bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing approaches for targeted integration of transgenic cassettes by integrase-mediated cassette exchange in mouse and human stem cells
Authors: Rath Phalguni , Kramer Philipp , Biggs Daniel , Preece Chris , Hortin Nicole , Diaz Rebeca , Perez-Alcantara Marta , Li Xiang , Bolard Arnaud , Beer Nicola , McCarthy Mark , Davies Benjamin 
Published: January 2025

Abstract
To enable robust expression of transgenes in stem cells, recombinase-mediated cassette exchange at safe harbor loci is frequently adopted. The choice of recombinase enzyme is a critical parameter to ensure maximum efficiency and accuracy of the integration event. We have explored the serine recombinase family of site-specific integrases and have directly compared the efficiency of PhiC31, W-beta, and Bxb1 integrase for targeted transgene integration at the Gt(ROSA)26Sor locus in mouse embryonic stem cells. All 3 integrases were found to be suitable for efficient engineering and long-term expression of each integrase was compatible with pluripotency, as evidenced by germline transmission. Bxb1 integrase was found to be 2-3 times more efficient than PhiC31 and W-beta. The Bxb1 system was adapted for cassette exchange at the AAVS1 locus in human induced pluripotent stem (iPS) cells, and the 2 commonly used ubiquitous promoters, CAG and Ef1α (EIF1A), were tested for their suitability in driving expression of the integrated transgenic cargo. AAVS1-integrated Ef1α promoter led to a very mosaic pattern of expression in targeted hiPS cells, whereas the AAVS1-integrated CAG promoter drove consistent and stable expression. To validate the system for the integration of functional machinery, the Bxb1 integrase system was used to integrate CAG-driven CRISPR-activation and CRISPR-inhibition machinery in human iPS cells and robust sgRNA-induced up- and downregulation of target genes was demonstrated.
Application of a quantitative uncertainty assessment to develop ranges of plausible toxicity values when using observational data in risk assessment: a case study examining associations between PFOA and PFOS exposures and vaccine response
Authors: Wikoff Daniele S , Vincent Melissa J , Heintz Melissa M , Pastula Susan T , Reichert Heidi , Klaren William D , Haws Laurie C 
Published: January 2025

Abstract
Traditional approaches for quantitatively characterizing uncertainty in risk assessment require adaptation to accommodate increased reliance on observational (vs experimental) studies in developing toxicity values. Herein, a case study with perfluorooctanoic acid (PFOA) and PFOS and vaccine response explores approaches for qualitative and—where possible—quantitative assessments of uncertainty at each step in the toxicity value development process when using observational data, including review and appraisal of individual studies, candidate study selection, dose–response modeling, and application of uncertainty factors. Each of the 15 studies identified had uncertainties due to risk of bias in confounding, outcome, and exposure ascertainment, likely contributing to the observed inconsistencies within and across studies, and resulting in lack of candidacy for dose–response assessment. Nonetheless, 2 representative studies were selected to demonstrate possible methods to quantify uncertainty in the remaining steps. Data simulations indicated lack of a clear dose–response relationship; dose–response models fit to representative simulations indicated high uncertainty in both the magnitude and direction of effect with simulated benchmark dose and its lower limit values varying at least 66- and 86-fold for PFOA and PFOS. Uncertainty factor application added minimal uncertainty. Combined, a high level of uncertainty was observed, precluding the ability to confidently assess causal dose–response relationships with the observational data, alone. This case study highlights the need for quantitative uncertainty analysis when developing toxicity values with observational data and, importantly, emphasizes the need for application of additional techniques to directly assess causality and the specificity of dose–response when relying on studies of association in quantitative risk assessment.
The human‐specific noncoding RNA RP11‐424G14.1 functions at the intersection of sexually dimorphic pathways in inflammation, senescence, and metabolism
Authors: Kennicott Kameron , Liang Yun 
Published: January 2025

AbstractSexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female‐biased genes, whereas male‐biased genetic factors remain understudied. Here, we show that the Y‐linked noncoding RNA, RP11‐424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF‐κB pathway as the top biological pathway affected by RP11‐424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11‐424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X‐linked long noncoding RNA XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11‐424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11‐424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11‐424G14.1‐IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11‐424G14.1 being a human‐specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes.
Defining the Need for Causal Inference to Understand the Impact of Social Determinants of Health: A Primer on Behalf of the Consortium for the Holistic Assessment of Risk in Transplantation (CHART)
Authors: Bhavsar Nrupen A. , Patzer Rachel E. , Taber David J. , Ross-Driscoll Katie , Deierhoi Reed Rhiannon , Caicedo-Ramirez Juan C. , Gordon Elisa J. , Matsouaka Roland A. , Rogers Ursula , Webster Wendy , Adams Andrew , Kirk Allan D. , McElroy Lisa M. 
Published: January 2025

Objective:
This study aims to introduce key concepts and methods that inform the design of studies that seek to quantify the causal effect of social determinants of health (SDOH) on access to and outcomes following organ transplant.

Background:
The causal pathways between SDOH and transplant outcomes are poorly understood. This is partially due to the unstandardized and incomplete capture of the complex interactions between patients, their neighborhood environments, the tertiary care system, and structural factors that impact access and outcomes. Designing studies to quantify the causal impact of these factors on transplant access and outcomes requires an understanding of the fundamental concepts of causal inference.

Methods:
We present an overview of fundamental concepts in causal inference, including the potential outcomes framework and direct acyclic graphs. We discuss how to conceptualize SDOH in a causal framework and provide applied examples to illustrate how bias is introduced.

Results:
There is a need for direct measures of SDOH, increased measurement of latent and mediating variables, and multi-level frameworks for research that examine health inequities across multiple health systems to generalize results. We illustrate that biases can arise due to socioeconomic status, race/ethnicity, and incongruencies in language between the patient and clinician.

Conclusions:
Progress towards an equitable transplant system requires establishing causal pathways between psychosocial risk factors, access, and outcomes. This is predicated on accurate and precise quantification of social risk, best facilitated by improved organization of health system data and multicenter efforts to collect and learn from it in ways relevant to specialties and service lines.
Socioeconomic Determinants and Health Outcomes of Financial Resilience Patterns
Authors: Liu Zewei , Chen Ji-Kang 
Published: January 2025

Background and Objectives:
Financial resilience describes an actionable financial capability to cope with emergencies and adversities. However, little is known about whether financial resilience patterns impact holistic health outcomes.

Methods:
This study conducted a 3-step latent profile analysis using an urban community sample (n = 3710) from a nationally representative database in China. A multinomial logistic regression model and multiple linear regression models were estimated to examine the proposed argument guided by social determinants of health and resilience theory.

Results:
Three latent subgroups were identified to differentiate population heterogeneity with high, moderate, and low financial resilience. Younger generations with lower employment participation, education, income, and assets were significantly less likely to be in moderate and high financial resilience subgroups. After controlling demographics and conventional socioeconomic covariates, financial resilience patterns were significantly negatively associated with mental illness, while positively associated with physical health, subjective happiness, and life satisfaction.

Conclusion:
Financial resilience could be a strength-based and actionable socioeconomic determinant of health. Research and practical implications are provided for addressing health inequalities. A new target in community health and social welfare is to enhance financial resilience among marginalized populations through family asset-building, financial inclusion policy, financial literacy education, and social capital investment.
Nodular plantar melanoma in a black male and the importance of tumor excision and inguinal lymph node dissection: a case report
Authors: Ali Mohamed Osama Mohamed , Mohammed Osman Saadia Abdulghani Abdulrahman , Ali Khawla Alawad Elbashir , Basher Mohamed Osman Suliman , Almahdi Taiba Ahmed Mohammed , Elgmar Habab Basheir Abdelgadir 
Published: January 2025

Background:
Nodular melanoma is a rare and aggressive malignant skin cancer. It is the third most common subtype of melanoma, following acral lentiginous melanoma and superficial spreading melanoma, and accounts for 5–8% of all melanoma subtypes among dark-skinned populations. This manuscript presents a case of nodular melanoma on the plantar surface of the foot with metastasis to the inguinal lymph nodes.

Case presentation:
An 82-year-old male with no significant medical history was referred by a dermatologist due to recurrent raised skin pigmentation on the plantar surface of the left foot. The lesion was black in color and associated with pain during walking. Wide-margin excision of the melanoma and inguinal lymph node dissection (ILND) were performed. The diagnosis of nodular melanoma was confirmed through clinical examination and histopathological analysis.

Clinical discussion:
This case highlights the rarity of nodular melanoma among patients of African descent. Its rarity among Africans is likely due to their darker skin and the presence of eumelanin, which filters twice as much ultraviolet radiation as lighter skin. ILND is a crucial strategy, as it can reduce recurrence and improve survival.

Conclusion:
Nodular melanoma is associated with substantially shorter disease-free survival and a higher case fatality rate compared to other melanoma subtypes. Surgical resection and lymph node dissection are effective in improving prognosis. The possibility of melanoma recurrence must always be considered.
Identification of optimal portal pressure decrease to control ascites while minimizing HE after TIPS: A multicenter study
Authors: Kabelitz Martin A. , Hartl Lukas , Schaub Golda , Tiede Anja , Rieland Hannah , Kornfehl Andrea , Hübener Peter , Jachs Mathias , Hinrichs Jan , Schütte Sarah L. , Riedel Christoph , Mauz Jim B. , Tergast Tammo L. , Meyer Bernhard C. , Bannas Peter , Kappel Julia , Wedemeyer Heiner , Kluwe Johannes , Piecha Felix , Reiberger Thomas , Sandmann Lisa , Maasoumy Benjamin 
Published: January 2025

Background and Aims:
Clinically significant portal hypertension in patients with liver cirrhosis can lead to refractory ascites. A TIPS treats clinically significant portal hypertension but may cause overt hepatic encephalopathy (oHE). Our aim was to determine the optimal reduction of the portal pressure gradient (PPG) through TIPS to control ascites without raising oHE risk.

Approach and Results:
This multicenter study screened 1509 patients from 3 European centers (Hannover, Vienna, and Hamburg) undergoing TIPS implantation between 2000 and 2023. Patients with TIPS indications other than refractory ascites/hepatic hydrothorax, vascular liver disease, HCC, or insufficient PPG data were excluded. PPG was measured before and after TIPS insertion. Outcome data were assessed up to 1 year after TIPS insertion. Analyses were conducted utilizing a modern machine learning model, namely a competing-risk random survival forest, partial dependence plots, and competing risk analyses with liver transplantation/death as competitors. The cohort was divided into a 60% derivation and 40% validation cohort. Overall, 729 patients (median MELD: 13 [IQR 10-16], 66% male, 23% oHE before TIPS) were analyzed. The derivation cohort comprised 438 patients, and the validation cohort comprised 291 patients. The optimal PPG reduction, determined by maximally selected Gray statistic and PDP of the random survival forest, was 60%–80%. In this range, patients showed significantly fewer hepatic decompensations due to ascites (HDA) (subdistribution hazard ratio [sHR]: 0.7 [0.52–0.96]) with similar oHE incidences (sHR: 0.92 [0.67–1.27]). The PPG range was confirmed in the validation cohort (HDA: sHR: 0.66 [0.46–0.96]; oHE: sHR: 0.89 [0.61–1.32]).

Conclusions:
A targeted PPG reduction of 60%–80% showed significantly reduced HDA without increased oHE risk. Therefore, PPG reduction within this range could be a valid reduction target.
Postintubation Sedation of Pediatric Patients in the Emergency Department
Authors: Wynia Emily , Baumgartner Kevin , Yaeger Lauren H. , Ancona Rachel , Wiltrakis Susan , Fuller Brian M. 
Published: January 2025

Context
Postintubation sedation is a critical intervention for patients undergoing mechanical ventilation. Research in the intensive care unit (ICU) and adult emergency department (ED) demonstrates that appropriate postintubation sedation has a significant impact on patient outcomes. There are minimal published data regarding postintubation sedation for pediatric ED patients.

Objective
To identify, describe, and critique published literature on postintubation sedation in pediatric ED patients.

Data Sources
Embase, Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.Gov.

Study Selection
Studies describing postintubation sedation in the ED for pediatric patients (<18 years of age) intubated in the ED via rapid sequence intubation (RSI) were included. Studies reporting intubation outside the ED, intubation not by RSI, or nonpediatric patients were excluded, as were studies not reporting novel human clinical research.

Data Extraction
Data were abstracted by 2 authors using a standardized worksheet. Data included study design & setting, demographics, medications for RSI and postintubation sedation, administration of any or appropriately timed postintubation sedation, and predictive factors for postintubation sedation-related outcomes.

Results
A total of 10 studies were included, all of which were nonrandomized; there was significant heterogeneity and many key variables and outcomes were not consistently reported. Meta-analysis of eligible studies demonstrated pooled estimates of 77.3% (95% confidence interval [CI]: 62.5–92.0) for proportion of patients receiving any postintubation sedation, 43.5% (95% CI: 29.3–57.6) for proportion of patients receiving appropriately timed postintubation sedation, and 18.6 minutes (95% CI: 12.5–24.7) for median time to postintubation sedation, all with significant heterogeneity.

Conclusions
Data on postintubation sedation in pediatric ED patients are limited. Administration of postintubation sedation is inconsistent and may be substantially delayed. Further high-quality research into the use of postintubation sedation in this setting is needed, and appropriate postintubation sedation should be a target for quality improvement.
Impact of Donor History on the Risk of Transfusion-Related Infections
Authors: Ogolla Collince Odiwuor , Guya Benard , Maima Apollo O. 
Published: January 2025

AbstractBackgroundTransfusion-related infections are a severe threat to the safety of transfusing blood products, internationally. Advances in screening procedures have not, nevertheless, rendered blood transfusion a risk-free procedure for transmitting infectious disease. Donor history, including previous donation history, medical conditions, and high-risk behavior, may influence transfusion-related infections.ObjectiveThe objective of this study was to determine donors’ histories that could influence the possibility of transfusion-related infections.MethodsThe cross-sectional study was done in January 2022 to December 2023 at KTRH. Out of 108 blood transfusions, data for 108 patients were retrieved from patient medical records and donor screening forms. Variables such as HIV and Hepatitis among donor medical conditions, previous donation history, and high-risk behaviors such as intravenous drug use were analyzed for their link with TRIs. The diagnosis of TRIs was established based on the results of a clinical examination and laboratory tests. Using descriptive statistics as well as Chi-square tests and logistic regression, data were analyzed.ResultsOf the total transfusion sample (n=108), 15 (13.9%) recipients developed infections after transfusion; in these cases, 4.6% had Hepatitis B infections, whereas 3.7% had HIV infections and 5.6% had malaria infections. Past donor experience and risky behavior, which include intravenous drug uses and other risky sexual practices, show a significant association between the increased risk of TRIs (p < 0.05). The odds of transfusion-transmitted infections among repeat donors as compared to first-time donors were marginally high (p=0.04). These independent risk factors for transfusion-related infections were hepatitis B and HIV.ConclusionThe current study calls for a deliberate consideration of donor history, especially previous donation records, medical conditions, and high-risk behaviors, in the prevention of transfusion-related infections. Improved donor screening protocols and monitoring of high-risk behaviors can further enhance safety in blood transfusion. Future research should investigate their effectiveness in targeted intervention strategies among high-risk donor populations.
The Inversion of Naïve-to-Memory T Cell Ratios With Age: Potential Links to Autoimmunity and the Role of Lifetime Infection History
Authors: Montgomery Richard Murdoch 
Published: January 2025

AbstractAs individuals grow older, their T cell repertoire progressively shifts from being dominated by naïve T lymphocytes to featuring a preponderance of memory T cells. This phenomenon—well-documented in immunological literature—is frequently attributed to repeated antigenic stimulation over the course of a lifetime, coupled with thymic involution and other age-associated changes. Although memory T cells are crucial for rapid responses to previously encountered pathogens, there is increasing interest in whether this dramatically shifted balance might predispose certain individuals to a higher risk of autoimmunity, especially when compounded by chronic stress and recurrent infections. In this article, we propose a conceptual model linking the age-related inversion of the naïve-to-memory T cell ratio to an elevated likelihood of immune dysregulation. We integrate mathematical equations to capture the dynamic interactions among key variables, present simulated data in four informative graphs, and discuss the implications and limitations of our approach. Our goal is to invite a deeper consideration of how infection history, stress-induced immune breakdowns, and the intrinsic remodeling of T cell populations with age could collectively contribute to autoimmunity.
RhCMV Expands CCR5 Memory T Cells and promotes SIV reservoir genesis in the Gut Mucosa
Authors: Perdios Chrysostomos , Babu Naveen Suresh , Coleman Celeste D. , Brown Anna T. , Mostrom Matilda J. , Allers Carolina , Doyle-Meyers Lara , Fennessey Christine M. , Keele Brandon F. , Kaur Amitinder , Freeman Michael L. , Mudd Joseph C. 
Published: January 2025

AbstractCytomegalovirus (CMV) is a prevalent β-herpesvirus that persists asymptomatically in immunocompetent hosts. In people with HIV-1 (PWH), CMV is associated with persistence of the HIV-1 reservoir and particular inflammatory related co-morbidities. The true causative role of CMV in HIV-associated pathologies remains unclear given that nearly all PWH are coinfected with CMV. In this study, we examined acute phase SIV dynamics in cohorts of rhesus macaques that were seropositive or -negative for rhesus CMV (RhCMV). We observed expansion of CCR5+ target CD4+ T cells in gut and lymph nodes (LN) that existed naturally in RhCMV-seropositive animals, the majority of which did not react to RhCMV lysate. These cells expressed high levels of the chemokine receptor CXCR3 and a ligand for this receptor, CXCL9, was systemically elevated in RhCMV-seropositive animals. RhCMV+ RMs also exhibited higher peak SIV viremia. CCR5 target memory CD4 T cells in the gut of RhCMV+ RMs were maintained during acute SIV and this was associated with greater seeding of SIV DNA in the intestine. Overall, our data suggests the ability of RhCMV to regulate chemotactic axes that direct lymphocyte trafficking and promote seeding of SIV in a diverse, polyclonal pool of memory CD4+ T cells.
Low Magnetic Fields Stimulate Cardiac Mitochondrial Bioenergetics with a Bell-Shaped Response: Possibly Via a Radical Pair Mechanism
Authors: Beutner Gisela , Yuh Huoy-Jen , Goldenberg Ilan , Wallace Douglas C. , Porter George A. , Moss Arthur J. , Sheu Shey-Shing 
Published: January 2025

AbstractStudies have shown that low magnetic fields (LMFs) of less than 1 × 10−3Tesla (T) affect numerous biological events, including bacteria and plant growth, bird migration, and human brain activity. On a cellular level, LMFs affect ion channel activities, intracellular Ca2+concentrations, and mitochondrial reactive oxygen species (mROS) generation. However, the mechanisms that could account for these effects are controversial. Here, we show that applying a static LMF, ranging from ∼2.7 × 10−4to ∼1.9 × 10−3T, to mitochondria isolated from adult rat hearts produced a bell-shaped increase in maximal respiration (Vmax) up to 40%. A similar LMF-induced increase in Vmax was also observed in mitochondria isolated from rat hearts subjected to ischemia-reperfusion (I-R) injury. We then obtained data showing that LMF- mediated bell-shaped response was also observed in the activity of several enzymes involved in oxidative phosphorylation (OXPHOS), including Complexes II, III, and V, and citrate synthase. By contrast, similar LMF caused little change in the enzymatic activity of Complex I. Interestingly, mROS generation responded to LMF with an inverted bell-shaped decrease. We propose a radical pair mechanism of magnetoreception in cytochromes, catalytical reactions, and iron-sulfur clusters within the OXPHOS enzymes to explain how an LMF can increase the likelihood of electron spin transitions from singlet to triplet state and reverse it as the magnetic field strength further increases, resulting in a bell-shaped response. Our results indicate that a narrow range of LMF can enhance mitochondrial bioenergetics and decrease mROS. This may provide a non-invasive approach to treating diseases, such as I-R injury, when energy generation is compromised and oxidative stress is magnified.