bluuebunny/crossref_metadata_2025 huggingface dataset:
Local and long-range input balance: A framework for investigating frontal cognitive circuit maturation in health and disease
Authors: Allen Samuel J. , Morishita Hirofumi
Published: September 2024

Frontal cortical circuits undergo prolonged maturation across childhood and adolescence; however, it remains unknown what specific changes are occurring at the circuit level to establish adult cognitive function. With the recent advent of circuit dissection techniques, it is now feasible to examine circuit-specific changes in connectivity, activity, and function in animal models. Here, we propose that the balance of local and long-range inputs onto frontal cognitive circuits is an understudied metric of circuit maturation. This review highlights research on a frontal-sensory attention circuit that undergoes refinement of local/long-range connectivity, regulated by circuit activity and neuromodulatory signaling, and evaluates how this process may occur generally in the frontal cortex to support adult cognitive behavior. Notably, this balance can be bidirectionally disrupted through various mechanisms relevant to psychiatric disorders. Pharmacological or environmental interventions to normalize or reset the local and long-range balance could hold great therapeutic promise to prevent or rescue cognitive deficits.
Development of an antigen-based approach to noninvasively image CAR T cells in real time and as a predictive tool
Authors: Fröse Julia , Rowley Jennifer , Farid Ali Salehi , Rakhshandehroo Taha , Leclerc Paul , Mak Howard , Allen Harris , Moravej Heydar , Munaretto Leila , Millan-Barea Luis , Codet Elisabeth , Glockner Hannah , Jacobson Caron , Hemann Michael , Rashidian Mohammad
Published: September 2024

CAR T cell therapy has revolutionized the treatment of a spectrum of blood-related malignancies. However, treatment responses vary among cancer types and patients. Accurate monitoring of CAR T cell dynamics is crucial for understanding and evaluating treatment efficacy. Positron emission tomography (PET) offers a comprehensive view of CAR T cell homing, especially in critical organs such as lymphoid structures and bone marrow. This information will help assess treatment response and predict relapse risk. Current PET imaging methods for CAR T require genetic modifications, limiting clinical use. To overcome this, we developed an antigen-based imaging approach enabling whole-body CAR T cell imaging. The probe detects CAR T cells in vivo without affecting their function. In an immunocompetent B cell leukemia model, CAR-PET signal in the spleen predicted early mortality risk. The antigen-based CAR-PET approach allows assessment of CAR T therapy responses without altering established clinical protocols. It seamlessly integrates with FDA-approved and future CAR T cell generations, facilitating broader clinical application.
Biological self-protection inspired engineering of nanomaterials to construct a robust bio-nano system for environmental applications
Authors: Xu Nuo , Zhang Xin , Guo Pu-Can , Xie Dong-Hua , Sheng Guo-Ping
Published: September 2024

Nanomaterials can empower microbial-based chemical production or pollutant removal, e.g., nano zero-valent iron (nZVI) as an electron source to enhance microbial reducing pollutants. Constructing bio-nano interfaces is critical for bio-nano system operation, but low interfacial compatibility due to nanotoxicity challenges the system performance. Inspired by microorganisms’ resistance to nanotoxicity by secreting extracellular polymeric substances (EPS), which can act as electron shuttling media, we design a highly compatible bio-nano interface by modifying nZVI with EPS, markedly improving the performance of a bio-nano system consisting of nZVI and bacteria. EPS modification reduced membrane damage and oxidative stress induced by nZVI. Moreover, EPS alleviated nZVI agglomeration and probably reduced bacterial rejection of nZVI by wrapping camouflage, contributing to the bio-nano interface formation, thereby facilitating nZVI to provide electrons for bacterial reducing pollutant via membrane-anchoring cytochrome c. This work provides a strategy for designing a highly biocompatible interface to construct robust and efficient bio-nano systems for environmental implication.
β-Silyl alkynoates: Versatile reagents for biocompatible and selective amide bond formation
Authors: Choudhuri Khokan , Zhang Zhenguo , Loh Teck-Peng
Published: September 2024

The study introduces a previously unidentified method for amide bond formation that addresses several limitations of conventional approaches. It uses the β-silyl alkynoate molecule, where the alkynyl group activates the ester for efficient amide formation, while the bulky TIPS (triisopropylsilane) group prevents unwanted 1,4-addition reactions. This approach exhibits high chemoselectivity for amines, making the method compatible with a wide range of substrates, including secondary amines, and targets the specific ε-amino group of lysine among the native amino ester’s derivatives. It maintains stereochemistry during amide bond formation and TIPS group removal, allowing a versatile platform for postsynthesis modifications such as click reactions and peptide-drug conjugations. These advancements hold substantial promise for pharmaceutical development and peptide engineering, opening avenues for research applications.
CCR2 cooperativity promotes hematopoietic stem cell homing to the bone marrow
Authors: Hurwitz Stephanie N. , Kobulsky Danielle R. , Jung Seul K. , Chia Jennifer J. , Butler Jason M. , Kurre Peter
Published: September 2024

Cross-talk between hematopoietic stem and progenitor cells (HSPCs) and bone marrow (BM) cells is critical for homing and sustained engraftment after transplantation. In particular, molecular and physical adaptation of sinusoidal endothelial cells (ECs) promote HSPC BM occupancy; however, signals that govern these events are not well understood. Extracellular vesicles (EVs) are mediators of cell-cell communication crucial in shaping tissue microenvironments. Here, we demonstrate that integrin α4β7 on murine HSPC EVs targets uptake into ECs. In BM ECs, HSPC EVs induce up-regulation of C-C motif chemokine receptor 2 (CCR2) ligands that synergize with CXCL12-CXCR4 signaling to promote BM homing. In nonirradiated murine models, marrow preconditioning with HSPC EVs or recombinant CCR2 ligands improves homing and early graft occupancy after transplantation. These findings identify a role for HSPC EVs in remodeling ECs, newly define CCR2-dependent graft homing, and inform novel translational conditioning strategies to improve HSPC transplantation.
Metabolic imaging in living plants: A promising field for chemical exchange saturation transfer (CEST) MRI
Authors: Mayer Simon , Rolletschek Hardy , Radchuk Volodymyr , Wagner Steffen , Ortleb Stefan , Gündel Andre , Dehmer Klaus J. , Gutjahr Fabian T. , Jakob Peter M. , Borisjuk Ljudmilla
Published: September 2024

Magnetic resonance imaging (MRI) is a versatile technique in the biomedical field, but its application to the study of plant metabolism in vivo remains challenging because of magnetic susceptibility problems. In this study, we report the establishment of chemical exchange saturation transfer (CEST) for plant MRI. This method enables noninvasive access to the metabolism of sugars and amino acids in complex sink organs (seeds, fruits, taproots, and tubers) of major crops (maize, barley, pea, potato, sugar beet, and sugarcane). Because of its high signal detection sensitivity and low susceptibility to magnetic field inhomogeneities, CEST analyzes heterogeneous botanical samples inaccessible to conventional magnetic resonance spectroscopy. The approach provides unprecedented insight into the dynamics and distribution of sugars and amino acids in intact, living plant tissue. The method is validated by chemical shift imaging, infrared microscopy, chromatography, and mass spectrometry. CEST is a versatile and promising tool for studying plant metabolism in vivo, with many applications in plant science and crop improvement.
Hexagonal electrohydraulic modules for rapidly reconfigurable high-speed robots
Authors: Yoder Zachary , Rumley Ellen H. , Schmidt Ingemar , Rothemund Philipp , Keplinger Christoph
Published: September 2024

Robots made from reconfigurable modular units feature versatility, cost efficiency, and improved sustainability compared with fixed designs. Reconfigurable modules driven by soft actuators provide adaptable actuation, safe interaction, and wide design freedom, but existing soft modules would benefit from high-speed and high-strain actuation, as well as driving methods well-suited to untethered operation. Here, we introduce a class of electrically actuated robotic modules that provide high-speed (a peak contractile strain rate of 4618% per second, 15.8-hertz bandwidth, and a peak specific power of 122 watts per kilogram), high-strain (49% contraction) actuation and that use magnets for reversible mechanical and electrical connections between neighboring modules, thereby serving as building blocks for rapidly reconfigurable and highly agile robotic systems. The actuation performance of each hexagonal electrohydraulic (HEXEL) module is enabled by a synergistic combination of soft and rigid components; a hexagonal exoskeleton of rigid plates amplifies the motion produced by soft electrohydraulic actuators and provides a mechanical structure and connection platform for reconfigurable robots composed of many modules. We characterize the actuation performance of individual HEXEL modules, present a model that captures their quasi-static force-stroke behavior, and demonstrate both a high-jumping and a fast pipe-crawling robot. Using embedded magnetic connections, we arranged multiple modules into reconfigurable robots with diverse functionality, including a high-stroke muscle, a multimodal active array, a table-top active platform, and a fast-rolling robot. We further leveraged the magnetic connections for hosting untethered, snap-on driving electronics, together highlighting the promise of HEXEL modules for creating rapidly reconfigurable high-speed robots.
A combination of four
Toxoplasma gondii
nuclear-targeted effectors protects against interferon gamma-driven human host cell death
Authors: Henry Brittany , Phillips Aubrey J. , Sibley L. David , Rosenberg Alex
Published: September 2024

In both mice and humans, Type II interferon gamma (IFNγ) is crucial for the regulation of
Toxoplasma gondii
(
T. gondii
) infection, during acute or chronic phases. To thwart this defense,
T. gondii
secretes protein effectors hindering the host’s immune response. For example,
T. gondii
relies on the MYR translocon complex to deploy soluble dense granule effectors (GRAs) into the host cell cytosol or nucleus. Recent genome-wide loss-of-function screens in IFNγ-primed primary human fibroblasts identified MYR translocon components as crucial for parasite resistance against IFNγ-driven vacuole clearance. However, these screens did not pinpoint specific MYR-dependent GRA proteins responsible for IFNγ signaling blockade, suggesting potential functional redundancy. Our study reveals that
T. gondii
depends on the MYR translocon complex to prevent parasite premature egress and host cell death in human cells stimulated with IFNγ post-infection, a unique phenotype observed in various human cell lines but not in murine cells. Intriguingly, inhibiting parasite egress did not prevent host cell death, indicating this mechanism is distinct from those described previously. Genome-wide loss-of-function screens uncovered TgIST, GRA16, GRA24, and GRA28 as effectors necessary for a complete block of IFNγ response. GRA24 and GRA28 directly influenced IFNγ-driven transcription, GRA24’s action depended on its interaction with p38 MAPK, while GRA28 disrupted histone acetyltransferase activity of CBP/p300. Given the intricate nature of the immune response to
T. gondii
, it appears that the parasite has evolved equally elaborate mechanisms to subvert IFNγ signaling, extending beyond direct interference with the JAK/STAT1 pathway, to encompass other signaling pathways as well.

IMPORTANCE

Toxoplasma gondii
, an intracellular parasite, affects nearly one-third of the global human population, posing significant risks for immunocompromised patients and infants infected
in utero
. In murine models, the core mechanisms of IFNγ-mediated immunity against
T. gondii
are consistently preserved, showcasing a remarkable conservation of immune defense mechanisms. In humans, the recognized restriction mechanisms vary among cell types, lacking a universally applicable mechanism. This difference underscores a significant variation in the genes employed by
T. gondii
to shield itself against the IFNγ response in human vs murine cells. Here, we identified a specific combination of four parasite-secreted effectors deployed into the host cell nucleus, disrupting IFNγ signaling. This disruption is crucial in preventing premature egress of the parasite and host cell death. Notably, this phenotype is exclusive to human cells, highlighting the intricate and unique mechanisms
T. gondii
employs to modulate host responses in the human cellular environment.
Physician performance scores used to predict emergency department admission numbers and excessive admissions burden
Authors: Eyre Andy , Stein Gideon Y , Chen Jacob , Alon Danny
Published: September 2024

Background

Overcrowding in hospitals is associated with a panoply of adverse events. Inappropriate decisions in the emergency department (ED) contribute to overcrowding. The performance of individual physicians as part of the admitting team is a critical factor in determining the overall rate of admissions. While previous attempts to model admission numbers have been based on a range of variables, none have included measures of individual staff performance. We construct reliable objective measures of staff performance and use these, among other factors, to predict the number of daily admissions. Such modelling will enable enhanced workforce planning and timely intervention to reduce inappropriate admissions and overcrowding.

Methods

A database was created of 232 245 ED attendances at Meir Medical Center in central Israel, spanning the years 2016–2021. We use several measures of physician performance together with historic caseload data and other variables to derive statistical models for the prediction of ED arrival and admission numbers.

Results

Our models predict arrival numbers with a mean absolute percentage error (MAPE) of 6.85%, and admission numbers with a MAPE of 10.6%, and provide a same-day alert for heavy admissions burden with 75% sensitivity for a false-positive rate of 20%. The inclusion of physician performance measures provides an essential boost to model performance.

Conclusions

Arrival number and admission numbers can be predicted with sufficient fidelity to enable interventions to reduce excess admissions and smooth patient flow. Individual staff performance has a strong effect on admission rates and is a critical variable for the effective modelling of admission numbers.
Association between stroke subtypes and outcomes of endovascular therapy: a post-hoc analysis of the ANGEL-ASPECT Trial
Authors: Lu Da , ­ Raynald , Sun Dapeng , Zheng Na , Zhang Bohao , Luo Leilei , Wang Sifei , Pan Sihu , Dou Yuchao , Wang Mengxing , Pan Yuesong , Huo Xiaochuan , Miao Zhongrong , Wei Ming
Published: September 2024

Objectives

Our study aims to examine the value of endovascular therapy (EVT) and its comparison to medical management (MM) in ischaemic stroke patients accompanied by large artery atherosclerosis (LAA) and non-LAA

Methods

modified Rankin scale score (mRS) was evaluated at 90 days post the stroke attack and was considered as the primary outcome. Other outcomes measured in this study included score changes of 0–2 and 0–3 on the mRS. The occurrence of symptomatic intracranial haemorrhage at 24 hours after EVT was also measured as a safety endpoint. Logistic regression analysis was used to determine the associations.

Results

In the LAA group, no significant difference in mRS at 90-day (median IQR 3 (2–5) vs 4 (3–4), 95% CI 0.53 to 2.00, p=0.924), mRS 0–2 and mRS 0–3 was observed between EVT and MM groups. However, in the non-LAA group, patients who underwent EVT had lower 90-day mRS scores (4 (2–5) vs 4 (3–5), generalised OR 1.47, 95% CI 1.14 to 1.88, p<0.001). No interaction effect on the primary outcomes between treatment options and aetiology. More intracranial haemorrhage events within 48 hours were identified in the EVT group for both LAA and non-LAA cohorts (LAA: 40.98% vs 9.62%, relative risk (RR) 4.26, 95% CI 1.76 to 10.34, p<0.001; non-LAA, 52.07% vs 19.65%, RR 2.65, 95% CI 1.90 to 3.70, respectively).

Conclusions

For large infarcts, EVT may be more effective than MM for patients with non-LAA aetiology, but not for those with LAA stroke. As no interaction effect was found, the benefit of EVT compared with MM did not vary by stroke subtypes.
In-season monitoring of harvest and effort from a large-scale subsistence salmon fishery in western Alaska
Authors: Staton Benjamin A. , Bechtol William R. , Coggins Lewis G. , Decossas Gary , Esquible Janessa
Published: September 2024

In-season management of salmon harvest requires real-time data. Specifically, following a brief period of open fishing, knowledge of harvest outcomes is useful when deciding the nature of subsequent fishing periods. This in-season management strategy is relatively new to the lower Kuskokwim River of western Alaska, where depressed salmon runs have caused restrictions to the subsistence fishery. We have developed an in-season monitoring program to rapidly inform managers about fishery outcomes from short-duration (6–24 h) fishery openings. Completed trip information and one or more aerial surveys are combined to estimate daily effort and harvest from drift gillnet fishers spanning 11 communities and ~130 river kilometers. We present a re-analysis of the 40 monitored openers in June–July 2016–2023, and validate harvest estimates of Chinook, chum, and sockeye salmon by comparing them to post-season estimates derived from an independent long-term monitoring program. Our results indicate that the program has produced estimates of sufficient quality to inform in-season managers, although it will likely need alterations to be successful in years with less restricted fishing.
A Photovoltaic Self-Powered Volatile Organic Compounds Sensor Based on Asymmetric Geometry 2D MoS2 Diodes
Authors: Fawzy Mirette , Mohammadzadeh Mohammad Reza , Abnavi Amin , De Silva Thushani , Ahmadi Ribwar , Ghanbari Hamidreza , Kabir Fahmid , Kavanagh Karen L. , Hasani Amirhossein , Adachi Michael M.
Published: September 2024

Transition metal dichalcogenides have gained considerable interest for vapour sensing applications due to their large surface-to-volume ratio and high sensitivity. Herein, we demonstrate a new self-powered volatile organic compounds (VOC) sensor based on asymmetric geometry multi-layer molybdenum disulfide (MoS2) diode. The asymmetric contact geometry of the MoS2 diode induces an internal built-in electric field resulting in self-powering via a photovoltaic response. While illuminated by UV-light, the sensor exhibited a high responsivity of ∼60% with a relatively fast response time of ∼10 sec to 200 ppm of acetone, without an external bias voltage. The MoS2 VOC diode sensor is a promising candidate for self-powered, fast, portable, and highly sensitive VOC sensor applications.
Magnitude of Psoriasis and Its Associated Factors, and Quality of Life of Psoriasis Patients among Patients Who Attend Dermatology Clinic at Tibebe Ghion Comprehensive Specialized and Addis Alem Primary Hospitals, North West Ethiopia, 2022: Institution‐Based Cross‐Sectional Study
Authors: Ketema Wosen , Ketema Bogale Solomon , Ketema Bogale Eyob
Published: September 2024

Background. Psoriasis is a common immune‐mediated papulosquamous inflammatory skin disease characterized by well‐demarcated, erythematous silvery scaly plaques. Prevalence rates of psoriasis showed a worldwide variation and have been reported to range between 0.09% and 5.1%. It has been associated with several intrinsic as well as extrinsic factors and has a detrimental effect on health‐related quality of life. Studies on the burden, factors associated with it, and quality of life of psoriasis are limited in the study area. Objectives. To assess the magnitude, factors associated with it, and quality of life of psoriasis patients. Methods. Institution‐based cross‐sectional study was conducted among patients who attend dermatology clinics at Tibebe Ghion comprehensive specialized and Addis Alem primary hospitals from June 8 to September 5, 2022. Systematic random sampling was applied to select study participants until the sample size (318) was fulfilled. A structured interviewer‐administered questionnaire was used to collect data. Collected data were coded and entered into EPI data version 3.1 and then exported to SPSS version 27 for analysis. Descriptive statistics and logistic regression analysis were done. Result. The mean age of study participants was 22.5 with a standard deviation (SD) of 18.2 years. The proportion of psoriasis was 5.3% with a 95% CI (3.1%, 8.4%). Stressful life events (AOR = 3.32, 95% CI (1.12, 9.86)) and alcohol consumption (AOR = 3.73, 95% CI (1.03, 13.51)) were significantly associated with psoriasis. Seven (41.2%) psoriasis patients had a large effect on their quality of life. The mean dermatology quality of life index (DLQI) was 9.82. Conclusion. The proportion of psoriasis in this study was comparable to earlier international and Ethiopian studies, but greater than studies from other African countries. Stressful life events and alcohol consumption were significantly associated with psoriasis. The majority of psoriasis patients had a large negative effect on their quality of life.
Phenotypic and Molecular Characterization of Hypervirulent and Multidrug‐Resistant Acinetobacter baumannii Isolated from ICU Respiratory Infections
Authors: Qiu Jinjun , Zhu Peng , Wagh Kailash , singh Neha , Dong Shaowei
Published: September 2024

The emergence of hypervirulent strains of Acinetobacter baumannii poses a significant threat in intensive care units (ICU). This study aimed to molecularly characterize hypervirulent A. baumannii strains isolated from ICU patients with respiratory infections. Six strains were isolated from ICU patients over one month. Isolates were identified by phenotypic characterization biochemical properties and 16s RNA sequencing. Antibiotic susceptibility testing was conducted followed by resistance genes detection by PCR. MLST, and PFGE were employed to analyse clonal relationships among strains. Plasmid replicon typing and plasmid transmission frequencies were determined. The isolated strains exhibited diverse clinical manifestations, including acute respiratory distress syndrome (ARDS). Antibiotic susceptibility testing revealed multidrug‐resistance phenotype. Molecular analysis revealed a complex genetic landscape of antibiotic resistance genes, including ESBLs and carbapenemases, as well as virulence genes such as ompA, csuE, and exoS. The multiple sequence types indicating genetic diversity among the strains as ST1512, ST622, and ST149 (each type two isolates). Plasmid characterization revealed the presence of diverse replicon types associated with multidrug resistance. This study provides comprehensive insights into the phenotypic, molecular, and epidemiological characteristics of hypervirulent A. baumannii outbark in ICU.
Critical Risk Factors of Stakeholder Collaboration Impacting BIM Implementation in High‐Rise Residential Building Projects Under the DBB System: A Delphi Survey
Authors: Ly Dang Huy , Moon Hyosoo , Shin Hyunkyu , Ahn Yonghan
Published: September 2024

Although the design‐bid‐build (DBB) system has poor stakeholder collaboration due to the separation between architects, engineers, and contractors in its linear process, resulting in longer schedules and cost overruns, DBB remains the most widely used project delivery system due to its benefits, such as higher competition and the owner’s absolute control over the project. Researchers and practitioners expect building information modeling (BIM) implementation to improve stakeholder collaboration due to its potential to bridge the collaboration gap between these stakeholders, ensuring better coordination and motivating cost reduction. However, the fragmented nature of DBB still poses significant challenges to effective stakeholder collaboration, impacting BIM implementation negatively. Therefore, the objective of this study is to identify and rank critical risk factors (CRFs) related to stakeholder collaboration impacting BIM implementation in the context of high‐rise residential building projects delivered by DBB. By adopting a Delphi procedure, this study identified such CRFs by triangulating the knowledge from the literature and the experience of an expert panel recruited from the construction industry. Seven CRFs were selected and ranked through three rounds of a Delphi survey. Analysis revealed that the rankings remained unchanged despite the increasing degree of consensus among experts. The highest‐ranking negative CRFs were “Inappropriate mindset of BIM collaboration process,” “Awareness of additional roles and responsibilities,” and “Disconnection in the information flow and BIM process.” A matrix of nine recommended solutions that can be applied across different CRFs was collected from the expert panel to improve the productivity of BIM collaboration under DBB. This study provides an in‐depth understanding of the CRFs of BIM‐based collaboration between stakeholders under a nonintegrated delivery system like DBB. The findings of this study can ensure successful project completion by creating awareness and allowing professionals and researchers to develop practical strategies for delivering BIM‐based DBB projects.
Table S1 from Estrogen Receptor Blockade Potentiates Immunotherapy for Liver Metastases by Altering the Liver Immunosuppressive Microenvironment
Authors: Benslimane Yasmine , Amalfi Kevin , Lapin Sara , Perrino Stephanie , Brodt Pnina
Published: September 2024

Immunofluorescence staining antibodies.
Youths with Extreme Obesity: A High-Risk Group for Pain and Mental Health Impairments
Authors: Schmidt Hannah , Menrath Ingo , Wiegand Susanna , Reinehr Thomas , Kiess Wieland , Hebebrand Johannes , von Schnurbein Julia , Holl Reinhard W. , Holle Rolf , Scherag André , Wabitsch Martin , Brandt-Heunemann Stephanie
Published: September 2024

Introduction: Youths with extreme obesity (body mass index [BMI] ≥40) are at increased risk for physical and mental health impairments. Nevertheless, this patient group has received little attention in research. This study aimed to analyze the pain experience and mental health impairments of youths with extreme obesity compared to those with mild and moderate obesity (BMI = 30–39.9) while also considering potential gender differences. Methods: Cross-sectional data of 431 obese youths (M = 16.6 years; SD = 2.3; range = 13–25 years; 53.1% female) were analyzed. Of these, 159 (36.8%) youths had extreme obesity. Self-reported sociodemographic data, variables related to back or leg pain, depression, and health-related quality of life (HRQoL) were assessed with standardized questionnaires. Data were analyzed with univariate tests and logistic regression models. Results: Youths with extreme obesity reported more pain in the last 4 weeks (p = 0.018), increased pain-related impairments in daily life (p = 0.009), more pain-related days of absence (p = 0.030), higher depression scores (p = 0.030), and reduced HRQoL (p = 0.005) compared to youths with mild and moderate obesity. The association between extreme obesity and pain in the last 4 weeks remained associated after including sociodemographic variables in the regression model. In the subgroup of youth with extreme obesity (n = 159), women (n = 83) reported more pain in the last 4 weeks (p = 0.001), higher depression scores (p < 0.001), and lower HRQoL (p < 0.001) compared to men (n = 76). The association between female gender and pain remained significant in the regression models, even after controlling for sociodemographic variables and depression. Conclusion: These findings highlight the need for standardized assessments of pain and mental health, particularly in the treatment of female youths with extreme obesity. Upcoming studies should analyze the reciprocal interactions of pain and mental health, since both are important barriers to lifestyle changes and weight loss.
Right Upper Lobe Large Cell Neuroendocrine Carcinoma with Atypical Carcinoid Features: Case Report
Authors: Lee Yelim , Rodrigs Ryan , Wallace William Dean , Wightman Sean C.
Published: September 2024

Introduction: Large cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC) tumor are two distinct types of pulmonary neuroendocrine tumors (NETs) that are considered genetically unrelated. AC is categorized as a well-differentiated NET, while LCNEC is considered a poorly differentiated NET with a significantly poorer prognosis. Case Presentation: In this case report, we present an 83-year-old male who presented with 2-day history of hemoptysis and subsequently diagnosed with a right upper lobe carcinoid tumor on pre-excision biopsy. After evaluation of the entire excised specimen, the tumor was subsequently reclassified as LCNEC. This case is rare as the tumor displayed pathologic features of AC (areas with low mitotic activity and punctate necrosis) alternating with areas of LCNEC (high mitotic activity with sheets of necrosis). Subsequent molecular studies were more characteristic of AC, with no mutations detected in Rb1 or p53. The patient underwent surgical resection (right upper lobectomy with bronchoplasty and mediastinal lymph node dissection) to remove the tumor. Conclusion: This report outlines the clinical presentation and the underlying pathology of this rare case, which underscores the complex molecular landscape of neuroendocrine neoplasms and the need for nuanced molecular analyses in refining diagnostic approaches.
Association of Obstructive Sleep Apnea on Heart Failure and Its Risk Factors: A Two-Step Mendelian Randomization Study
Authors: Liu Jianhui , Chen Zhikui , Cai Dihui
Published: September 2024

Introduction: Recent studies have indicated that obstructive sleep apnea (OSA) is linked to a higher likelihood of heart failure (HF). However, the causal connection between the two conditions is uncertain. We aimed to investigate the causal association of OSA with HF and its risk factors. Methods: The OSA summary statistics are derived from the FinnGen database, including 38,998 cases and 336,659 controls. HF summary statistics come from HERMES, the UK Biobank, and the FinnGen database. A two-sample mendelian randomization (MR) analysis was conducted to examine the causality of OSA on HF risk. Furthermore, the mediator effect of potential risk factors was assessed by a two-step MR. Results: The results of MR analysis demonstrated that genetically determined OSA is causal associated with the higher likelihood of HF (HERME: odds ratio [OR] = 1.222; 95% confidence interval [CI]: 1.091, 1.369; p = 5.19 × 10−4) (FinnGen: OR = 1.233; 95% CI: 1.129, 1.346; p = 3.32 × 10−6) (UK Biobank: OR = 1.002; 95% CI: 1.000, 1.003; p = 0.014). Two-step MR analysis indicated that obesity, blood glucose, depression, and other CVDs have significant mediating effects on the causal effect between OSA and HF. Conclusion: This MR study emphasizes the causal effect of OSA on HF risk. Adiposity traits play a major role in the process of OSA leading to HF. Considering the detrimental impact of OSA on HF, it becomes imperative to prioritize the prevention and management of HF in individuals afflicted with OSA. The foremost intervention strategy should revolve around effective obesity management.
Lysinuric Protein Intolerance: Not Only a Disorder for Pediatric Nephrologists – Case Report
Authors: Rigoldi Miriam , Mele Caterina , Breno Matteo , Noris Marina , Imeraj Amantia , Gamba Sara , Schieppati Arrigo , Daina Erica ,   on behalf of  Italian Undiagnosed Rare Diseases Network (IURDN)
Published: September 2024

Introduction: Lysinuric protein intolerance (LPI) is a multisystemic inborn error of metabolism with a variable clinical expressivity that usually begins in childhood with growth failure and gastroenterological/neurological problems related to the altered urea cycle and, later, with complications involving the renal, pulmonary, and immunohematological systems. Case Report: We present the case of a 40-year-old woman suffering from chronic kidney disease in the context of a LPI, whose diagnosis was challenging because the signs of the disease were always blurred and the patient never manifested critical episodes typical of this multisystemic disease. In addition to renal disease, splenomegaly, thrombocytopenia, elevated lactate dehydrogenase (LDH), hyperferritinemia, and hypertriglyceridemia were also present. A thorough investigation of the patient’s food preferences revealed her spontaneous aversion to protein-containing foods and excessive drowsiness during the occurrence of infectious episodes or on the rare occasions of excessive protein intake, although without ever coming to medical attention. These nuanced signs led us to suspect an impairment of the urea cycle and ultimately allowed us to narrow down the diagnosis to LPI through biochemical and genetic investigations. Conclusion: Nephrologists should consider LPI in the differential diagnosis, whenever a patient presents with mixed proteinuria, tubular dysfunction, and/or chronic kidney disease of unknown origin. In these circumstances, we suggest looking for other signs such as growth failure, signs and symptoms ascribed to urea-cycle impairment, pulmonary involvement, hepatosplenomegaly, and laboratory alterations such as pancytopenia, hyperferritinemia, lipid abnormalities, and elevated LDH.
Prenatal Diagnosis of Anomalous Origin of the Left Pulmonary Artery in Fetus with a Right-Sided Aortic Arch: Case Report and Review of the Literature
Authors: Szlang Laura , Chaoui Rabih , Opgen-Rhein Bernd , Cho Mi-Young , Henrich Wolfgang
Published: September 2024

Introduction: Anomalous origin of the left pulmonary artery (AOLPA) is an exceptionally rare congenital malformation, requiring particular care to be detected during fetal echocardiography. Case Presentation: A 30-year-old woman, gravida 1, para 0, was referred for a mid-trimester anomaly scan. The three-vessel tracheal view in fetal echocardiographic examination led to the prenatal detection of an AOLPA in the presence of a right-sided aortic arch. Additionally, a bilateral arterial duct and the ductal origin of the left pulmonary artery (LPA) were detected postnatally. Prenatal diagnosis enabled the scheduling of the delivery in a tertiary perinatal center, immediate postnatal treatment with prostaglandin E1 to avoid obstruction of the isolated LPA, as well as surgical repair of the anomaly. Conclusion: The rareness of the disease led to only sporadically published cases of prenatal diagnosis of AOLPA. However, early detection makes prenatal diagnosis crucial regarding the infants’ outcome. This case report underlines the importance of a meticulous examination of the bifurcation of the pulmonary trunk during fetal echocardiography.
Mitophagy Regulates Kidney Diseases
Authors: Fan Xiaolu , Wu Linlin , Wang Fengqi , Liu Dong , Cen Xufeng , Xia Hongguang
Published: September 2024

Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions. Summary: Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin, the main mitophagy regulatory proteins, represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials. Key Message: This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.
Equity in Heart Failure Care: A Get With the Guidelines Analysis of Between- and Within-Hospital Differences in Care by Sex, Race, Ethnicity, and Insurance
Authors: Sandhu Alexander T. , Grau-Sepulveda Maria V. , Witting Celeste , Tisdale Rebecca L. , Zheng Jimmy , Rodriguez Fatima , Edward Justin A. , Ambrosy Andrew P. , Greene Stephen J. , Alhanti Brooke , Fonarow Gregg C. , Joynt Maddox Karen E. , Heidenreich Paul A.
Published: September 2024

BACKGROUND:

Disparities in guideline-based quality measures likely contribute to differences in heart failure (HF) outcomes. We evaluated between- and within-hospital differences in the quality of care across sex, race, ethnicity, and insurance for patients hospitalized for HF.

METHODS:

This retrospective analysis included patients hospitalized for HF across 596 hospitals in the Get With the Guidelines-HF registry between 2016 and 2021. We evaluated performance across 7 measures stratified by patient sex, race, ethnicity, and insurance. We evaluated differences in performance with and without adjustment for the treating hospital. We also measured variation in hospital-specific disparities.

RESULTS:

Among 685 227 patients, the median patient age was 72 (interquartile range, 61–82) and 47.2% were women. Measure performance was significantly lower (worse) for women compared with men for all 7 measures before adjustment. For 4 of 7 measures, there were no significant sex-related differences after patient-level adjustment. For 20 of 25 other comparisons, racial and ethnic minorities and Medicaid/uninsured patients had similar or higher (better) adjusted measure performance compared with White and Medicare/privately insured patients, respectively. Angiotensin receptor neprilysin inhibitor measure performance was significantly lower for Asian, Hispanic, and Medicaid/uninsured patients, and cardiac resynchronization therapy implant/prescription was lower among women and Black patients after hospital adjustment, indicating within-hospital differences. There was hospital-level variation in these differences. For cardiac resynchronization therapy implantation/prescription, 278 hospitals (46.6%) had ≥2% lower implant/prescription for Black versus White patients compared with 109 hospitals (18.3%) with the same or higher cardiac resynchronization therapy implantation/prescription for Black patients.

CONCLUSIONS:

HF quality measure performance was equitable for most measures. There were within-hospital differences in angiotensin receptor neprilysin inhibitor and cardiac resynchronization therapy implant/prescription for historically marginalized groups. The magnitude of hospital-specific disparities varied across hospitals.
Preventing Site-Specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-Induced Excitation-Contraction Uncoupling and Heart Failure Development
Authors: Wang Jinxi , Chen Biyi , Shi Qian , Ciampa Grace , Zhao Weiyang , Zhang Guangqin , Weiss Robert M. , Peng Tianqing , Hall Duane D. , Song Long-Sheng
Published: September 2024

BACKGROUND:

Excitation-contraction (E-C) coupling processes become disrupted in heart failure (HF), resulting in abnormal Ca
2+
homeostasis, maladaptive structural and transcriptional remodeling, and cardiac dysfunction. Junctophilin-2 (JP2) is an essential component of the E-C coupling apparatus but becomes site-specifically cleaved by calpain, leading to disruption of E-C coupling, plasmalemmal transverse tubule degeneration, abnormal Ca
2+
homeostasis, and HF. However, it is not clear whether preventing site-specific calpain cleavage of JP2 is sufficient to protect the heart against stress-induced pathological cardiac remodeling in vivo.

METHODS:

Calpain-resistant JP2 knock-in mice (JP2
CR
) were generated by deleting the primary JP2 calpain cleavage site. Stress-dependent JP2 cleavage was assessed through in vitro cleavage assays and in isolated cardiomyocytes treated with 1 μmol/L isoproterenol by immunofluorescence. Cardiac outcomes were assessed in wild-type and JP2
CR
mice 5 weeks after transverse aortic constriction compared with sham surgery using echocardiography, histology, and RNA-sequencing methods. E-C coupling efficiency was measured by in situ confocal microscopy. E-C coupling proteins were evaluated by calpain assays and Western blotting. The effectiveness of adeno-associated virus gene therapy with JP2
CR
, JP2, or green fluorescent protein to slow HF progression was evaluated in mice with established cardiac dysfunction.

RESULTS:

JP2 proteolysis by calpain and in response to transverse aortic constriction and isoproterenol was blocked in JP2
CR
cardiomyocytes. JP2
CR
hearts are more resistant to pressure-overload stress, having significantly improved Ca
2+
homeostasis and transverse tubule organization with significantly attenuated cardiac dysfunction, hypertrophy, lung edema, fibrosis, and gene expression changes relative to wild-type mice. JP2
CR
preserves the integrity of calpain-sensitive E-C coupling–related proteins, including ryanodine receptor 2, Ca
V
1.2, and sarcoplasmic reticulum calcium ATPase 2a, by attenuating transverse aortic constriction–induced increases in calpain activity. Furthermore, JP2
CR
gene therapy after the onset of cardiac dysfunction was found to be effective at slowing the progression of HF and superior to wild-type JP2.

CONCLUSIONS:

The data presented here demonstrate that preserving JP2-dependent E-C coupling by prohibiting the site-specific calpain cleavage of JP2 offers multifaceted beneficial effects, conferring cardiac protection against stress-induced proteolysis, hypertrophy, and HF. Our data also indicate that specifically targeting the primary calpain cleavage site of JP2 by gene therapy approaches holds great therapeutic potential as a novel precision medicine for treating HF.
In‐Hospital Mortality and Treatment in Patients With Acute Coronary Syndrome With and Without Standard Modifiable Cardiovascular Risk Factors: Findings From the CCC‐ACS Project
Authors: Gong Wei , Yan Yan , Liu Jing , Wang Xiao , Zheng Wen , Que Bin , Ai Hui , Smith Sidney C. , Fonarow Gregg C. , Morgan Louise , Zhao Dong , Ma Changsheng , Han Yaling , Nie Shaoping ,   the CCC‐ACS Investigators
Published: September 2024

Background

Patients with acute coronary syndrome without standard modifiable cardiovascular risk factors (SMuRFs; hypertension, smoking, dyslipidemia, diabetes) have not been well studied, with little known about their characteristics, quality of care, or outcomes. We sought to systematically analyze patients with ACS without SMuRFs, especially to evaluate the effectiveness of guideline‐directed medical therapy for these patients.

Methods and Results

In the CCC‐ACS (Improving Care for Cardiovascular Disease in China‐Acute Coronary Syndrome) project (2014–2019), we examined the presence and absence of SMuRFs and features among 89 462 patients with initial acute coronary syndrome. The main outcome was in‐hospital all‐cause mortality. Among eligible patients, 11.0% had none of the SMuRFs (SMuRF‐less). SMuRF‐less patients had higher in‐hospital mortality (unadjusted hazard ratio [HR], 1.49 [95% CI, 1.19–1.87]). After adjustment for clinical characteristics and treatments, the associations between SMuRF status and in‐hospital mortality persisted (adjusted HR, 1.35 [95% CI, 1.07–1.70]). Guideline‐directed optimal medical therapy (receiving angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, β‐blockers, and statins) was not associated with lower mortality (adjusted HR, 0.98 [95% CI, 0.58–1.67]) in SMuRF‐less patients, unlike the association in patients with SMuRFs (adjusted HR, 0.80 [95% CI, 0.66–0.98]). Sensitivity analyses were consistent with these results.

Conclusions

SMuRF‐less patients were associated with an increased risk of in‐hospital mortality. Guideline‐directed medical therapy was less effective in SMuRF‐less patients than in patients with SMuRFs. Dedicated studies are needed to confirm the optimal therapy for SMuRF‐less patients.

REGISTRATION

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02306616.
Effects of Long‐Term Exposure to Ambient Formaldehyde on Hypertension and Angina Pectoris Symptoms: Evidence From the WHO SAGE Cohort Study
Authors: Xu Jiahong , Shi Yan , He Guanhao , Guo Yanfei , Ruan Ye , Hu Jianxiong , Zhu Qijiong , Chen Zhiqing , Liang Shuru , Zheng Yuan , Huang Zhongguo , Yu Siwen , Zhu Ruotong , Dong Xiaomei , Wu Fan , Ma Wenjun , Liu Tao
Published: September 2024

Background

We aimed to investigate the associations of long‐term exposure to ambient formaldehyde with hypertension and angina pectoris symptoms in Chinese adults.

Methods and Results

Participants' information was obtained from the WHO SAGE (World Health Organization Study on Global Aging and Adult Health) study. The Cox proportional hazards regression model was applied to estimate the associations of formaldehyde with hypertension and angina pectoris symptoms. Mediating effect analysis was used to investigate the mediating effect of hypertension between formaldehyde exposure and angina pectoris symptoms. Long‐term exposure to formaldehyde was positively associated with the risk of angina pectoris symptoms (hazard ratio [HR], 1.66 [95% CI, 1.29–2.13], per interquartile range [IQR], 3.33, 10
15
molecules/cm
2
) and hypertension (HR, 1.17 [95% CI, 1.02–1.34], per IQR, 3.34, 10
15
molecules/cm
2
). The associations between formaldehyde and angina pectoris symptoms were greater in participants aged ≥65 years (HR, 1.90 [95% CI, 1.29–2.80]) and in rural areas (HR, 2.71 [95% CI, 1.54–4.77]), whereas the associations of formaldehyde with hypertension were stronger in men (HR, 1.27 [95% CI, 1.02–1.58]), rural areas (HR, 1.22 [95% CI, 0.94–1.59]), and in ever smokers (HR, 1.33 [95% CI, 1.02–1.72]). The mediation effect analysis indicated that 18.44% (95% CI, 2.17–37.65) of the association between formaldehyde exposure and angina pectoris symptoms was mediated by hypertension.

Conclusions

Long‐term exposure to ambient formaldehyde was positively associated with hypertension and angina pectoris symptoms. The effects of formaldehyde may be modified by age, sex, urbanicity, and smoking status. Hypertension might play a mediating effect in formaldehyde‐induced angina pectoris symptoms.