bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival
Authors: Yuan Wenjia , Zhang Hedong , Peng Longkai , Chen Chao , Feng Chen , Tang Zhouqi , Cui Pengcheng , Li Yaguang , Li Tengfang , Qiu Xia , Cui Yan , Zeng Yinqi , Luo Jiadi , Xie Xubiao , Guo Yong , Jiang Xin , Dai Helong 
Published: May 2024

Abstract

Background:
T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction.

Methods:
A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.

Results:

In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg−1·day−1) and Rapamycin (0.1 mg·kg−1·day−1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression.

Conclusions:
Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Efficacy and safety of EUS-guided hepatogastrostomy: A systematic review and meta-analysis
Authors: Moond Vishali , Loganathan Priyadarshini , Koyani Bhargav , Khan Shahab R. , Kassab Lena L. , Chandan Saurabh , Mohan Babu P. , Broder Arkady , Adler Douglas G. 
Published: May 2024

Abstract
EUS-guided hepaticogastrostomy (EUS-HGS) is one of the preferred methods in biliary drainage where ERCP fails or is contraindicated. The clinical outcomes of EUS-HGS are not well studied because of variability in procedure technique. We conducted a search of multiple electronic databases and conference proceedings from inception through January 2023. The clinical outcomes studied were pooled technical success, clinical success, and adverse events. Standard meta-analysis methods were used using the random-effects model, and heterogeneity was studied by I
2 statistics. We analyzed 44 studies, which included 19 prospective and 25 retrospective studies. The pooled technical success rate of EUS-HGS was 94.4% (confidence interval [CI], 92.4%–95.9%; I
2 = 0%), and the pooled clinical success rate was 88.6% (CI, 83.7%–92.2%; I
2 = 0%). The pooled adverse outcomes with EUS-HGS were 23.8% (CI, 19.6%–28.5%; I
2 = 0%). The mild adverse event rate associated with HGS was 5.8% (4.2%–8.1%; I
2 = 0%), moderate adverse event rate was 12.1% (9.1%–15.8%; I
2 = 16%), and severe adverse event rate was 4.2% (3.0%–5.7%; I
2 = 61%), whereas fatal adverse event rate was 3.2% (1.9%–5.4%; I
2 = 62%). On subgroup analysis, the pooled rate of adverse events of EUS-guided hepaticogastrostomy with antegrade stenting was 13.3% (95% CI, 8.2%–21.0%). The pooled technical success with EUS-guided hepaticogastrostomy with antegrade stenting was 89.7% (95% CI, 82.6%–94.2%), and clinical success was 92.5% (95% CI, 77.9%–97.7%). On the basis of our analysis of EUS-HGS, the overall technical success was 94.4%, and the clinical success rate was 88.6%, and the overall adverse events were reported to be 23.8%. These data can also help improve the clinical benefits of EUS-HGS in the selected patients in whom it is performed.
Incidental Serous Tubal Intraepithelial Carcinoma Finding in a Nepalese Patient Undergoing Opportunistic Salpingectomy and the Discovery of a BRCA1 Pathogenic Variant
Authors: Tischer Kristin M. , Yadav Siddhartha , Bell Debra , Hansen Kathleen , Veres Larissa N. , Maddy Brandon , Bakkum-Gamez Jamie N. 
Published: May 2024

BACKGROUND:
Serous tubal intraepithelial carcinoma lesions are the precursor to high-grade serous ovarian carcinomas, which have the highest mortality rate among gynecologic malignancies. In women diagnosed with high-grade serous ovarian carcinoma, 20% of the carcinomas are found to be secondary to hereditary causes, with the majority being associated with germline pathogenic variants in BRCA1 and BRCA2 genes. Patients with a pathogenic variant are at high risk for developing high-grade serous ovarian carcinoma, so it is recommended that they undergo risk-reducing salpingo-oophorectomy in their 30s–40s. Opportunistic salpingectomy is the only ovarian cancer prevention method available for patients at average risk. Although serous tubal intraepithelial carcinoma lesions are rare in women at average risk, studies quote incidental serous tubal intraepithelial carcinoma lesion findings in 1–7% of patients undergoing opportunistic salpingectomy.

CASE:
A 38-year-old woman, gravida 2 para 2, of Nepalese ethnicity had an incidental finding of a serous tubal intraepithelial carcinoma lesion at the time of opportunistic salpingectomy for permanent sterilization at cesarean delivery. The serous tubal intraepithelial carcinoma lesion was found with representative sampling of the fallopian tubes because the patient was considered to be at average risk for ovarian cancer. This method is much less sensitive than the Sectioning and Extensively Examining the Fimbriated End (SEE-FIM) protocol, which is used with women known to be at high risk. This ultimately led to discovery of a BRCA1 mutation in the patient.

CONCLUSION:
The SEE-FIM protocol is used to identify serous tubal intraepithelial carcinoma lesions, but it is not routinely used on fallopian tubes of patients at average risk. Using the SEE-FIM protocol would lead to fewer missed serous tubal intraepithelial carcinoma lesions, but it is unclear how much extra cost and effort would be required to implement this protocol. There are knowledge gaps when it comes to understudied populations and hereditary breast and ovarian cancer gene prevalence. Studies show that current BRCA prediction models underestimate hereditary breast and ovarian cancer gene prevalence in Asian populations. Diagnosing serous tubal intraepithelial carcinoma lesions in understudied populations could lead to the discovery of a hereditary breast and ovarian cancer pathogenic variant that the patient may not have discovered until after a cancer diagnosis. Identification of a serous tubal intraepithelial carcinoma in a patient at average risk should lead to a referral for genetic counseling and screening.
The effect of care interruptions on mortality in adults resuming antiretroviral therapy
Authors: Moolla Haroon , Davies Mary-Ann , Davies Claire , Euvrard Jonathan , Prozesky Hans W. , Fox Matthew P. , Orrell Catherine , Von Groote Per , Johnson Leigh F. ,   for the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) Collaboration
Published: May 2024

Objective:
To estimate the relative rate of all-cause mortality amongst those on antiretroviral treatment (ART) with a history of interruptions compared with those with no previous interruptions in care.

Design:
Retrospective cohort study.

Methods:
We used data from four South African cohorts participating in the International epidemiology Databases to Evaluate AIDS Southern Africa collaboration. We included adults who started ART between 2004 and 2019. We defined a care interruption as a gap in contact longer than 180 days. Observation time prior to interruption was allocated to a ‘no interruption’ group. Observation time after interruption was allocated to one of two groups based on whether the first interruption started before 6 months of ART (’early interruption’) or later (’late interruption’). We used Cox regression to estimate hazard ratios.

Results:
Sixty-three thousand six hundred and ninety-two participants contributed 162 916 person-years of observation. There were 3469 deaths. Most participants were female individuals (67.4%) and the median age at ART initiation was 33.3 years (interquartile range: 27.5–40.7). Seventeen thousand and eleven (26.7%) participants experienced care interruptions. Those resuming ART experienced increased mortality compared with those with no interruptions: early interrupters had a hazard ratio of 4.37 (95% confidence interval (CI) 3.87–4.95) and late interrupters had a hazard ratio of 2.74 (95% CI 2.39–3.15). In sensitivity analyses, effect sizes were found to be proportional to the length of time used to define interruptions.

Conclusion:
Our findings highlight the need to improve retention in care, regardless of treatment duration. Programmes to encourage return to care also need to be strengthened.
Prevalence of detectable HIV-DNA and HIV-RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy
Authors: Wagner Thor A. , Tierney Camlin , Huang Sharon , Nichols Sharon , Malee Kathleen M. , Montañez Nicole A. , Coletti Anne , Spiegel Hans M.L. , Krotje Chelsea , Bone Frederic , Wilkins Megan , Abuogi Lisa , Purswani Murli , Bearden Allison , Wiznia Andrew , Agwu Allison , Chadwick Ellen G. , Richman Douglas , Gandhi Monica , Mehta Patrick , Macatangay Bernard , Spector Stephen A. , Spudich Serena , Persaud Deborah , Chahroudi Ann 
Published: May 2024

Objective:
Central nervous system (CNS) HIV infection can impact cognition and may be an obstacle to cure in adolescents and young adults with perinatal HIV (AYAPHIV). IMPAACT2015 enrolled AYAPHIV on suppressive antiretroviral therapy (ART) with cognitive impairment to detect and quantify HIV in blood and cerebrospinal fluid (CSF).

Design:
IMPAACT2015 was a U.S.-based multi-site, exploratory, observational study.

Methods:
Cognitive impairment was defined as NIH Toolbox Fluid Cognition Composite score (FCCS) more than 1 standard deviation below age-adjusted normative group mean. Cell-free HIV-RNA and cell-associated HIVpol/gag-DNA and 10 biomarkers of inflammation/neuronal injury were measured in paired CSF and blood. ART exposure concentrations were quantified in hair.

Results:
Among 24 participants, 20 had successful CSF collection and 18 also met viral suppression criteria. Nine of 18 (50%) were female sex-at-birth, and 14 of 18 (78%) were black. Median (range) age was 20 years (13–27), time on ART was 18.3 years (8.0–25.5), and FCCS was 68 (53–80). HIV-DNA was detected in PBMCs from all participants. In CSF, two of 18 (11%, 95% CI: 1.4–34.7%) participants had detectable cell-free HIV-RNA, while HIVgag or pol-DNA was detectable in 13 of 18 (72%, 95% confidence interval: 47–90). Detectable HIV-DNA in CSF was associated with male sex-at-birth (P = 0.051), lower CD4+ cell count at enrollment (P = 0.016), and higher PBMC HIVpol-DNA copies (P = 0.058). Hair antiretroviral concentrations and biomarkers were not associated with CSF HIV-DNA detection.

Conclusion:
We found that a high proportion of AYAPHIV with neurocognitive impairment had CSF cells harboring HIV-DNA during long-term virologic suppression. This evidence of persistent HIV-DNA in CSF suggests that the CNS should be considered in treatment and cure studies.
HISTOLOGICAL COMPARISON OF REPEATED MILD WEIGHT DROP AND LATERAL FLUID PERCUSSION INJURY MODELS OF TRAUMATIC BRAIN INJURY IN FEMALE AND MALE RATS
Authors: Vita Sydney M. , Cruise Shealan C. , Gilpin Nicholas W. , Molina Patricia E. 
Published: May 2024

ABSTRACT
In preclinical traumatic brain injury (TBI) research, the animal model should be selected based on the research question and outcome measures of interest. Direct side-by-side comparisons of different injury models are essential for informing such decisions. Here, we used immunohistochemistry to compare the outcomes from two common models of TBI, lateral fluid percussion (LFP) and repeated mild weight drop (rmWD) in adult female and male Wistar rats. Specifically, we measured the effects of LFP and rmWD on markers of cerebrovascular and tight junction disruption, neuroinflammation, mature neurons, and perineuronal nets in the cortical site of injury, cortex adjacent to injury, dentate gyrus, and the CA 2/3 area of the hippocampus. Animals were randomized into the LFP or rmWD group. On day 1, the LFP group received a craniotomy, and on day 4, injury (or sham procedure; randomly assigned). The rmWD animals underwent either injury or isoflurane only (randomly assigned) on each of those 4 days. Seven days after injury, brains were harvested for analysis. Overall, our observations revealed that the most significant disruptions were evident in response to LFP, followed by craniotomy only, whereas rmWD animals showed the least residual changes compared with isoflurane-only controls, supporting consideration of rmWD as a mild injury. LFP led to longer-lasting disruptions, perhaps more representative of moderate TBI. We also report that craniotomy and LFP produced greater disruptions in females relative to males. These findings will assist the field in the selection of animal models based on target severity of postinjury outcomes and support the inclusion of both sexes and appropriate control groups.
The Blue Ribbon Committee II Report and Recommendations on Surgical Education and Training in the United States: 2024
Authors: Stain Steven C. , Ellison E. Christopher , Farmer Diana L. , Flynn Timothy C. , Freischlag Julie A. , Matthews Jeffrey B. , Newman Rachel W. , Chen Xiaodong , Stefanidis Dimitrios , Britt L.D. , Buyske Jo , Fisher Karen , Sachdeva Ajit K. , Turner Patricia L. ,   the Blue Ribbon Committee II
Published: May 2024

Objective:
An expert panel made recommendations to optimize surgical education and training based on the effects of contemporary challenges.

Background:
The inaugural Blue Ribbon Committee (BRC I) proposed sweeping recommendations for surgical education and training in 2004. In light of those findings, a second BRC (BRC II) was convened to make recommendations to optimize surgical training considering the current landscape in medical education.

Methods:
BRC II was a panel of 67 experts selected on the basis of experience and leadership in surgical education and training. It was organized into subcommittees which met virtually over the course of a year. They developed recommendations, along with the Steering Committee, based on areas of focus and then presented them to the entire BRC II. The Delphi method was chosen to obtain consensus, defined as ≥80% agreement among the panel. Cronbach α was computed to assess the internal consistency of 3 Delphi rounds.

Results:
Of the 50 recommendations, 31 obtained consensus in the following aspects of surgical training (# of consensus recommendation/# of proposed): Workforce (1/5); Medical Student Education (3/8); Work Life Integration (4/6); Resident Education (5/7); Goals, Structure, and Financing of Training (5/8); Education Support and Faculty Development (5/6); Research Training (7/9); and Educational Technology and Assessment (1/1). The internal consistency was good in Rounds 1 and 2 and acceptable in Round 3.

Conclusions:
BRC II used the Delphi approach to identify and recommend 31 priorities for surgical education in 2024. We advise establishing a multidisciplinary surgical educational group to oversee, monitor, and facilitate implementation of these recommendations.
Triadic Communication in Medical Encounters Including Individuals With Dementia
Authors: Wollney Easton N. , Armstrong Melissa J. , Hampton Chelsea N. , McCall-Junkin Patti , Bedenfield Noheli , Fisher Carla L. , Bylund Carma L. 
Published: May 2024

Purpose:
The overall goal of this review was to identify what is known about triadic (clinician–patient–caregiver) communication in mild cognitive impairment (MCI) and dementia care settings throughout the care continuum.

Methods:
Using a structured search, we conducted a systematic scoping review of relevant published journal articles across 5 databases. Study titles/abstracts and selected full-text articles were screened by 2 investigators in Covidence systematic review software. Articles were excluded if they were not about clinical communication, focused only on caregiver–patient communication or communication in residential care, were interventional, lacked empirical data, or were not in English. Extracted data were documented using Google Forms.

Results:
The study team screened 3426 article titles and abstracts and 112 full-text articles. Forty-four articles were included in the final review. Results were categorized by 3 communication scenarios: diagnostic communication (n=22), general communication (n=16), and advanced care planning communication (n=6).

Conclusions and Relevance:
Across the included articles, the conceptualization and assessment of communication lacked homogeneity. Future directions include addressing these research gaps, establishing recommendations for clinicians to effectively communicate with individuals with dementia and caregivers, and creating and testing communication skills trainings for caregivers/family members, clinicians, and/or individuals with dementia to facilitate effective communication.
The good, the BATV, and the ugly - first report of BATV vector competence inCulex quinquefasciatusfrom the Southern United States
Authors: Clark Samantha D , Turner Erik A , Vivien Jordan M , Buras Grace B. , Christofferson Rebecca C. 
Published: May 2024

AbstractBatai virus is an arbovirus with wide geographic, host, and climactic ranges. BATV infects primarily avian species but can cause disease in ruminants and humans. Louisiana is at particular risk for overlaps in natural and agricultural systems as the Mississippi Flyway passes through the state. We assessed the vector competence of LouisianaCx. quinquefasciatusfor BATV and found infection and dissemination rates of 22% and 11.1% at 7 days post-exposure (dpe), and 15.8% and 5.3% at 21dpe. The current H5N1 avian influenza outbreak in dairy cows demonstrates the importance of understanding the overlap in avian and other vertebrate species to inform public health and agricultural biosecurity. Results indicate a moderate vector competence of regional LouisianaCx. quinquefasciatusfor BATV. This study presents the first known report of vector competence of BATV in US mosquitoes and establishes the non-zero risk of its emergence in the southern US.
Use of machine learning for quantification of retinal pigment epithelium tight junctions improves assay sensitivity
Authors: Gao Yan , Bray Mark-Anthony , Twarog Michael , Xu YongYao , Buchanan Natasha , Zhang Yiyun , Medley Quintus , Saint-Geniez Magali , Prasanna Ganesh , Zhang Qin 
Published: May 2024

AbstractThe retinal pigment epithelium (RPE) is critical for maintaining outer retinal barrier homeostasis. In age-related macular degeneration (AMD), the RPE can undergo a dedifferentiation process that includes tight junction (TJ) loss and displacement of zonula occludens-1 (ZO-1), which may impair structural and functional integrity of the RPE barrier and contribute to disease pathogenesis. Our objective was to develop an automated and sensitive quantification method for TJ aberrations in an RPE immunofluorescence imaging assay, following treatment with TNFα or TGFβ2. However, quantifying ZO-1 morphological changes in the RPE using standard image analysis methods did not provide a satisfactory assay window. To address this challenge, we developed an imaging assay to quantify ZO-1 changes using a machine learning approach, enabling enhanced phenotypic characterization of the ZO-1 changes in RPE cells and improved assay sensitivity. We were also able to capture and quantify the reversal of these changes using etanercept, an TNFα inhibitor, with this imaging assay. Our findings indicated that this machine learning ZO-1 quantification assay could serve as a potential phenotypic readout for RPE dedifferentiation and enabling large-scale mechanistic studies.
Gene regulatory network inference from single-cell data using optimal transport
Authors: Lamoline François , Haasler Isabel , Karlsson Johan , Gonçalves Jorge , Aalto Atte 
Published: May 2024

AbstractModelling gene expression is a central problem in systems biology. Single-cell technologies have revolutionised the field by enabling sequencing at the resolution of individual cells. This results in a much richer data compared to what is obtained by bulk technologies, offering new possibilities and challenges for gene regulatory network inference. Here we introduce GRIT — a method to fit a differential equation model and to infer gene regulatory networks from single-cell data using the theory of optimal transport. The idea consists in tracking the evolution of the cell distribution over time and finding the system that minimises the transport cost between consecutive time points.
INSIHGT: An accessible multi-scale, multi-modal 3D spatial biology platform
Authors: Yau Chun Ngo , Hung Jacky Tin Shing , Campbell Robert A. A. , Wong Thomas Chun Yip , Huang Bei , Wong Ben Tin Yan , Chow Nick King Ngai , Zhang Lichun , Tsoi Eldric Pui Lam , Tan Yuqi , Li Joshua Jing Xi , Wing Yun Kwok , Lai Hei Ming 
Published: May 2024

AbstractBiological systems are complex, encompassing intertwined spatial, molecular and functional features. However, methodological constraints always limit the completeness of information that can be extracted. Here, we report the development of INSIHGT, a minimally perturbative, accessible and cost-efficient three-dimensional (3D) spatial biology method utilizing superchaotropes and host-guest chemistry. This allows highly multiplexed and multi-modal readout of tissue biomolecules in biological systems up to centimeter scales, permitting radio-histological correlation of phosphorylated alpha-synuclein pathologies in human hemi-brainstem. The homogeneous penetration permits reliable semi-quantitative signals in 3D compared to reference signals. Diverse antigens, mRNA transcripts, neurotransmitters, and post-translational and epigenetic modifications, are well-preserved and visualized. INSIHGT also allows multi-round molecular probing for high-dimensional spatial biology and compatibility with downstream traditional histology. With INSIHGT, we mapped previously undescribed podocyte-to-parietal epithelial cell microfilaments and demonstrated their geodesic clustering in mouse glomeruli, and catalogued sparsely located neurofilament-intensive inclusion bodies in the human cerebellum, and identified NPY-proximal cell types defined by spatial morpho-proteomics in mouse hypothalamus. We anticipate INSIHGT can form the foundations for 3D spatial multi-omics technology development and holistic systems biology studies.