220.2.0000.0096 (April 02, 2020)
Machine Learning-Based Prediction of Coronary Care Unit Readmission: A Multi-Hospital Validation Study
Authors: Yau Fei-Fei Flora , Chiu I-Min , Wu Kuan-Han , Cheng Chi-Yung , Lee Wei-Chieh , Chen Huang-Chung , Cheng Cheng-I , Chen Tien-Yu
Published: March 2024

Readmission to the Coronary Care Unit (CCU) has significant implications for patient outcomes and healthcare expenditure, emphasizing the urgency to accurately identify patients at high readmission risk. This study aims to construct and externally validate a predictive model for CCU readmission using machine learning (ML) algorithms across multiple hospitals. Patient information, including demographics, medical history, and laboratory test results were collected from electronic health record system and contributed to a total of 40 features. Three ML models, Logistic Regression, Random Forest, and Gradient Boosting were employed to estimate the readmission risk. The gradient boosting model was selected demonstrated superior performance with an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.887 in the internal validation set. Further external validation in hold-out test set and three other medical centers upheld the model’s robustness with consistent high AUCs, ranging from 0.852 to 0.879. The results endorse the integration of ML algorithms in healthcare to enhance patient risk stratification, potentially optimizing clinical interventions and diminishing the burden of CCU readmissions.

Key learning points

What is already known:

Readmission to the CCU has significant implications for both patient outcomes and healthcare costs.

Accurately distinguishing patients at high or low risk for CCU readmission is essential for clinicians to allocate resources effectively

What this study adds:

A predictive model for CCU readmission was constructed using machine learning algorithms trained from one medical center and validated externally in three major medical centers.

Among the ML models evaluated, the Gradient Boosting model showed the highest performance with an AUC of 0.879 in hold-out test set, and its robustness was further confirmed in external validation across three medical centers with an AUC range from 0.848-0.863.

By using different cut-off thresholds to prioritize the model’s sensitivity or specificity, clinicians can distinguish between high-risk and low-risk patients, enabling them to determine the appropriate level of monitoring and treatment planning for those at high risk.
Spatial Interaction Analysis of Infectious Disease Import and Export Between Regions
Authors: Lyu Mingdong , Liu Kuofu , Hall Randolph W.
Published: March 2024

Human travel plays a crucial role in the spread of infectious disease between regions. Travel of infected individuals from one region to another can transport a virus to places that were previously unaffected or may accelerate the spread of disease in places where the disease is not yet well established. We develop and apply models and metrics to analyze the role of inter-regional travel relative to the spread of disease, drawing from data on Covid-19 in the United States. To better understand how transportation affects disease transmission, we established a multi-regional time-varying compartmental disease model with spatial interaction. The compartmental model was integrated with statistical estimates of travel between regions. From the integrated model, we derived a transmission import index to assess the risk of Covid-19 transmission between states. Based on the index, we determined states with high risk for disease spreading to other states at months scale, and we analyzed how the index changed over time during 2020. Our model provides a tool for policymakers to evaluate the influence of travel between regions on disease transmission in support of strategies for epidemic control.
Multi-Site Investigation of Gut Microbiota in CDKL5 Deficiency Disorder Mouse Models: Targeting Dysbiosis to Improve Neurological Outcomes
Authors: Damiani Francesca , Giuliano Maria Grazia , Cornuti Sara , Putignano Elena , Tognozzi Andrea , Suckow Vanessa , Kalscheuer Vera M. , Tognini Paola
Published: March 2024

Background

Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) is a rare X-linked developmental encephalopathy caused by pathogenic variants of the CDKL5 gene. In addition to a diverse range of neurological symptoms, CDD patients frequently manifest gastrointestinal (GI) issues and subclinical immune dysregulation. This comorbidity suggests a potential association with the intestinal microbiota, prompting an investigation into whether gut dysbiosis contributes to the severity of both GI and neurological symptoms.

Methods

We examined the gut microbiota composition in two CDKL5 null (KO) mouse models in males at three different developmental stages: postnatal day (P) 25 and P32 during youth, and P70 during adulthood.

Results

Changes in diversity and composition were observed, particularly during juvenile ages, suggesting a potential gut microbiota dysbiosis in the CDD mouse models. To further understand the role of the gut microbiota in CDD, we administered an antibiotic cocktail to the mice and conducted functional and behavioral assessments. Remarkably, significant improvement in visual cortical responses and reductions in hyperactive behavior were observed. To shed light on the cellular mechanisms we focused on microglia. Alterations in specific aspects of microglia morphology, indicative of activation state and surveillance of the microenvironment, were observed in the CDKL5 KO mice and ameliorated by antibiotic administration.

Conclusions

Our findings highlight the potential impact of modifications in the intestinal microbiota on the severity of CDD symptoms, expanding our understanding beyond GI disturbances to encompass influences on neurological outcomes. This cross-border study provides valuable insights into the intricate interplay between gut microbiota and neurodevelopmental disorders.
Generation of human-pig chimeric renal organoids using iPSC technology
Authors: Fujimori Koki , Yamanaka Shuichiro , Shimada Kentaro , Matsui Kenji , Kawagoe Shiho , Kuroda Takao , Ikeda Atsushi , Inoue Makoto , Kobayashi Eiji , Yokoo Takashi
Published: March 2024

The potential of using porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation has garnered growing attention. However, both approaches still face technological challenges. Interspecies chimeric organ production using human iPSCs is expected to be another promising approach that addresses the challenges associated with organ production. Our research group successfully generated human-mouse chimeric renal organoids by utilizing human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology has limited engraftment and development capabilities for human NPCs, and there have been no reports of generating interspecies chimeric renal organoids in larger animals, limited only to rodents. Therefore, in this study, we embarked on the production of human-pig chimeric renal organoids using the pig kidney, which is considered the most promising source of organs for interspecies transplantation to humans. To construct a human-pig chimeric renal organoid culture system, we first modified the existing human-mouse chimeric renal organoid culture system and developed a method that enables the survival and continued renal development of both species. This method was found to be applicable to porcine fetal kidney cells, and ultimately, we successfully produced human-pig chimeric renal organoids. Furthermore, this culture method can also be applied to the generation of human interspecies chimeric kidneys for future clinical applications.

The findings of this study serve as a foundational technology that will greatly accelerate future research in humanized pig kidney production for clinical purposes, and are also expected to be used as an evaluation technique to ensure the quality of human NPCs for xenotransplantation.
CRISPR-Cas9-assisted genome editing inE. colielevates the frequency of unintended mutations
Authors: Widney Karl A. , Yang Dong-Dong , Rusch Leo M. , Copley Shelley D.
Published: March 2024

Cas-assisted lambda Red recombineering techniques have rapidly become a mainstay of bacterial genome editing. Such techniques have been used to construct both individual mutants and massive libraries to assess the effects of genomic changes. We have found that a commonly used Cas9-assisted editing method results in unintended mutations elsewhere in the genome in 26% of edited clones. The unintended mutations are frequently found over 200 kb from the intended edit site and even over 10 kb from potential off-target sites. We attribute the high frequency of unintended mutations to error-prone polymerases expressed in response to dsDNA breaks introduced at the edit site. Most unintended mutations occur in regulatory or coding regions and thus may have phenotypic effects. Our findings highlight the risks associated with genome editing techniques involving dsDNA breaks inE. coliand likely other bacteria and emphasize the importance of sequencing the genomes of edited cells to ensure the absence of unintended mutations.

GRAPHICAL ABSTRACT
Long read sequencing provides an insight into plasmids found among carbapenemase producingEnterobacteralesfrom hospitals in the United Kingdom during 2021 to 2023
Authors: Turton Jane F , Turton Jack A
Published: March 2024

107 isolates ofEnterobacteralesconsisting ofKlebsiella pneumoniae(n=90),Escherichia coli(n=7),Enterobacter cloacaecomplex (n=6),Klebsiella oxytocacomplex (n=3) andCitrobacter freundi(n=1) and additionally an isolate ofAcinetobacter baumanniicarrying genes encoding NDM (NDM-1, NDM-5 and NDM-14), KPC (KPC-2 and KPC-3), OXA-48-like (OXA-48, OXA-181 and OXA-232) and IMP (IMP-1 and IMP-4) carbapenemases were sequenced using q20 nanopore chemistry to provide complete/near-complete assemblies and relevant plasmids compared. Investigation of potential ‘plasmid outbreaks’ in individual hospitals among isolates of different types and species revealed a mixed situation with some isolates carrying similar plasmids, but with segments missing/added and some plasmids that were clearly distinct.

While most plasmids carryingblaOXA-48were typical IncL plasmids of approximately 60 kb that are widely described, there was some variation among these. One isolate carried an IncR plasmid that had only limited homology with the others. Identical 51,479 bp ColKP3/IncX3 plasmids carryingblaOXA-181were found from isolates from different hospitals that exactly matched those on GenBank from other countries. In other isolatesblaOXA-181was carried on IncFII plasmids.blaOXA-232was found in highly conserved small ColKP3 plasmids that matched those found in other countries and continents. These observations highlight the importance of understanding the wider distribution of plasmids of concern.

IncHI2/IncHI2A plasmids were important vehicles for carbapenemase genes and were found withblaKPC-2,blaIMP-1,blaIMP-4orblaNDM-1, sometimes with the colistin resistance genemcr-9in addition. Representatives ofK. pneumoniaesequence type (ST) 147 from seven hospitals carried IncFIB(pNDM-Mar)/IncHI1B(pNDM-MAR) hybrid virulence resistance plasmids of 325 to 352 kb that combinedblaNDM-5and other resistance genes with genes found in virulence plasmids. A similar plasmid was also found in an isolate ofK. pneumoniaeST1558 and has been described in representatives of ST383.

Nanopore sequencing has been instrumental in improving our knowledge of plasmids carrying carbapenemase genes leading to a better understanding of their epidemiology.
Molecular basis of mRNA delivery to the bacterial ribosome
Authors: Webster Michael W. , Chauvier Adrien , Rahil Huma , Graziadei Andrea , Charles Kristine , Takacs Maria , Saint-André Charlotte , Rappsilber Juri , Walter Nils G. , Weixlbaumer Albert
Published: March 2024

Protein synthesis begins with the formation of a ribosome-mRNA complex. In bacteria, the 30S ribosomal subunit is recruited to many mRNAs through base pairing with the Shine Dalgarno (SD) sequence and RNA binding by ribosomal protein bS1. Translation can initiate on nascent mRNAs and RNA polymerase (RNAP) can promote recruitment of the pioneering 30S subunit. Here we examined ribosome recruitment to nascent mRNAs using cryo-EM, single-molecule fluorescence co-localization, and in-cell crosslinking mass spectrometry. We show that bS1 delivers the mRNA to the ribosome for SD duplex formation and 30S subunit activation. Additionally, bS1 mediates the stimulation of translation initiation by RNAP. Together, our work provides a mechanistic framework for how the SD duplex, ribosomal proteins and RNAP cooperate in 30S recruitment to mRNAs and establish transcription-translation coupling.
Calcineurin promotes adaptation to chronic stress through two distinct mechanisms
Authors: Flynn Mackenzie J. , Harper Nicholas W. , Li Rui , Zhu Lihua Julie , Lee Michael J. , Benanti Jennifer A.
Published: March 2024

Adaptation to environmental stress requires coordination between stress-defense programs and cell cycle progression. The immediate response to many stressors has been well characterized, but how cells survive in challenging environments long-term is unknown. Here, we investigate the role of the stress-activated phosphatase calcineurin (CN) in adaptation to chronic CaCl2stress inSaccharomyces cerevisiae.We find that prolonged exposure to CaCl2impairs mitochondrial function and demonstrate that cells respond to this stressor using two CN-dependent mechanisms – one that requires the downstream transcription factor Crz1 and another that is Crz1-independent. Our data indicate that CN maintains cellular fitness by promoting cell cycle progression and preventing CaCl2-induced cell death. When Crz1 is present, transient CN activation suppresses cell death and promotes adaptation despite high levels of mitochondrial loss. However, in the absence of Crz1, prolonged activation of CN prevents mitochondrial loss and further cell death by upregulating glutathione (GSH) biosynthesis genes thereby mitigating damage from reactive oxygen species. These findings illustrate how cells maintain long-term fitness during chronic stress and suggest that CN promotes adaptation in challenging environments by multiple mechanisms.
Causal Interactions between Phase- and Amplitude-Coupling in Cortical Networks
Authors: Galindo-Leon Edgar E. , Nolte Guido , Pieper Florian , Engler Gerhard , Engel Andreas K.
Published: March 2024

Phase coherence and amplitude correlations across brain regions are two main mechanisms of connectivity that govern brain dynamics at multiple scales. However, despite the increasing evidence that associates these mechanisms with brain functions and cognitive processes, the relationship between these different coupling modes is not well understood. Here, we study the causal relation between both types of functional coupling across multiple cortical areas. While most of the studies adopt a definition based on pairs of electrodes or regions of interest, we here employ a multichannel approach that provides us with a time-resolved definition of phase and amplitude coupling parameters. Using data recorded with a multichannel µECoG array from the ferret brain, we found that the transmission of information between both modes can be unidirectional or bidirectional, depending on the frequency band of the underlying signal. These results were reproduced in magnetoencephalography (MEG) data recorded during resting from the human brain. We show that this transmission of information occurs in a model of coupled oscillators and may represent a generic feature of a dynamical system. Together, our findings open the possibility of a general mechanism that may govern multi-scale interactions in brain dynamics.
The bidirectional role of GABAAand GABABreceptors during the differentiation process of neural precursor cells of the subventricular zone
Authors: Gutierrez-Castañeda Estefanía , Martínez-Rojas Vladimir Alex , Ochoa-de la Paz Lenin David , Galván Emilio J.
Published: March 2024

The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified that serve as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAAreceptor and the metabotropic GABABreceptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAAreceptors inhibits these effects, whereas the stimulation of GABABreceptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABABreceptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone.