bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding Platelet Activation in the Aeson Bioprosthetic Total Artificial Heart: Insights From Aspirin Treatment and Outcomes
Authors: Smadja David M. , Roux de Bezieux Joseph , Peronino Christophe , Jilet Léa , Pya Yuri , Philippe Aurélien , Latremouille Christian , Gustafsson Finn , Ramjankhan Faiz Z. , Roussel Jean Christian , Courbebaisse Marie , Parfait Béatrice , Lebeaux David , Friedlander Gérard , Vincentelli André , Flecher Erwan , Gaussem Pascale , Jansen Piet , Netuka Ivan
Published: February 2025

This study aimed to assess platelet activation following implantation of the Aeson bioprosthetic total artificial heart (A-TAH). We monitored plasma levels of platelet activation markers in patients receiving A-TAH support (n = 16) throughout the follow-up period. Before implantation, soluble CD40 ligand (sCD40L) levels averaged 3,909.06 pg/ml (standard deviation [SD] = 3,772.37), remaining stable postimplantation at 3,964.56 pg/ml (SD = 2,198.85) during months 1–3 and at 3,519.27 pg/ml (SD = 1,647.04) during months 3–6. Similarly, P-selectin (sP-sel) levels were 35,235.36 pg/ml (SD = 14,940.47) before implantation, stabilizing to 33,158.96 pg/ml (SD = 9,023.11) (1–3 months) and 31,022.58 pg/ml (SD = 9,249.95) (3–6 months). Preimplantation platelet factor 4 (PF4) measured 2,593.47 ng/ml (SD = 2,167.85), remaining consistent at 2,136.10 ng/ml (SD = 1,264.47) (1–3 months) and 1,991.26 ng/ml (SD = 1,234.16) (3–6 months). Levels of neutrophil-activating peptide 2 (NAP2) were also steady, measuring 785.63 ng/ml (SD = 605.26) preimplantation, 935.10 ng/ml (SD = 517.73) at 1–3 months, and 907.21 ng/ml (SD = 501.96) at 3–6 months postimplantation. Importantly, neither aspirin nor heparin treatment affected these platelet biomarker levels. No correlation was observed between platelet activation marker levels and clinical outcomes such as pericardial effusion, nor with the timing of aspirin initiation and drain removal. Our findings confirm that A-TAH does not trigger platelet activation. The lack of association between aspirin, platelet activation, and clinical outcomes suggests the possibility of discontinuing antiplatelet therapy following A-TAH implantation in the future.
Breastfeeding after gestational diabetes mellitus: maternal, milk and infant outcomes
Authors: Geddes Donna T. , Gridneva Zoya , Perrella Sharon L.
Published: February 2025

Purpose of review

This review examines the complex relationship between gestational diabetes mellitus (GDM) and breastfeeding outcomes, integrating recent evidence on maternal health benefits, milk composition, and clinical support strategies. Understanding these relationships is important as GDM affects approximately 14% of pregnancies worldwide, with rates continuing to rise alongside increasing obesity and maternal age.

Recent findings

Women who breastfeed for longer periods after GDM show significant improvements in metabolic health, including reduced weight retention and better cardiometabolic profiles. While macronutrient content of breast milk appears preserved, significant differences exist in human milk oligosaccharides and milk fat globule membrane proteins. A previous history of predominant breastfeeding shows a 47% reduction in abnormal fasting glucose odds in subsequent pregnancies. Initial positive indications of personalized support programs, particularly during pregnancy, are emerging however evaluation in comparison to current evidence-based interventions is yet to be carried out. Lifestyle factors are known to reduce subsequent diabetes after a GDM and recent evidence suggests these are important in pregnancy and may improve breastfeeding outcomes.

Despite the challenges of delayed secretory activation and reduced milk supply in women with GDM, successful breastfeeding offers substantial health benefits. Healthcare providers could implement comprehensive, individualized support strategies beginning in pregnancy and extending through the postpartum period to optimize outcomes for both mother and infant.
Endoscopic submucosal dissection combined surgery for the treatment of ectopic gastric mucosa and ectopic pancreas in muscularis propria and serosal layer of the stomach: A rare case report and review of the literature
Authors: Chen Yindi , Cao Yanbing , Zhi Lingran , Huang Rui
Published: February 2025

Rationale:

Ectopic gastric mucosa (EGM) and ectopic pancreas (EP) in the stomach is a rare congenital anomaly. No research on the coexistence of EGM and EP in the stomach has been found. However, several studies have shown canceration of EGM outside the stomach and EP. Active surgical treatment may be necessary. This paper introduces a new case of ectopic gastric mucosa and ectopic pancreas in muscularis propria and serosal layer of the stomach and which were ultimately removed by endoscopic submucosal dissection combined surgery.

Patient concerns:

The patient was a 25-year-old male. Upper gastrointestinal endoscopy showed a subepithelial lesion in gastric antrum.

Diagnoses:

Postoperative pathology confirmed a diagnosis of EGM and EP.

Interventions:

Enhanced computed tomography scan and endoscopic ultrasonography showed a submucosal tumor. Then endoscopic submucosal dissection was performed, during which a lesion was observed on the anterior wall of the stomach near the pylorus. This lesion invades the muscularis propria of the stomach and the large lesions near the pylorus may lead to pyloric obstruction. Considering these situations comprehensively, the patient ultimately underwent surgical resection of gastric lesion and partial gastrectomy.

Outcomes:

After 3 months of follow-up, the patient was recovering well and no recurrence of the lesion was found so far.

Lessons:

EGM along with EP in the stomach is a rare condition. Due to its rarity, there was a lack of sufficient data support for its treatment and prognosis. Due to the EGM and EP may become cancerous, clinical attention should be paid to it. In this study, we present a new case report of EGM along with EP in the stomach and review the existing literature to explore treatment options for it.
The efficacy of Shenyankangfu tablets in combination with valsartan in diabetic nephropathy: A systematic review and meta-analysis
Authors: Yang Yang , Zhang Xinyu , Yuan Yin , Wang Mengyang , Xue Yuqing , Wang Hongwu , Zhao Tieniu
Published: February 2025

Background:

Diabetic nephropathy (DN) is the most prevalent and critical microvascular complication of diabetes mellitus, constituting a significant contributor to end-stage renal disease. Shenyankangfu tablets (SYKFP) are a pure traditional Chinese medicine compound. Current studies have shown that SYKFP combined with valsartan in the treatment of DN had therapeutic advantages. However, there is still a lack of systematic research. Therefore, meta-analysis was used to systematically evaluate the efficacy and safety of SYKFP combined with valsartan in treating DN and to provide evidence-based medical evidence for clinical application.

Methods:

CNKI, VIP, Wanfang, Chinese Biomedical Literature Service System, American Clinical Trial Registry, Embase, Web of Science, PubMed, and Cochrane Library databases were searched from the date of database establishment to August 2024. All randomized controlled trials of SYKFP in combination with valsartan for treating DN were collected, and the data of clinical trials that met the inclusion criteria were extracted. Meta-analysis was performed using Review Manager 5.4 and Stata 17.0.

Results:

Sixty-nine pieces of literature were retrieved, and 14 eligible randomized controlled trials were selected, with 1281 participants. The results of the meta-analysis showed that compared with valsartan alone in the treatment of DN, Shenyanangfu tablets combined with valsartan can improve the clinical efficacy rate (relative risk = 1.16, 95% CI [1.11, 1.22], P < .00001) and reduce blood creatinine (mean difference [MD] = −28.79, 95% CI [−31.16, −26.42], P < .00001), urea nitrogen (MD = −1.37, 95% CI [−1.52, −1.22], P < .00001), 24-hour urine protein quantification (MD = −0.59, 95% CI [−0.77, −0.40], P < .00001), fasting blood glucose (MD = −0.51, 95% CI [−0.77, −0.25], P = .0001) and the incidence of adverse events (relative risk = 0.74, 95% CI [0.43, 1.23], P = .24) were better than valsartan alone, and the difference was statistically significant.

Conclusion:

SYKFP combined with valsartan can improve the clinical treatment efficiency of DN. They can effectively reduce the occurrence of urea nitrogen, blood creatinine, 24-hour urine protein quantification, fasting blood glucose, and adverse events.
HLA genotyping in cardiac and other extrapulmonary manifestations of sarcoidosis
Authors: Şenay Ece Ünüvar , Korkmaz Celalettin , Zamani Ayşegül , Zamani Adil , Demirbaş Soner , Yildirim Mahmut Selman
Published: February 2025

Background:

Although numerous candidate genes have been identified in studies investigating the role of genetics in sarcoidosis, the strongest association has been reported with the Major Histocompatibility Complex/Human Leucocyte Antigen (MHC/HLA) region. This study aimed to evaluate HLA polymorphism and assess its association with cardiac and other extrapulmonary involvement in sarcoidosis patients.

Methods:

The study included 67 patients diagnosed with sarcoidosis. A control group of 100 bone marrow donors, who had undergone HLA genotyping previously, was also included. Blood samples were collected from all participants for HLA gene polymorphism analysis. The differences in HLA genotypes were investigated between patients with and without cardiac and other extrapulmonary involvement, and between these groups and the control group.

Results:

Cardiac involvement, was present in 17.9% of the patients. The most frequently affected extrapulmonary organ was the skin (23.8%). HLA DQB103 and HLA DQB106 alleles were expressed more frequently in patients with only pulmonary involvement compared to those with extrapulmonary involvement. Conversely, HLA DQA101 was expressed more frequently in patients with extrapulmonary involvement. No statistically significant difference in the expression of HLA DRB1, HLA DQB1, and HLA DQA1 alleles was observed between sarcoidosis patients with and without cardiac involvement.

Conclusion:

Our findings suggest that HLA DQB103 and HLA DQB106 alleles might be protective against extrapulmonary organ involvement, while HLA DQA101 could be a risk factor. These findings may contribute to the prediction of treatment response and prognosis in sarcoidosis patients.
Elevated isoleucine may be a protective factor for primary hypertension: A pooled causal effect study
Authors: Shi Ying , Liu Hairun , Chen Yi
Published: February 2025

Hypertension continues to pose a huge burden to global public health. Abnormal metabolism not only serves as a risk factor for hypertension but also acts as a driving force in its aggravation. However, there remains a lack of large-scale causal demonstration based on extensive samples. Our study aims to investigate the causal relationship between metabolism and primary hypertension (PH) using Mendelian randomization analysis. We used genome-wide association studies instrumental variables for Mendelian randomization association analysis integrating the diagnosis results of PH in 3 populations from East Asia, the Middle East, and Africa with serum metabolites and metabolite ratios. This allowed us to identify predictive metabolites and metabolic pathways for diagnosing or treating PH. Inverse-variance weighting was the main model for establishing causal associations. In addition horizontal pleiotropy test, linkage disequilibrium test, and sensitivity analysis were employed to test the explanatory power of instrumental variables. A total of 10,922 cases of PH and 8299 cases of metabolomics detection cohorts were included in the study. In East Asian, Middle Eastern, and African populations, we found 36, 57, and 40 known metabolites respectively strongly associated with PH (P < .05). Cross-section and meta-analysis of these strongly correlated metabolites across the 3 ethnic groups revealed 7 common metabolites. Notably, elevated isoleucine (odds ratio = 0.74, 95% confidence interval: 0.56–0.96) was demonstrated as a potential protective factor against PH across 3 ethnic groups. The metabolites associated with PH have certain polymorphisms in different populations. Isoleucine may be a promising biomarker for PH diagnosis or treatment, but more clinical validation is needed.
Acquired tracheoesophageal fistula in an adult due to mango endocarp: a case report
Authors: Sapkota Ranjan , Luitel Prajjwol , Rayamajhi Shivani , Pandey Anupama , Thapa Anjila
Published: February 2025

Introduction and importance:

Tracheoesophageal fistulas (TEF) resulting from foreign body (FB) ingestion often present late, leading to delayed diagnosis. To the best of our knowledge, this is the first reported case of TEF caused by the accidental ingestion of a mango endocarp in the English literature.

Case presentation:

A 27-year-old female was referred for persistent cough for 4 months, following accidental ingestion of a mango endocarp. She initially complained of short-lived throat pain, foreign body sensation, and difficulty swallowing. At our facility, imaging revealed a TEF at the T1 vertebral level. Intraoperative localization was achieved with a bronchoscope and the fistulous tract was dissected and excised. The esophagus and trachea were repaired in two and one layers, respectively, and a sternohyoid flap was mobilized to buttress the repairs. She had a smooth recovery, with normal swallowing and voice preservation, and remains asymptomatic at 2 years.

Clinical discussion:

Although the majority of esophageal FBs are uncomplicated, delayed presentations can lead to severe complications like bleeding, perforation, or TEF. In our case, the initial symptoms of throat pain and mild dysphagia might have been the result of an initial laceration by the mango endocarp or impaction resulting in ulceration. The ulcer might have eroded deep into the trachea causing a fistula due to delay in seeking care.

Conclusion:

Mango endocarp ingestion can be a rare cause of TEF in adults and has to be considered in an appropriate setting.
Leveraging Media Monitoring to Inform Targeted Health Communications for Adolescents, Older Adults, and LGBTQ+ People
Authors: Bonnevie Erika , Smith Sierra , Kapur Maddie , Smyser Joe , Castrucci Brian C.
Published: February 2025

Objective:

This manuscript assesses how media monitoring can guide the tailoring of public health communications for adolescents, older adults, and LGBTQ+ individuals, addressing their unique mental health challenges.

Design:

The study employed a thematic analysis of publicly available digital and social media data.

Setting:

Research was conducted using media monitoring platforms, with a focus on conversations relevant to specific groups within the United States.

Participants:

The dataset included millions of public posts relevant to mental health issues among adolescents, older adults, and LGBTQ+ communities, collected over a one-year period. Main Outcome Measures: Key themes and patterns within mental health discussions were identified.

Results:

Discussions around the “youth mental health crisis” were prominent, with 25% of adolescent-related posts reflecting this sentiment, often highlighting the impact of social media and academic pressures. For older adults, themes of loneliness and financial struggles were recurrent, with discussions showing a lack of practical support and resources. In LGBTQ+ conversations, there was an emphasis on the challenges of discrimination and identity-related misconceptions, with 28% of the mentions relating to mental health crises involving suicide or self-harm. These discussions underscored the critical need for inclusive and affirmative support tailored to the unique challenges faced by these groups.

Conclusions:

Media monitoring provides essential insights that can improve public health messaging by identifying trending mental health discussions and sentiments. By acknowledging and addressing the specific needs and challenges of specific population groups, public health communicators can develop more effective strategies that not only highlight problems but also offer clear, actionable solutions to promote better mental health outcomes and support. This approach is crucial for adapting health communications to the evolving landscape of media and public discourse, ensuring that messages are both relevant and supportive.
Outcomes of Kidney Transplantation From Donors on Renal Replacement Therapy
Authors: Goussous Naeem , Alghannam Karima , Than Peter A. , Wang Aileen X. , Chen Ling-Xin , Alexopoulos Sophoclis P. , Sageshima Junichiro , Perez Richard V.
Published: February 2025

Background.

The increasing demand for organs has pushed transplant providers to expand kidney acceptance criteria. The use of kidneys from donors with AKI has been shown to provide good long-term graft survival. We aim to evaluate and compare the outcomes of deceased donor kidney transplantation from donors with acute kidney injury (AKI), either with or without renal replacement therapy (AKI-RRT) before donation.

Methods.

A single-center retrospective review of all patients who underwent deceased donor kidney transplantation from AKI donors between 2009 and 2020 was performed. AKI donors were defined on the basis of donor terminal creatinine ≥2.0 mg/dL or use of RRT before donation. We compared the outcomes of recipients receiving a kidney from a donor with AKI versus AKI-RRT. Data are presented as medians (interquartile ranges) and numbers (percentages).

Results.

Four hundred ninety-six patients were identified, of whom 300 (60.4%) were men with a median age of 57 y at transplantation. Thirty-nine patients received an AKI-RRT, whereas 457 received an AKI kidney. Donors in the AKI-RRT group were younger (28 versus 40), had less incidence of hypertension (15.3% versus 31.9%), and were more likely to be imported (94.9% versus 76.8%). There was a higher incidence of delayed graft function (72% versus 44%, P < 0.001) in the AKI-RRT group. Recipients in both groups had similar 90-d (100% versus 95.2%) and 1-y (100% versus 91.9%) graft survival. With a median follow-up of 5 y, there was no difference in death-censored graft survival in both groups (P = 0.83).

Conclusions.

Careful selection of kidneys from donors with AKI on RRT can be safely used for kidney transplantation with favorable clinical outcomes.
Nurses’ use of the five rights of medication administration in a comprehensive care unit: a best practice implementation project
Authors: Smith Jaclyn M. , Upchurch Linda
Published: February 2025

Introduction:

The “five rights” of medication administration are used by nurses daily to prevent patient medication errors. The five rights of medication administration are the right patient, drug, route, dose, and time. In the United States alone, between 7,000 and 9,000 medication administration errors occur annually. Internationally, medication errors are a leading cause of injury and harm.

Objectives:

This project aimed to improve compliance with medication administration rights in a comprehensive care unit among nurses in the acute care hospital setting.

Methods:

This project was conducted using an audit and feedback strategy, as recommended by the JBI Evidence Implementation Framework. Included in the project was the use of the JBI Practical Application of Clinical Evidence System (PACES) for pre- and post-audit data analysis and the JBI Getting Research into Practice (GRiP) approach to identify barriers, strategies, and outcomes. The project identified eight best practice criteria for medication administration to be used by nurses, including the five rights. After the baseline audit, barriers were identified, and educational interventions were implemented to improve adherence to best practices. A follow-up audit was conducted, and the results of both audits were compared.

Results:

In the baseline audit, two of the eight criteria, including checking the expiry date of medication and verbal identification of patient identifiers, were found to have lower adherence. Nursing staff education and visual reminders were implemented. A post-implementation audit was conducted, showing improved compliance with medication administration best practices.

Conclusions:

Staff education and visual reminders for best practices improved adherence to the five rights of medication administration. Annual competency training to reinforce best practices will prevent the incidence of medication errors, thereby maintaining quality and safety in patient care.

Spanish abstract:

http://links.lww.com/IJEBH/A321
Use of Electroconvulsive Therapy in a University Psychiatric Hospital in Brazil
Authors: Pereira-Soares Elaine Loureiro , Nascimento Antonio Leandro , dos Santos Gabriel Caetano , Horato Natia , Nardi Antonio Egidio
Published: February 2025

Objectives

The aim of the study were to describe the practice of electroconvulsive therapy (ECT) at the Institute of Psychiatry (IPUB) of the Federal University of Rio de Janeiro (UFRJ) from 2015 to 2019 and to compare it with previous years at the same institute and with international practices.

Methods

Sociodemographic and epidemiological data, along with information on ECT and anesthetic techniques, were collected from the medical records of all patients who received ECT at IPUB-UFRJ between 2015 and 2019.

Results

A total of 238 patients underwent 4110 ECT sessions during the study period. A slight predominance of female patients (55.9%) was observed. Most patients were aged between 21 and 40 years (46.2%). Over half of the patients were outpatients (63.4%), with bipolar affective disorder being the most common diagnosis, accounting for 35.7% of ECT indications. Consent for ECT was obtained from all patients. Most treatments (85.2%) were conducted during the acute phase of illness. The average number of ECT sessions per patient was 5.4. All patients received anesthesia, and no deaths or severe complications related to ECT occurred. Monitoring cognitive effects and discharge criteria were the responsibility of the attending physician.

Conclusions

The practice of ECT at IPUB-UFRJ adhered to both local and international guidelines. There has been a notable shift in the utilization patterns of ECT at the institute compared to previous years. Standardized monitoring of cognitive effects and discharge criteria remains essential.
Antimicrobial resistance patterns of isolates from bloodstream infections at Jinja Regional Referral Hospital in Uganda
Authors: Lwigale Fahad
Published: February 2025

Background:
Bloodstream infections (BSIs) are common acute syndromes of variable origin with high chances for extreme health effects including death. Empirical therapy is usually employed to manage the BSIs despite the high resistance to the antibacterial agents used including cefriaxone and/or metronindazole. This study determined the aetiologic agents responsible for bloodstream infections, their antimicrobial susceptibility patterns, and infection sources in Eastern-central Uganda.
Patients and methods:
This retrospective cross-sectional study involved analysis of data from all non-duplicate blood culture reports from 2019 to 2021. These were earlier generated using single set blood culture, conventional microbiology techniques and disc diffusion-based antimicrobial susceptibility testing (AST) guided by the Clinical and Laboratory Standards Institute (CLSI) guidelines. World Health Organization Network (WHONET) 2022 desktop software and Microsoft Excel were utilised for data analysis.
Results:
The 1364 reports showed a diagnostic yield of 6.8% (93/1364) and a 1.5%(21/1364) contamination rate. Overall, 37% and 13% of infections were hospital-acquired and community-acquired respectively. Most etiologic agents were Gram-positive bacteria dominated by Staphylococcus aureus 39/114 (34.2%). Polymicrobial growth existed in 4/1364(0.3%) cases. Staphylococcus aureus was mainly resistant to penicillin G (100%) and most susceptible to gentamicin (%S=74.1, 95% C.I:53.4-88.1).  Escherichia coli and unspecified Coliforms together showed high resistance to ampicillin (87.5%) and third-generation cephalosporins (100%). The least resistance was to chloramphenicol and carbapenems.
Conclusion:
Staphylococcus aureus highly sensitive to gentamicin was the commonest cause of BSIs in this setting. Therefore, empirical management of suspected BSI cases in the region should include gentamicin. Use of Microbiology services including culture and sensitivity to guide targeted antimicrobial use and monitor resistance trends is required to strengthen antimicrobial stewardship.
Structural basis of pro-inflammatory signaling via the Interleukin-36 receptor (IL-36R) mediated by IL-36γ and IL-37
Authors: Andries Julie , Toul Martin , Felix Jan , Clancy Danielle M. , Savvides Savvas N.
Published: February 2025

Interleukin-36 receptor (IL-36R) is activated by IL-36α, IL-36β, and IL-36 γ to elicit pro-inflammatory signaling and is targeted in acute skin inflammation by the approved antibody spesolimab. IL-37 was recently proposed as a new IL-36R agonist. Such diverse agonist repertoire together with the antagonistic IL-36Ra and IL-38 create a fascinating structure-function landscape for IL-36R, albeit one that is poorly understood. Here, we elucidate how IL-36R grapples IL-36γ with low affinity to enable facile recruitment of the shared receptor IL-1RAcP with high-affinity. In contrast, IL-36R interacts with IL-37 via the exact opposite binding signature. Comparative interrogation of IL-36R activation by IL-36γ and IL-37 confirmed their common pro-inflammatory signature and distinguished IL-36γ as markedly more pro-inflammatory. Structural comparisons of cytokine-activated versus spesolimab-antagonized IL-36R revealed that spesolimab serves as an allosteric antagonist. Collectively, our study provides the structural and mechanistic blueprint of IL-36R activation by distinct cytokines and will facilitate its therapeutic targeting.
Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation
Authors: Alshehri Ahmad , Baker India-May , English David M , Fairall Louise , Collins Mark O , Schwabe John WR , Cowley Shaun M
Published: February 2025

Histone deacetylase 1 and 2 (HDAC1/2) are highly related enzymes that regulate histone acetylation levels in all cells, as catalytic and structural components of six unique multiprotein complexes: SIN3, NuRD, CoREST, MIDAC, MIER and RERE. Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry revealed that 92% of HDAC1 in mouse embryonic stem cells resides in 3 complexes, NuRD (49%), CoREST (28%) and SIN3 (15%). We compared the structures of MTA1:HDAC1 and MIDAC:HDAC1 to identify critical binding residues on the surface of HDAC1. Surprisingly, a single mutation, Y48E, disrupts binding to all complexes except SIN3. Rescue experiments performed with HDAC1-Y48E in HDAC1/2 double-knockout cells, showed that retention of SIN3 binding alone is sufficient for cell viability. Gene expression and histone acetylation patterns were perturbed in both Y48E and a second mutant cell line, HDAC1-E63R, indicating that cells require a full repertoire of the HDAC1/2 complexes to regulate their transcriptome appropriately. Comparative analysis of MTA1/HDAC1 and SIN3B/HDAC2 structures confirmed the differential modes of HDAC1 recruitment, such that Y48 interacts with ELM2/SANT domain-containing proteins, but not SIN3. The E63R mutation shows markedly reduced binding to NuRD and MiDAC complexes, but retains some CoREST binding. We provide novel molecular insights into the abundance, co-factors and assemblies of this crucial family of chromatin modifying machines.
ERC 2.0 - evolutionary rate covariation update provides more powerful inference of functional interactions across large phylogenies
Authors: Little Jordan H , Meyer Guillermo Hoffmann , Grover Aakash , Francette Alex Michael , Partha Raghavendran , Arndt Karen M. , Smith Martin , Clark Nathan , Chikina Maria
Published: February 2025

Evolutionary Rate Covariation (ERC) is an established comparative genomics method that identifies sets of genes sharing patterns of sequence evolution, which suggests shared function. Whereas many functional predictions of ERC have been empirically validated, its predictive power has hitherto been limited by its inability to tackle the large numbers of species in contemporary comparative genomics datasets. This study introduces ERC2.0, an enhanced methodology for studying ERC across phylogenies with hundreds of species and tens of thousands of genes. ERC2.0 improves upon previous iterations of ERC both in compute time and in its statistical power to predict biological function. In exemplar yeast and mammalian datasets, we demonstrate that the predictive power of ERC2.0 is improved relative to the previous method, ERC1.0, and that further improvements are obtained by using larger yeast and mammalian phylogenies. We attribute the improvements to both the larger datasets and improved rate normalization. We demonstrate that ERC2.0 has high predictive accuracy for known annotations and can predict the functions of genes in non-model systems. Our findings underscore the potential for ERC2.0 to be used as a single-pass computational tool in candidate gene screening and functional predictions.
Early White Matter Microstructure Alterations in Infants with Down Syndrome
Authors: Azrak Omar , Garic Dea , Nasir Aleeshah , Swanson Meghan R. , Grzadzinski Rebecca L. , Al-Ali Khalid , Shen Mark D. , Girault Jessica B. , St. John Tanya , Pandey Juhi , Zwaigenbaum Lonnie , Estes Annette M. , Wolff Jason J. , Dager Stephen R. , Schultz Robert T. , Evans Alan C. , Elison Jed T. , Yacoub Essa , Kim Sun Hyung , McKinstry Robert C. , Gerig Guido , Pruett John R. , Piven Joseph , Botteron Kelly N. , Hazlett Heather , Marrus Natasha , Styner Martin A. ,   Infant Brain Imaging Study (IBIS) Network
Published: February 2025

Importance

Down syndrome, resulting from trisomy 21, is the most prevalent chromosomal disorder and a leading cause of intellectual disability. Despite its significant impact on brain development, research on the white matter microstructure in infants with Down syndrome remains limited.

Objective

To investigate early white matter microstructure in infants with Down syndrome using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI).

Design

Infants were recruited and scanned between March 2019 and May 2024 as participants in prospective studies conducted by the Infant Brain Imaging Study (IBIS) Network. Data were analyzed in October 2024.

Setting

Data collection occurred at five research centers in Minnesota, Missouri, North Carolina, Pennsylvania, and Washington.

Participants

Down syndrome and control infants were scanned at 6 months of age. Control infants had no Down syndrome diagnosis and either had a typically developing older sibling or, if they had an older sibling with autism, were confirmed not to meet clinical best estimate criteria for an autism diagnosis.

Exposure

Diagnosis of Down syndrome.

Main Outcomes and Measures

The outcome of interest was white matter microstructure quantified using DTI and NODDI measures.

Results

A total of 49 Down syndrome (28 [57.14%] female) and 37 control (18 [48.65%] female) infants were included. Infants with Down syndrome showed significant reductions in fractional anisotropy and neurite density index across multiple association tracts, particularly in the inferior fronto-occipital fasciculus and superior longitudinal fasciculus II, consistent with reduced structural integrity and neurite density. These tracts also demonstrated increased radial diffusivity, suggesting delayed myelination. The inferior fronto-occipital fasciculus and uncinate fasciculus exhibited increased neurite dispersion and fanning in Down syndrome infants, reflected by elevated orientation dispersion index. Notably, the optic tracts in Down syndrome infants exhibited a distinct pattern of elevated fractional anisotropy and axial diffusivity, and lower radial diffusivity and orientation dispersion index, suggesting an early maturation of these pathways.

Conclusions and Relevance

This first characterization of white matter microstructure in Down syndrome infants reveals widespread white matter developmental delays. These findings provide new insights into the early neurodevelopment of Down syndrome and may inform early therapeutic interventions.
Phenotypic age acceleration through a lens of intersectional inequalities in the German national cohort (NAKO)
Authors: Alonso-Perez Enrique , O'Sullivan Julie Lorraine , Fuellen Georg , Gellert Paul , Rudolf Henrik
Published: February 2025

Background Differences in biological aging have been linked to sociodemographic characteristics, but how multiple social inequalities intersect to shape biological aging differences across population subgroups remains unclear. By integrating a perspective of biology of aging with intersectionality theory, we aimed to investigate the joint influence of multiple social determinants on phenotypic age acceleration (i.e., difference between biological and chronological age). Methods We analysed data from 173,925 participants in the German NAKO study to calculate phenotypic age acceleration. We then created intersectional social strata based on individual sociodemographic characteristics to assess differences in phenotypic age acceleration through an intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA). Results All intersectional strata displayed phenotypic age deceleration (i.e., were biologically younger than their chronological age). This advantage was weakest among men without a migration background, living alone and with low socioeconomic status. Substantial discriminatory accuracy of the strata (7.13%) implied intersectional inequalities. Most differences were driven by additive effects, with modest multiplicative effects due to intersectional interactions. We found multiplicative effects representing increased risk for individuals with migration background, not living alone and with medium/high socioeconomic status, or those without migration background, living alone and with medium/low socioeconomic status. Conclusion Our study provides novel insights on the intersectional stratification of biological aging, highlighting the significance of bio x social interactions for the aging process. Future epidemiological studies should focus on the mechanisms linking multiple social inequalities and accelerated biological aging, using intersectionally-informed targeted interventions that address both social and aging-related inequalities.
Non-additive interactions between multiple mutualists and host plant genotype simultaneously promote increased plant growth and pathogen defense
Authors: Rawstern Amanda H , Carbajal Lucas J , Slade Tyler J , Afkhami Michelle E
Published: February 2025

Understanding the impact of microbial interactions on plants is critical for maintaining healthy native ecosystems and sustainable agricultural practices. Despite the reality that genetically distinct plants host multiple microbes-of-large effect in the field, it remains unclear the extent to which host genotypes modulate non-additive microbial interactions and how these interactions differ between benign/pathogenic environments. Our study fills this gap by performing a large-scale manipulative microbiome experiment across 7 genotypes of the model legume Medicago truncatula. We combine plant performance metrics, survival analyses, predictive modeling, RNA extractions, and targeted gene expression to assess how host genotype and microbes non-additively interact to shape plant growth and disease ecology. Our results reveal three important findings: (1) host genotypes with high tolerance to pathogens benefit more from multiple mutualist interactions than susceptible genotypes, (2) mutualists confer the same non-additive plant performance benefits in both benign and pathogenic environments, and (3) the quality of the symbiotic relationship with mutualists is a strong predictor of host survival against pathogenic disease. By applying these findings towards developing crops that promote synergistic microbial interactions, yields and pathogen defense could be simultaneously increased while reducing the need for toxic fertilizers and pesticides.
Aphid effector Mp10 balances immune suppression and defence activation through EDS1-dependent modulation of plant DAMP responses
Authors: Gravino Matteo , Mugford Sam T. , Pontiggia Daniela , Joyce Joshua , Drurey Claire , Prince David C. , Cervone Felice , De Lorenzo Giulia , Hogenhout Saskia A.
Published: February 2025

Damage-associated molecular pattern (DAMP)-triggered immunity (DTI) serves as a crucial first line of defence against aphid attack, yet the mechanisms by which aphids suppress this response remain unclear. By investigating the colonisation of Arabidopsis thaliana by the highly polyphagous peach-potato aphid (Myzus persicae), we identified cell wall-derived DAMPs, specifically oligogalacturonides (OGs), as key in inducing DTI against aphids. The OG-responsive immune components BAK1/BKK1, CPK5/CPK6, GRP3, and EDS1 collectively contribute to DTI limiting aphid colonisation. We found that aphids limit OG production during feeding. Additionally, the salivary chemosensory protein (CSP) effector Mp10/CSP4, which is known to be delivered into the cytoplasm of plant cells early in aphid attack, inhibits OG-induced DTI. While Mp10 suppresses OG-induced DTI, it also interacts with EDS1-mediated defences, enhancing aphid fecundity in the absence of EDS1 but restoring OG responsiveness under attack, revealing its broader role in immune modulation and effector-driven host adaptation.
Differential Cellular Mechanisms Underlie Language and Executive Decline in Amyotrophic Lateral Sclerosis
Authors: Petrescu Joana , Roque Claudio Gouveia , Jackson Chris , Daly Aidan , Kang Kristy , Casel Obadele , Leung Mathew , Reilly Luke , Eschbach Jacqueline , McDade Karina , Gregory Jenna M , Smith Colin , Phatnani Hemali
Published: February 2025

Half of all amyotrophic lateral sclerosis (ALS) patients demonstrate a spectrum of cognitive and behavioral changes over the course of the disease, but the mechanisms underlying this heterogeneity remain unclear. We assemble a high-resolution cellular map of prefrontal cortex regions of the ALS brain by integrating spatial and single-nucleus transcriptomic profiles of a cognitively stratified ALS patient cohort that includes non-neuropathological controls. We find cellular programs characteristic of ALS, including a frequent gliotic response. We also find that executive and language cognitive impairments differ from ALS without cognitive impairment, and from each other, in the extent and pattern of neuronal dysregulation and neuron-glial interactions across different brain regions. These findings reveal a relationship between cognitive phenotype and prefrontal cortex dysfunction in ALS.
Machine Learning Classification of Mild Cognitive Impairment using Advanced Multi-Shell Diffusion MRI and CSF Biomarkers
Authors: Guo Alexander Y. , Laporte John P. , Singh Kavita , Bae Jonghyun , Bergeron Keagan , de Rouen Angelique , Fox Noam Y. , Zhang Nathan , Faulkner Mary E. , Carino Isabel , Benjamini Dan , Gong Zhaoyuan , Bouhrara Mustapha
Published: February 2025

INTRODUCTION: Machine learning applied to neuroimaging can help with medical diagnosis and early detection by identifying biomarkers of subtle changes in brain structure and function. The effectiveness of advanced diffusion MRI (dMRI) imaging methods for pre-dementia classification remains largely unexplored, particularly when combined with CSF biomarkers. METHODS: We implemented XGBoost machine learning models to evaluate the classification potential of dMRI parameters (derived using NODDI, C-NODDI, MAP, or SMI), CSF biomarkers of Alzheimer's pathology (Tau, pTau, AB42, AB40), and pairwise dMRI + CSF combinations in distinguishing cognitive normality from mild cognitive impairment. RESULTS: MAP-RTAP (AUC=0.78) and pTau/AB42 (AUC=0.76) were the best performing individual biomarkers. Combining C-NODDI-C-NDI and AB42/AB40 achieved the highest performance (AUC=0.84) and accuracy (0.84), while other combinations optimized either sensitivity (0.93) or specificity (0.88). DISCUSSION: dMRI biomarkers demonstrate comparable performance to CSF biomarkers, with notable improvements achieved when combined. This study highlights dMRI's potential for enhancing early AD detection. Key words: Machine Learning, Early Diagnostics, Mild Cognitive Impairment, Diffusion MRI, CSF Biomarkers, Alzheimer's Disease, Neuroimaging
GABAAreceptor availability in clinical high-risk and first-episode psychosis: a [11C]Ro15-4513 positron emission tomography study
Authors: Lukow Paulina B , Schubert Julia J , Severino Mario , Knight Samuel , Kiemes Amanda , Livingston Nicholar R , Davies James , de Micheli Andrea , Spencer Thomas J , Fusar-Poli Paolo , Haege Beata , Vorontsova Natasha , Donocik Jacek , Rabiner Eugenii A , Grace Anthony A , Williams Steven C , McGuire Philip , Veronese Mattia , Turkheimer Federico E , Modinos Gemma
Published: February 2025

Disrupted gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of schizophrenia. Reductions in hippocampal GABAergic neurons have been found in schizophrenia, and increased hippocampal perfusion has been described in schizophrenia and in people at clinical high-risk for psychosis (CHRp). We have also found decreases in hippocampal GABAAreceptors containing the α 5 subunit (GABAAα5) in a well-validated neurodevelopmental rat model of relevance for schizophrenia. Positive allosteric modulation of these receptors in the hippocampus using a specific compound was shown to reverse the behavioural and neurophysiological phenotypes of this model. However, whether GABAARα5 availability is dysregulated in the psychosis spectrum at the regional or network levels is unknown. We addressed this issue by using [11C]Ro15-4513 and positron emission tomography (PET) in 22 individuals at CHRp, 10 people with a first-episode psychosis (FEP) and 23 healthy controls (HC). We quantified GABAARα5 availability in the hippocampus and across the brain, and employed a perturbation covariance method to assess individual molecular covariance deviations in CHRp and FEP groups compared to the HC group. Hippocampal GABAARα5 availability was not significantly different between groups (F(2,50)=0.25, p=0.78). However, network analysis identified significant deviations in GABAARα5 covariance between groups, both across all regions (all p<0.001, pairwise Cohen′sd= 0.07-0.5) and relative to the hippocampus (all p<0.001, pairwise Cohen′sd= 0.01-0.67). These findings suggest that psychosis symptoms are associated with alterations to the brain-wide organisation of the GABAARα5 system, rather than changes at a regional level.
Integrating Genome-wide and Epigenome-wide Associations for Antipsychotic Induced Extrapyramidal Side Effects
Authors: Yao Kai , Thygesen Johan H , Lock Siobhan Ker , Pardinas Antonio F. , Pritchard Antonia L. , O'Donovan Michael C. , Owen Michael J. , Walters James T. R. , Clair David St , Bass Nick , McQuillin Andrew
Published: February 2025

Background and Hypothesis: Antipsychotic medications are the first-line treatment for schizophrenia. However, around 40% of people with schizophrenia who are treated with antipsychotics could develop extrapyramidal side-effects (EPSE) including: 1) Dyskinesias, 2) Parkinsonism, 3) Akathisia, and 4) Dystonia. Study Design: We conducted Genome-wide association (GWAS) and Epigenome-wide association (EWAS) meta-analysis of EPSE utilising data from previous schizophrenia case control studies. We integrated significant EWAS findings to an EPSE GWAS meta-analysis to enhance our understanding of the functional impact of common variants on EPSE. We also investigated whether polygenic risk scores (PRS) for schizophrenia, Parkinson's disease, and Lewy-body dementia could be predictive of EPSE development. Study Results: The top index SNP rs2709733 (A/G) from EPSE GWAS (p=2.214x10-7) mapped to a long intergenic non-protein coding RNA, LINC01162 with consistent effects across all cohorts. We identified 9 differentially methylated positions (DMPs) associated with EPSE when controlling for methylation age, sex, derived estimates of cell composition, smoking score, and schizophrenia PRS. Four of the DMPs cg14531564, cg20647656, cg12004641, cg22845912, and their affiliated genes (SDF4, ANKMY1, TNS1, SLA) were associated with the risk of developing EPSE and not with schizophrenia risk. Another DMP (cg12044923) which mapped to the STK32B gene, showed significant enrichment for association with risk of EPSE. Conclusions: Our study sheds new light on the potential biological mechanisms underlying EPSE development in schizophrenia, highlighting the importance of exploring both methylation shifts and common SNP associations. Further research with larger samples sizes and a focus on the role of STK32B are encouraged.
Sunflower yield modeling with XAI: Historical weather impacts and forecasting
Authors: Majumder Sambadi , Mason Chase
Published: February 2025

This study applies explainable artificial intelligence (XAI) to analyze the impact of inter-year variation in weather conditions on oilseed sunflower yields across the United States. By integrating historical yield data from 1976 to 2022 with meteorological data, we identified key weather predictors influencing sunflower yields at national and state levels along with critical yield-sensitive threshold temperature and precipitation values that predict reduced yield. Using machine learning algorithms, we developed predictive models to forecast future yields under different Shared Socioeconomic Pathways (SSPs) from 2021 to 2080. Our findings reveal significant yield declines due to increased temperatures and altered precipitation patterns, but with regional variability in the magnitude of these impacts. The most critical climate variables identified include maximum temperatures and total precipitation during summer months. Our XAI approach enhances model transparency, offering valuable insights for farmers and policymakers to develop adaptive strategies for sunflower cultivation under climate change. Future research incorporating additional factors like soil characteristics and agricultural practices can further refine yield predictions.