bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer caregivers’ health literacy in Macao: Understanding influencing factors and promoting support – an observational study
Authors: Tsai Nana , Fong Pedro , Lam Fongieng , Zhang Qi , Meng Lirong
Published: February 2025

The health literacy level of caregivers for cancer patients can significantly impact the well-being of the patients. There is a notable scarcity of research on this topic in mainland China, and none in Macao’s diverse healthcare cultural city. This study aimed to evaluate the health literacy of family caregivers tending to cancer patients undergoing treatment in Macao, identify key influencing factors, and promote community awareness to better support these caregivers’ needs. This cross-sectional study utilised a self-designed demographic questionnaire alongside the Health Literacy of Caregivers Scale-Cancer (HLCS-C, Chinese version) to gather insights from 376 family caregivers at Macao’s sole public hospital. This study uncovered that the health literacy scores of Macao’s family caregivers averaged at a moderate level (138.18 ± 14.64), with the category of “proactive communication with healthcare professionals” achieving the highest score at 3.65 ± 0.61, while ‘thorough understanding of cancer and cancer management information’ received the lowest score at 2.76 ± 0.47. Significant factors affecting health literacy levels encompass age, physical well-being, the relationship with the patients, and the channels employed to access health-related information. This study highlights the need to enhance support for Macao’s caregivers through educational programmes covering caregiving techniques, health resource utilisation, and personal growth for improved health literacy and patient outcomes. This study revealed that married women aged 31 to 50 constituted the primary demographic responsible for the care of cancer patients. As a result, they represent the key target audience for any health literacy educational initiatives.
Prognostic and clinicopathological significance of long noncoding RNA SNHG in patients with breast cancer: A systematic review and meta-analysis
Authors: Koh Hyun Min , Han Nayoung , Hyun Chang Lim
Published: February 2025

Background:

Small nucleolar RNA host genes (SNHG), a novel long non-coding RNA is involved in cancer cell proliferation, migration, and invasion. Moreover, there are some reports that SNHG is associated with prognosis in cancer patients and may contribute to diagnosis or prognostic prediction of cancer. This study analyzes the association between SNHGs expression and prognosis and clinicopathological factors in breast cancer.

Methods:

Eligible studies were searched through the PubMed, Embase, and Cochrane library until February 14, 2024. Pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated to elucidate the prognostic and clinicopathological significance of SNHG expression in breast cancer.

Results:

Nine studies with a total of 2268 breast cancer patients analyzed. The pooled results proved that high expression of SNHG was associated with unfavorable overall survival (OS) in patients with breast cancer (HR 1.39, 95% CI 1.22–1.59, P < .001). High expression of SNHG was significantly correlated with advanced clinicopathological factors, including larger tumor size (OR 2.31, 95% CI 1.42–3.76, P = .001), lymph node metastasis (OR 4.02, 95% CI 2.46–6.56, P < .001) and tumor-node-metastasis stage (OR 3.47, 95% CI 1.70–7.07, P = .001).

Conclusion:

High expression of SNHG was associated with unfavorable OS and advanced clinicopathological factors, suggesting that SHNG may be serve as a novel prognostic biomarker in patients with breast cancer.
Distinguishing MPLCs from IPMs using NGS-based molecular algorithms and histological assessment: A systematic review and validation study
Authors: Yang Desong , Sheng Xiaolong , Gong Lianghui , Wu Xun , Tang Jinming , Wang Wenxiang
Published: February 2025

Distinguishing between multiple primary lung cancers and intrapulmonary metastases is crucial for staging, therapeutic planning, and prognosis. Traditional histological assessment provides a foundation for diagnosis, which can be limited when tumors showed identical or similar histological types. This systematic review and independent validation study aimed to evaluate the performance of next-generation sequencing (NGS)-based molecular algorithms alongside histological methods for the classification of multiple lung adenocarcinomas (MLAs). We conducted a literature search to identify relevant studies and selected algorithms for validation using a cohort of patients with MLAs. Our analysis included 27 patients with MLAs and compared histological assessment using Martini and Melamed criteria and comprehensive histologic assessment combined with a low-grade lepidic component (CHA & lepidic) with NGS data. We found a high consistency between CHA & lepidic and NGS-based diagnoses, although some discrepancies remained, particularly in cases with no somatic mutations or distant metastases. NGS-based molecular algorithms offer a high degree of accuracy in determining the origin of MLAs, supporting or challenging histological diagnoses. However, histological methods remain valuable, especially when NGS data are inconclusive. This study underscores the complementary nature of histology and molecular diagnostics in the precise classification of MLAs.
Identity formation, personality, and well-being in adolescent and emerging adult siblings of survivors of pediatric cancer
Authors: Lemiere Jurgen , Raymaekers Koen , Prikken Sofie , Van Laere Elise , Sleurs Charlotte , Uyttebroeck Anne , Luyckx Koen
Published: February 2025

Background:

Siblings of pediatric cancer survivors are increasingly recognized as a potential vulnerable group requiring focused psychosocial support. However, little is known whether the experience of having a sibling with cancer affects their identity formation and personality traits. This study aimed to compare adolescent and emerging adult siblings of pediatric cancer survivors and control participants on identity formation, personality traits, and general well-being.

Methods:

Each sibling (n=80; mean age: 19.13 years; 49% male; age range: 14–25; mean time since diagnosis: 10.57 years) was matched on age and gender with two community youths without a history of having a chronic disease. Analysis of variance was used to assess group differences in the measures of identity formation, personality traits, and general well-being.

Results:

Siblings of pediatric cancer survivors exhibited lower levels of agreeableness, conscientiousness, openness, self-esteem, and life satisfaction compared with community youth. Gender played a significant role in identity and personality among siblings, with female siblings showing higher scores on identity confusion, neuroticism, and openness and lower scores on identity synthesis than male siblings. Other demographic or clinical variables showed no significant relationship. Siblings' self-esteem, life satisfaction, and depressive symptoms were strongly associated with their identity formation and personality traits, similar to patterns observed in the general community.

Conclusions:

Our study suggests that siblings of pediatric cancer survivors may face changes in personality traits and overall well-being, although their identity development is largely comparable with that of community youth. Not only are pediatric cancer survivors and their parents vulnerable for potential psychosocial sequelae, but so are survivors' siblings. Our results highlight the importance of assessing and targeting broader aspects of psychosocial well-being, considering both positive and negative indicators of well-being, and also aspects of identity and personality.
Efficacy and Safety of the Two-Drug Regimen Dolutegravir/Lamivudine in Adolescents Living With HIV-1 Naive to Antiretroviral Therapy at 48 Weeks (DANCE): A Single-Arm, Open-label, Phase 3b Trial
Authors: Puthanakit Thanyawee , Aurpibul Linda , Lopez Monica , Wang Marcia , Ciuffa Marika , Bontempo Gilda , Cheung S. Y. Amy , Deprez Isabelle , Buchanan Ann M. , Vavro Cindy , McKenna Michael , Min Sherene , Tan Lionel K.
Published: February 2025

Background:

Dolutegravir/Lamivudine is recommended for initial antiretroviral therapy (ART) in adults living with HIV-1; however, no clinical trials have assessed this regimen in adolescents, a potentially more challenging population to treat. We evaluated efficacy, safety, and pharmacokinetics of dolutegravir/lamivudine as initial ART in adolescents living with HIV-1.

Setting:

Nine centers in Thailand, Kenya, and South Africa.

Methods:

In the single-arm, open-label, phase 3b DANCE study (NCT03682848), adolescents naive to ART aged ≥12 to <18 years, weighing ≥25 kg, with plasma HIV-1 RNA 1000 to ≤500,000 copies/mL received single once-daily dolutegravir/lamivudine fixed-dose combination tablet orally for 48 weeks (treatment phase). The primary endpoint was proportion of participants with HIV-1 RNA <50 copies/mL at Week 48 (Snapshot; intention-to-treat–exposed [ITT-E] population). Safety outcomes were evaluated in the safety population. Both the ITT-E and safety populations consisted of participants who received ≥1 dose of dolutegravir/lamivudine (N=32). A sensitivity analysis was performed using data from all but two participants who were withdrawn before Week 48 due to site closure (n=30).

Results:

At Week 48, 26/32 (81%; 95% CI, 64%-93%) participants had HIV-1 RNA <50 copies/mL; in sensitivity analyses, 26/30 (87%; 95% CI, 69%-96%) achieved virologic suppression. No confirmed virologic withdrawals or deaths were reported. One drug-related adverse event was reported (grade 3 decreased glomerular filtration rate) and was the only adverse event leading to study withdrawal at data cut. Pharmacokinetic parameters were comparable to adult systemic exposure ranges.

Conclusion:

Dolutegravir/Lamivudine demonstrated efficacy and safety as initial ART in adolescents with HIV-1 through 48 weeks.
FDG PET/CT of Atypical Myeloid Sarcoma After CAR T-Cell Therapy
Authors: Gray Daniel L. , Fair Joanna
Published: February 2025

A 23-year-old man with a history of Ph-Like B-cell acute lymphoblastic leukemia (B-ALL) with JAK2 rearrangement presented with innumerable skin lesions developing over 1 week. Before presentation, he had multiple relapses of his B-ALL and underwent autologous UCD-19 chimeric antigen receptor (CAR) T-cell therapy. Lesions appeared 1.5 months after completion of therapy. Biopsies showed new onset myeloid sarcoma (MS), with continued remission of B-ALL. 18F-FDG PET/CT showed numerous markedly hypermetabolic soft tissue lesions located in the skin and subcutaneous tissues, muscles, osseous structures, mucosa, pleura, mediastinum, peritoneum, retroperitoneum, and testes.
Breast Metastases From ACTH Secreting Thymic Carcinoid
Authors: Edamadaka Yeshwanth , Malhotra Gaurav , Arora Aditi
Published: February 2025

A 33-year-old woman with Cushing syndrome (CS), who underwent incomplete resection of ACTH-secreting thymic carcinoid, presented with a recurrence of Cushingoid features after 3 months of surgery. CECT and PET/CT scans (18F-FDG and 68Ga-DOTATATE) revealed anterior mediastinal lesion encasing the aorta, mediastinal adenopathy, lung nodules, and left breast lesions, the latter being pathologically proven to be metastases from the neuroendocrine tumor (NET). Breast metastases from NET are rare, with their diagnosis being challenging due to considerable overlap with invasive breast cancer. Nevertheless, metastatic lesions to the breast in patients of NET should be ruled out before considering aggressive surgical management.
Concomitant ATTR and AL Cardiac Amyloidosis With Matching 99mTc-DPD Scintigraphy and 18F-Flutemetamol PET/CT
Authors: O. Joo Hyun , Youn Jong-Chan , Han Eun Ji , Jung Mi-Hyang , Lee Jung Yeon , Park Sung-Soo , Sung Yeoun Eun , Min Chang-Ki
Published: February 2025

Two distinct types of systemic amyloidosis—transthyretin (ATTR) and light chain (AL)—account for the majority of cardiac amyloidosis (CA), which have been considered mutually exclusive. Diagnostic confusion can arise when both proteins are identified from an amyloid deposit. We present a rare occurrence of histopathologically confirmed concomitant ATTR and AL CA captured on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scan and 18F-flutemetamol (FMM) PET/CT.
Pelvic Floor Health Knowledge With Enhanced Education During Pregnancy
Authors: Nicola-Ducey Lauren , Ward Lucy , Holland Amanda , Cichowski Sara , Boniface Emily , Gregory W. Thomas
Published: February 2025

Importance

Prior to delivery, there are postpartum pelvic floor recovery topics to provide education on; however, because of a variety of factors, the majority of these are commonly unaddressed, leaving a patient unknowledgeable and unsatisfied.

Objective

The primary aim of this study was to determine if providing tailored/targeted pelvic floor disorder education in the peripartum period will improve nulliparous patients' knowledge of pelvic organ prolapse (POP) and urinary incontinence (UI). Our secondary aim was to evaluate if a difference exists in patient satisfaction and understanding.

Study Design

This was a single-site nonrandomized interventional study evaluating pregnant patients currently enrolled in an interactive electronic educational platform. We evaluated the change in Prolapse and Incontinence Knowledge Questionnaire (PIKQ) scores at 26–27 weeks antepartum and 6 weeks postpartum in 2 separate cohorts, before and after our education intervention was implemented. We also compared the magnitude of the change in PIKQ scores between the nonintervention and intervention postpartum cohorts as our primary outcome.

Results

We compared the change in PIKQ mean scores between the control and intervention cohorts and found no statistical difference in change of UI (0.1 ± 1.8 vs 0.5 ± 1.9, P = 0.218) or POP knowledge (0.9 ± 2.5 vs 0.8 ± 2.4, P = 0.681). In addition, no significant change was detected in mean PIKQ UI scores for the control group between the antepartum and postpartum period (9.9 ± 2.4 vs 10.1 ± 2.1, P = 0.445), but there was a statistically significant change in POP knowledge scores (7.0 ± 3.3 vs 7.9 ± 3.1, P < 0.001). In the intervention cohort, there was a statistically significant change in both UI (9.3 ± 2.6 vs 9.8 ± 2.2, P = 0.012) and POP knowledge scores (6.7 ± 3.4 vs 7.5 ± 3.2, P = 0.001).

Conclusions

We did not detect a significant difference in mean score change between our cohorts following implementation of a targeted educational intervention using an online educational platform. However, both cohorts had higher than anticipated baseline knowledge on pelvic floor disorders.
Polygenic susceptibility to dilated cardiomyopathy underlies peripartum, alcohol-induced, and cancer therapy-related cardiomyopathies
Authors: Maamari Dimitri J. , Biddinger Kiran J. , Jurgens Sean J. , Rämö Joel T. , Gaziano Liam , Zheng Alice , Hayes Dolphurs , Gongora Carlos A. ,   FinnGen, Choi Seung Hoan , Arany Zoltan , Thavendiranathan Paaladinesh , Fahed Akl C. , Sarma Amy A. , Neilan Tomas G. , Khera Amit V. , Ellinor Patrick T. , Aragam Krishna G.
Published: February 2025

Background

Rare (monogenic) variants linked to non-ischemic dilated cardiomyopathy (DCM) are enriched among individuals with peripartum (PPCM), alcohol-induced (ALCM), and cancer therapy-related (CCM) cardiomyopathies, but are present in less than 15% of cases. Whether a common variant (polygenic) predisposition to DCM also pervades these secondary cardiomyopathies remains unclear.

Methods

We evaluated the association of a DCM polygenic score with PPCM, ALCM, and CCM in the Mass General Brigham (MGB) Biobank (n = 42,137), with replication in the UK Biobank (n = 295,160) and FinnGen (n = 417,950). We then assessed the proportion of cases with a monogenic variant and/or a high polygenic score (defined as > 80thpercentile of the score distribution). Finally, we queried medical charts to ascertain whether cardiomyopathy onset in those at high polygenic risk might have been heralded by relevant clinical risk factors.

Results

We identified 415 individuals with a secondary cardiomyopathy (30 with PPCM, 275 with ALCM, and 110 for CCM) across the three cohorts. The DCM polygenic score associated with PPCM (OR = 1.88 per 1 standard deviation (SD) increase in polygenic score, p= 0.001), ALCM (OR per SD = 1.38, p = 1.46E-07), and CCM (OR per SD = 1.58, p = 2.97E-06). Monogenic DCM variants were strongly associated with PPCM, ALCM, and CCM, but were present in less than 10% of cases. Roughly 40% of all secondary cardiomyopathy cases had a high polygenic score, which conferred ∼3-fold odds of cardiomyopathy (p <0.001). Most secondary cardiomyopathy cases lacked known antecedent clinical risk factors.

Conclusion

Cases of PPCM, ALCM, and CCM are enriched for monogenic DCM variants and a high DCM polygenic score, further supporting a shared genetic susceptibility influenced by distinct environmental precipitants. Considering both monogenic and polygenic risk for DCM may improve identification of individuals predisposed to secondary cardiomyopathies, particularly among those lacking established clinical risk factors.
Revealing Gender Differences in Concussion Reporting: A Detailed Analysis of SCAT Assessment Self-Report Symptom Ratings
Authors: Edelstein Rachel , Schmidt Karen M. , Van Horn John Darrell
Published: February 2025

Current concussion assessments used by the NCAA are typically applied across both male and female athletes to assess the effects of sports-related head impacts. However, increasing evidence suggests that female athletes exhibit different physiological and psychosocial responses to concussions compared to their male counterparts, raising concerns about the appropriateness of gender-blind concussion assessment. This study analyzes data from 1,021 NCAA athletes (379 females, 642 males) who completed the SCAT3 Symptom Severity Checklist post-concussion. A systematic use of multivariate statistical approaches including Exploratory Graph Analysis (EGA), Principal Component Analysis (PCA), Exploratory Factor Analysis (EFA), Linear Discriminant Analysis (LDA), and Rasch Partial Credit Modeling (PCM) was employed on this 22-item instrument to explore the latent factor structure and to detect assessment items sensitive to potential gender differences. Differential Item Functioning (DIF) analysis was used to investigate gender disparities in symptom reporting. Based on EGA and PCA, the SCAT3 exhibited a four-factor substructure, with an EFA accounting for 62.44% of the variance. LDA between males and females displayed a statistically significant difference in the multivariate distributions of male and female scores (χ2(22) = 130.56, p < .001), indicating that emotional and physical symptom items loaded negatively, whereas cognitive and sensory-based items loaded positively. A closer examination of each assessment item via Rasch analysis revealed three items having zero difference between males and females. In contrast, nine symptoms indicated males were more likely to report higher severity. However, males generally reported overall lower total symptom severity scores (M = 30.06, SD = 20.88) and males (M = 24.71, SD = 21.18), t(765.06) = 3.85, p < .001. These differences in how athletes of differing genders present symptoms post-concussion may indicate that 1) males may be more conservative in their reporting and only endorse symptoms when they are felt to be more intense, contributing to high scores on a smaller number of symptoms, whereas 2) females may emphasize emotional and physical symptoms more readily. The results of this examination suggest that attention to gender differences in concussion symptom reporting should be considered in making clinical recommendations on concussion recovery and return-to-play decision-making.
Strategic Decision Making in Biological and Artificial Brains
Authors: Deshpande Anushka
Published: February 2025

The aim of this paper is twofold. First, it seeks to uncover the algorithms that humans and other animals employ for learning in decision-making strategies within non-zero-sum games, specifically focusing on fully observable iterated prisoner’s dilemma scenarios. Second, it aims to develop a new model to explain strategic decision-making which reflects previous neurobiological findings showing that different brain circuits are responsible for self-referential processing and understanding others. The model stems from the actor-critic framework and incorporates multiple critics to allow for distinct processing of both self and others’ state. We validate the biological plausibility and transferability of our algorithm through comparisons with experimental data from human on the iterated prisoner’s dilemma game.
Immunological characterization of peritoneal exudate cells in liver cirrhosis patients
Authors: Kaji Shiori , Sasaki Izumi , Kunimoto Satoko , Wakaki-Nishiyama Naoko , Tosuji Emi , Kurara Ayano , Kato Takashi , Mutsukawa Chisako , Okuzaki Daisuke , Okamoto Chizuyo , Yamano Yukiko , Shimizu Ryo , Maeshima Shuya , Ida Yoshiyuki , Yamashita Yasunobu , Hashimoto Tadamichi , Iwabuchi Sadahiro , Hashimoto Shinichi , Saitoh Shin-Ichiroh , Araki Shin-ichi , Kitano Masayuki , Kaisho Tsuneyasu
Published: February 2025

BACKGROUND AND AIMS

Liver cirrhosis (LC) is the end stage of liver fibrosis caused by various chronic liver diseases. Patients with LC often develop ascites containing peritoneal exudate cells (PECs). However, those cells have not been fully immunologically characterized. In this study, we clarify immune cell profiles of PECs from patients with LC.

APPROACH AND RESULTS

PECs were collected from patients with LC or patients receiving continuous ambulatory peritoneal dialysis (CAPD) as a non-cirrhotic control and subjected to single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq) and flowcytometry analyses. Analysis of scRNA-seq revealed that dendritic cells (DCs) and macrophages were major populations in CAPD patient-derived PECs, while those cells were decreased and T cells were most abundant in LC patient-derived PECs. Notably,FCGR3A-expressing macrophages were dominant over DCs andGATA6-expressing macrophages in LC patient-derived PECs. Bulk RNA-seq analysis further clarified expression of a set of genes was up- or down-regulated along with LC severity. Especially, expression of T cell signature genes was featured by its increase at Child-Pugh class B, but decrease at Child-Pugh class C. Flowcytometry analysis showed increase of T cells, decrease of DCs and macrophages, and increased expression of CD16 and CD163 in CD1cintCD14highcells corresponding toFCGR3A-expressing macrophages in LC patient-derived PECs.

CONCLUSIONS

In LC patient-derived PECs, myeloid and T cell populations and their gene expression profiles were fluctuated with severity. Our findings should contribute to further development of diagnosis or therapeutic maneuver for LC.
Somatic repetitive element insertions Define New Biomarkers in Pan-cancer genome
Authors: Xia Lin , Tu Kailing , Wang Huan , Liu Xuyan , Liu Yahui , Zhang Qilin , Feng Ziting , Yu Chunyan , Li Maolin , Huang Yan , Wang Jing , Wei Ranlei , Zeng Tianfu , Pi Xuenan , Ling Chen , Zhang Qianwen , Qiao Yixin , Hou Shengzhong , Zhang Zhuoyuan , Wei Ailin , Liao Haotian , Liu Jifeng , Wu Zhong , Wang Zhoufeng , Li Ang , Li Weiming , Xie Dan
Published: February 2025

Repetitive elements insertions (REIs), including tandem repeat insertions (TRIs) and transposable element insertions (TEIs), which account for over 90% of large-scale (>50 bp) somatic insertions, are known to cause diseases and serve as biomarkers for precision oncology in cancers. However, the genomic landscape of large-scale REIs has not been systematically characterized in pan-cancer, primarily due to the limitations of short-read sequencing (SRS). Here, we precisely detected somatic REIs in 325 cancer genomes spanning 12 cancer types using long-read whole-genome sequencing technology and customized algorithms. The diverse sequence patterns of somatic TRIs and the insertion mechanisms of somatic TEs were characterized across different cancer types. A total of 152 high-frequency somatic TRIs were identified. Among these, 10 TRIs demonstrated significant pan-cancer shared characteristics, including somatic TRI events located within the intron ofSHROOM2andPALMD, as well as in the distal enhancer region upstream ofPTPRZ1. The MHC class II gene cluster exhibited the highest somatic TEI abundance, affecting ∼40% tumors. Adenocarcinomas and squamous cell carcinomas exhibit differing TEI distributions and varying levels of abundance within this region. Overall, our study suggests that REIs are important but under-explored sources of markers for personalized cancer diagnosis and immunotherapy.
Spatial Total RNA Sequencing of Formalin-Fixed Paraffin Embedded Tissues by spRandom-seq
Authors: Liao Yuan , Chen Jiaye , Zhang Shunji , Chen Yu-sheng , Zhu Bin , Chen Haide , Zhu Yuyi , Xu Ziye , Yin Yafei , Xiong Xushen , Liu Nan , Guo Hongshan , Wang Yongcheng
Published: February 2025

Current sequencing-based spatial transcriptomic methods have been widely used to resolve gene expression; however, these methods are limited to fresh or fresh-frozen samples due to the low efficiency of oligo(dT) primers in capturing RNA transcripts in degraded samples. Here, we have developed a random primer-based spatial total RNA sequencing (spRandom-seq) technology for capturing full-length total RNAs in partially degraded (low RIN values) formalin-fixed paraffin-embedded (FFPE) tissues. Our spRandom-seq approach exhibited no discernible biases at the 3'-or 5'-ends within gene bodies and could be integrated with the commercially available 10X Visium and other well-established sequencing-based spatial transcriptomic platforms. Our spRandom-seq approach outperformed oligo(dT)-based 10X Visium with an 8-fold higher capturing rate for long-non-coding RNA (lncRNA) and other non-polyadenylated RNA biotypes, including miRNA, snRNA, and miscRNA. The unsupervised clustering with solely non-coding RNAs (ncRNAs) resulted in region-specific clusters aligned perfectly with mouse brain anatomic regions. Furthermore, in the clinical FFPE sections of breast cancer, our study revealed distinct expression patterns of MUCL1 and JCHAIN within the tumor region, highlighting the inherent heterogeneity. spRandom-seq provided a potential spatial method for clinical FFPE specimens with well-established and commercially available spatial platforms, ensuring ease of operation and commercial scalability for large-scale applications.
Y665F variant of mouseStat5bprotects against acute kidney injury through transcriptomic shifts in renal gene expression
Authors: Jankowski Jakub , Lee Hye Kyung , Hennighausen Lothar
Published: February 2025

The impact of single nucleotide polymorphisms (SNP) on physiology is often underestimated. One amino acid change can result in a variety of phenotypes apparent only in response to disease or injury. Even known pathogenic SNPs have widespread effects that are currently unaccounted for. In this study, we investigated the impact of the known activating and pathogenicSTAT5BY665Fmutation in a renal injury context in mice carrying this variant. Using ischemia-reperfusion model of acute kidney injury, immunohistochemistry, RNA-seq and ChIP-seq, we establish the protective role of STAT5B activation in renal epithelium and showcase the shifts in transcriptomic landscape in a tissue not associated with the usual human phenotype of theStat5bY665Fmutation. Our data indicate new links between the JAK/STAT pathway and known kidney injury markers, contribute to the understanding of the sexual dimorphism of renal disease, and provide new potential targets for JAK inhibitor– and amino acid transport modulation-based therapies.
PRDM16 controls smooth muscle cell fate in atherosclerosis
Authors: Tan Josephine M.E. , Cheng Lan , Calhoun Ryan P. , Weller Angela H. , Drareni Karima , Fong Skylar , Barbara Eirlys , Lim Hee-Woong , Xue Chenyi , Winter Hanna , Auguste Gaëlle , Miller Clint L. , Reilly Muredach P. , Maegdefessel Lars , Lutgens Esther , Seale Patrick
Published: February 2025

Vascular smooth muscle cells (SMCs) normally exist in a contractile state but can undergo fate switching to produce various cell phenotypes in response to pathologic stimuli1–3. In atherosclerosis, these phenotypically modulated SMCs regulate plaque composition and influence the risk of major adverse cardiovascular events4,5. We found that PRDM16, a transcription factor that is genetically associated with cardiovascular disease, is highly expressed in arterial SMCs and downregulated during SMC fate switching in human and mouse atherosclerosis. Loss ofPrdm16in SMCs of mice activates a synthetic modulation program under homeostatic conditions. Single cell analyses show that loss ofPrdm16drives a synthetic program in all SMC populations. Upon exposure to atherogenic stimuli, SMC-selectivePrdm16deficient mice develop SMC-rich, fibroproliferative plaques that contain few foam cells. Acute loss ofPrdm16results in the formation of collagen-rich lesions with thick fibrous caps. Reciprocally, increasing PRDM16 expression in SMCs blocks synthetic processes, including migration, proliferation, and fibrosis. Mechanistically, PRDM16 binds to chromatin and decreases activating histone marks at synthetic genes. Altogether, these results define PRDM16 as a critical determinant of SMC identity and atherosclerotic lesion composition.
Intervention Mapping: A Multi-stage investigation to Control Respiratory Tract Infections at Primary Level
Authors: Mahmood Shahzad , Chaudary Nauman Ali , Nawaz Mariam , Nazir Mohsin , Mahmood Muhammad Shahid
Published: February 2025

Respiratory Tract Infections are the major health hazard to humanity, nowadays. This research aims at the development and implementation of evidence-based intervention at primary healthcare level, in order to control Respiratory Tract Infections, called Intervention Mapping(IM). It comprises multiple phases, focussing on specific needs of the target population and ensuring that intervention should be based on behavioral and systematic change. The study has a mixed design, quantitative and qualitative approach, involving multiple stakeholders, community’s participation and healthcare worker’s collaboration, to control infectious diseases at primary healthcare level and thereby to reduce the burden of diseases.

The study comprises three phases including a pre-intervention phase in which disease load was assessed and the need of particular intervention was analyzed. A multi-targeted public health intervention, incorporating health education, environmental modification, and policy changes, was designed and applied after community analysis. This phase is preceded by the insight development phase which showcased the vitality of community based intervention. The infectivity of respiratory tract infections is studied under two categories. The gender based segregation provided an insight on the spread of respiratory tract infections in males and females, and a subsequent reduction in disease load among both the genders. The second form of study is focussed of age based separation and disease load. The effectiveness of the research can be analyzed by a remarkable decrease in the respiratory diseases in a community.

According to the study’s findings, epidemiologic burden of respiratory infectious diseases can be trimmed by community strengthening activities including population sensitization, community health initiatives, targeting at-risk population, and engaging key actors of the area. This translational research provides a policy recommendation for health promotion, disease prevention, and intervention mapping in a resource-constrained environment. However, the pathway stipulated by the study revolves around shifting from a curative model of healthcare to the preventive model at primary health level.
Cardiac rehabilitation for outpatients aged over 80 years with cardiovascular diseases
Authors: Someya Ryoko , Matsuzawa Yasushi , Shimizu Yoshitaka , Nakahashi Hidefumi , Konishi Masaaki , Akiyama Eiichi , Hanajima Yohei , Kondo Hisaya , Yoshii Tomohiro , Sato Ryosuke , Hayashi Kazuko , Okada Kozo , Sugano Teruyasu , Hibi Kiyoshi
Published: February 2025

Background

In 2023, Japan had the highest proportion of the elderly in the world, with one in 10 individuals aged ≥80 years. Consequently, the number of patients with cardiovascular diseases is increasing. Older patients often have comorbidities such as frailty, sarcopenia, and cognitive decline that leads to a decreased quality of life (QOL). We analyzed the effects of outpatient cardiac rehabilitation (OCR) in elderly patients with cardiovascular disease.

Methods

The comprehensive OCR had been provided by a multidisciplinary team. We analyzed data from 49 patients with cardiovascular diseases, aged ≥80 years, who received cardiopulmonary exercise (CPX) tests based OCR. Frailty, physical function, QOL, exercise tolerance, and vascular endothelial function were assessed before and after OCR.

Results

All 49 patients had completed the OCR program. The mean patients’ age was 84.1 ± 3.6 years and 32.7% were male. The proportion of frailty and pre-frailty participants significantly decreased from 92% to 67% following OCR. The QOL (KCCQ: 76.8 ± 18.4 vs. 81.4 ± 20.4; P = 0.0196), exercise tolerance (peak VO₂: 14.1 ± 4.0 vs. 15.4 ± 3.9 mL/min/kg; P = 0.0017), and vascular endothelial function (Ln-RHI: 0.48 ± 0.39 vs. 0.57 ± 0.3; P = 0.027) significantly improved after OCR.

Conclusions

The comprehensive OCR with CPX-based exercise therapy and the multidisciplinary approach significantly improved frailty, the QOL, physical function, exercise tolerance, and vascular endothelial function in patients with cardiovascular diseases aged ≥80 years.
Kinase interplay centered on two regulatory elements confines the checkpoint protein Lte1 to the bud cell cortical compartment
Authors: Geymonat Marco , Peng Qiuran , Chen Hanlu , Parmar Sneha , Mott Helen , Owen Darerca , Segal Marisa
Published: February 2025

In budding yeast, Lte1, a component of the spindle position checkpoint, must be confined to the bud for correctly coupling chromosomal segregation across the bud neck with mitotic exit. Bud compartmentalization involves a phospho-dependent program with Ras-GTP acting as the ultimate cortical anchor. Here we have dissected this program by identifying an Lte1 domain participating in Ras binding and two phospho-regulatory motifs, the N- and C-LREs (Lte1 Regulatory Elements). The C-LRE mediates control of Lte1 cortical recruitment by the p21-activated kinase, Cla4. The N-LRE modulates Lte1 binding to Ras more directly and is phosphorylated by the yeast MARK/PAR-1 protein kinases, Kin1/2. Along with previously described CDK phosphorylation sites, the N- and C-LREs were required for Lte1 localization and timely mitotic exit. These studies uncover the coordinated interplay between multiple protein kinases allowing Lte1 to integrate cell polarity and cell cycle cues for strict compartmentalization at the bud cell cortex.
Neuronal differentiation enhances a cytoplasmic pool of tousled-like kinase 2 (TLK2)
Authors: Nuhu-Soso Lubna , Denton Heidi , Goffin Darren L , Hahn Ines , Evans Gareth J.O.
Published: February 2025

Mental retardation autosomal dominant 57 (MRD57) is a rare neurodevelopmental disorder characterised by delayed language and psychomotor development, intellectual disability, hypotonia, gastrointestinal issues and facial dysmorphia. It is linked to genetic mutations in the serine/threonine kinase TLK2, characterised by haploinsufficiency and in some cases, its loss or impaired kinase function. TLK2 is an established cell cycle regulator that has been extensively studied in mitotic cells. It is upregulated in cancers, driving tumour growth, however, the role of TLK2 in postmitotic neurons is not understood. We therefore aimed to gain insight into how TLK2 mutations cause MRD57 by determining where TLK2 is expressed in the brain and its subcellular localisation during neuronal differentiation. Public human and mouse brain transcriptomic data revealed splice variant diversity in the N-terminus of TLK2, which contains its nuclear localisation sequence (NLS). Using splice-specific in situ hybridisation probes, we observed expression of TLK2 isoforms that contain and lack the NLS in the mouse hippocampus and cerebellum. We confirmed these findings in human SH-SY5Y neuroblastoma cells, and found that neuronal differentiation of these cells enhances a cytoplasmic pool of TLK2 by two mechanisms: nuclear export of full length TLK2 and increased expression of TLK2 splice variants lacking the NLS. Finally, acute stimuli that mimic synaptic activity were sufficient to elicit nuclear export of TLK2. Our data highlight the need to establish the neuronal cytoplasmic substrates of TLK2 and determine how the loss of TLK2 activity in MRD57 might impact their function in the developing and mature brain.
Genomic Epidemiology of Respiratory Syncytial Virus in a New England Hospital System, 2024
Authors: LaVerriere Emily , Behar Sasha , Sher-Jan Cole , Liang Yan Mei , Sagar Manish , Connor John H.
Published: February 2025

Respiratory syncytial virus (RSV) is one of the main seasonal respiratory pathogens in the United States and causes up to 240,000 hospitalizations per year among children under five and adults over 60. RSV is classified into two subtypes, RSV-A and RSV-B. Although several RSV vaccines and a preventative monoclonal antibody, nirsevimab, were recently approved by the FDA, vaccination and prevention measures remain low even among age groups at higher risk for hospitalization. To better understand the epidemiology of RSV, we analyzed RSV-positive nasopharyngeal swabs from Boston Medical Center and its satellite clinics from January to June 2024 using amplicon-based whole-genome sequencing. Of the 59 samples collected, 19 were from children under five years of age, and 17 were from adults over the age of 60. Fifty-four samples sequenced successfully, with over 90% of the genome at a minimum of 20-fold coverage.

We found that over 80% of the samples were RSV-B; 48 RSV-B samples and 6 RSV-A samples. This represents a major switch from 2022, when Boston RSV samples were ~90% RSV-A. 45 of 48 RSV-B samples mapped into a single clade (B.D.E.1). These samples do not cluster to a single source within the B.D.E.1 clade, suggesting that the predominance of RSV-B is multifactorial, not the selective expansion of a single variant. We also found examples of identical/highly related genomes among our samples, suggesting clustered transmission. One infant had documented nirsevimab therapy forty days prior to RSV isolation. None of the adults had documented RSV vaccination, and mutations associated with nirsevimab resistance or vaccine escape were not observed. Our work highlights the importance of genomic surveillance for respiratory pathogens as a means to monitor transmission dynamics, such as the unexpected switch from RSV-A to RSV-B subtype dominance, to identify examples of superspreading events, and to understand the epidemiological changes that may be associated with nirsevimab and RSV vaccines.
Integrating Nowcasts into an Ensemble of Data-Driven Forecasting Models for SARI Hospitalizations in Germany
Authors: Wolffram Daniel , Bracher Johannes ,   The RESPINOW Study Group, Schienle Melanie
Published: February 2025

Predictive epidemic modeling can enhance situational awareness during emerging and seasonal outbreaks and has received increasing interest in recent years. A common distinction is between nowcasting, which corrects recent incidence data for reporting delays, and forecasting, which predicts future trends. This paper presents an integrated system for nowcasting and multi-model short-term forecasting of hospitalizations from severe acute respiratory infections (SARI) in Germany (November 2023–September 2024). We propose a modular approach combining a statistical nowcasting model with various data-driven forecasting methods, including a time series model, a gradient boosting approach, and a neural network. These are combined into an ensemble approach, which achieves the best average performance. The resulting forecasts are overall well-calibrated up to four weeks ahead, but struggled to capture the unusual double peak which occurred during the test season. While the presented analysis is retrospective, it serves as a blueprint for a collaborative real-time forecasting platform for respiratory diseases in Germany (theRESPINOW Hub). We conclude with an outlook on this system, which was launched in the fall of 2024 and covers a broader range of data sources and modeling approaches.
A novel decision modeling framework for health policy analyses when outcomes are influenced by social and disease processes
Authors: Cusick Marika M. , Alarid-Escudero Fernando , Goldhaber-Fiebert Jeremy D. , Rose Sherri
Published: February 2025

Purpose

Health policy simulation models incorporate disease processes but often ignore social processes that influence health outcomes, potentially leading to suboptimal policy recommendations. To address this gap, we developed a novel decision-analytic modeling framework to integrate social processes.

Methods

We evaluated a simplified decision problem using two models: a standard decision-analytic model and a model incorporating our social factors framework. The standard model simulated individuals transitioning through three disease natural history states–healthy, sick, and dead–without accounting for differential health system utilization. Our social factors framework incorporated heterogeneous health insurance coverage, which influenced disease progression and health system utilization. We assessed the impact of a new treatment on a cohort of 100,000 healthy, non-Hispanic Black and non-Hispanic white 40-year-old adults. Main outcomes included life expectancy, cumulative incidence and duration of sickness, and health system utilization over the lifetime. Secondary outcomes included costs, quality-adjusted life years, and incremental cost-effectiveness ratios.

Results

In the standard model, the new treatment increased life expectancy by 2.7 years for both non-Hispanic Black and non-Hispanic white adults, without affecting racial/ethnic gaps in life expectancy. However, incorporating known racial/ethnic disparities in health insurance coverage with the social factors framework led to smaller life expectancy gains for non-Hispanic Black adults (2.0 years) compared to non-Hispanic white adults (2.2 years), increasing racial/ethnic disparities in life expectancy.

Limitations

The availability of social factors and complexity of causal pathways between factors may pose challenges in applying our social factors framework.

Conclusions

Excluding social processes from health policy modeling can result in unrealistic projections and biased policy recommendations. Incorporating a social factors framework enhances simulation models’ effectiveness in evaluating interventions with health equity implications.
Comparing AI- versus clinician-authored summaries of simulated primary care electronic health records
Authors: Shemtob Lara , Nouri Abdullah , Sullivan Adam , Qiu Connor S , Martin Jonathan , Martin Martha , Noden Sara , Rob Tanveer , Neves Ana Luisa , Majeed Azeem , Clarke Jonathan , Beaney Thomas
Published: February 2025

Structured abstract

Objective

To compare clinical summaries generated from simulated patient primary care electronic health records (EHRs) by ChatGPT-4 to summaries generated by clinicians on multiple domains of quality including utility, concision, accuracy and bias.

Materials and Methods

Seven primary care physicians generated 70 simulated patient EHR notes, each representing 10 appointments with the practice over at least two years. Each record was summarised by a different clinician and by ChatGPT-4. AI- and clinician-authored summaries were rated blind by clinicians according to eight domains of quality and an overall rating.

Results

The median time taken for a clinician to read through and assimilate the information in the EHRs before summarising, was seven minutes. Clinicians rated clinician-authored summaries higher than AI-authored summaries overall (7.39 versus 7.00 out of 10; p=0.02), but with greater variability in clinician-authored summary ratings. AI and clinician-authored summaries had similar accuracy and AI-authored summaries were less likely to omit important information and more likely to use patient-friendly language.

Discussion

Although AI-authored summaries were rated slightly lower overall compared with clinician-authored summaries, they demonstrated similar accuracy and greater consistency. This demonstrates potential applications for generating summaries in primary care, particularly in the context of the substantial time taken for clinicians to undertake this work.

Conclusion

The results suggest the feasibility, utility and acceptability of using AI-authored summaries to integrate into EHRs to support clinicians in primary care. AI summarisation tools have the potential to improve healthcare productivity, including by enabling clinicians to spend more time on direct patient care.
Epigenetic entropy, social disparity, and health and lifespan in the Women’s Health Initiative
Authors: Mozhui Khyobeni , Starlard-Davenport Athena , Sun Yangbo , Shadyab Aladdin H. , Casanova Ramon , Thomas Fridtjof , Wallace Robert B , Fowke Jay H , Johnson Karen C
Published: February 2025

ABSTRACT

The pace of aging varies between individuals and is marked by changes in DNA methylation (DNAm) including an increase in randomness or entropy. Here, we computed epigenetic scores of aging and entropy using DNAm datasets from the Women’s Health Initiative (WHI). We investigated how different epigenetic aging metrics relate to demographic and health variables, and mortality risk. Income and education, two proxies of socioeconomics (SE), had consistent associations with epigenetic aging and entropy. Notably, stochastic increases in DNAm at sites targeted by the polycomb proteins were significantly related to both aging and SE. While higher income was associated with reduced age-related DNAm changes in White women, the protective effect of income was diminished in Black and Hispanic women, and on average, Black and Hispanic women had relatively more aged epigenomes. Faster pace of aging, as estimated by the DunedinPACE, predicted higher mortality risk, while the maintenance of methylation at enhancer regions was associated with improved survival. Our findings demonstrate close ties between social and economic factors and aspects of epigenetic aging, suggesting potential biological mechanisms through which societal disparities may contribute to differences in health outcomes and lifespan across demographic groups.