bluuebunny/crossref_metadata_2025 huggingface dataset:
Deal or no deal: U.S. homeowners’ willingness to pay for residential building retrofits
Authors: Berzolla Zachary , Meng Ting , Reinhart Christoph
Published: January 2025

With buildings accounting for nearly 40% of global carbon emissions, deep energy retrofits to reduce emissions in the majority of existing buildings are necessary to meet global climate goals. Yet a deep retrofit can easily cost $50 000 or more, limiting its affordability and thus likelihood of adoption for many households. This paper presents a model of homeowners willingness to pay for different retrofits. The model is meant to quantify the willingness of homeowners to make the economic decision to upgrade their buildings. It can be used to inform the required subsidies to catalyze adoption across the socio-economic spectrum and thus achieve emissions reduction goals. The model is based on a survey of 1200 homeowners in the Northeastern U.S. A logistic regression is carried out on whether or not a respondent is willing to pay for a retrofit. The predictor variables are based on the socioeconomic factors asked in the survey. Key factors influencing homeowners’ willingness to pay include the upfront cost, their income, and their concern about emissions from their home. Notably, increasing concern about emissions for all respondents from the median of ‘slightly concerned’ to ‘extremely concerned’ led to a 50% savings in retrofit subsidy cost. The model can help jurisdictions throughout the U.S. better allocate limited resources to catalyze higher adoption rates of building retrofits.
Using satellite-based sun-induced chlorophyll fluorescence and spectral reflectance for improving terrestrial CO2 flux estimates of India
Authors: Ravi Aparnna , Pillai Dhanyalekshmi , Gerbig Christoph , Sitch Stephen , Zaehle Sonke , Thilakan Vishnu , Jha Chandra Shekhar , Mathew Thara Anna
Published: January 2025

Significant uncertainties in terrestrial carbon fluxes exist in regions with limited ground-based observations, impacting our understanding of ecosystem carbon dynamics and emission reduction needs. This is particularly true for areas with sparse measurement networks, like India. To address this, we explore the potential of satellite measurements from various missions such as Sentinel-5 Precursor (S5P) and the Orbiting Carbon Observatory-2 (OCO-2) to improve terrestrial biosphere CO2 fluxes of India. We follow a data-driven approach, which simulates spatial and temporal distributions of Gross Primary Productivity (GPP), Net Ecosystem Exchange (NEE), and ecosystem Respiration (Reco). We improve these model predictions by additionally using satellite-based Solar Induced chlorophyll Fluorescence (SIF), Soil Temperature (ST), and Soil Moisture (SM) specific to the vegetation classes of the domain. Different model refinements were performed to present the improved hourly distributions of terrestrial biospheric CO2 fluxes on a 0.1◦×0.1◦ grid from 2012 to 2020. Among them, the best-performing model simulations show reasonable agreement with eddy covariance observations for 2012 - 2018. For example, our best NEE and GPP predictions are highly correlated with observations with squared correlation coefficient (R2) values of 0.68 (NEE) and 0.74 (GPP) at the monthly scale for 2018. Based on our improved estimations, the annual NEE and GPP show values within the range from -0.38 Pg C yr-1 to -0.53 Pg C yr-1 (land C sink) and 3.39 Pg C yr-1 to 3.88 Pg C yr-1, respectively over India for 2012 - 2020. Our novel approach and findings highlight the potential of satellite-based SIF measurements to detail the ecosystem-scale vegetation responses across various biomes in India. The use of satellite observations, as demonstrated in this study, offers a scalable solution for regions lacking sufficient ground-based observations to estimate biospheric carbon fluxes reliably.
Near-infrared photoimmunotherapy: mechanisms, applications, and future perspectives in cancer research
Authors: Allen Derek , Szoo Madeline JoAnna , van Bergen Tessa D , Seppelin Ani , Oh Jeonghyun , Saad Mohammad A
Published: January 2025

Photoimmunotherapy (PIT) involves the targeted delivery of a photosensitizer through antibody conjugation, which, upon binding to its cellular target and activation by external irradiation, induces localized toxicity. This approach addresses several limitations of conventional cancer therapies, such as chemo- and radiotherapies, which result in off-target effects that significantly reduce patient quality of life. Furthermore, PIT improves on the challenges encountered with photodynamic therapy (PDT), such as nonspecific localization of the photosensitizer, which often results in unintended toxicities. Although PIT was first proposed in the early 1980s, its clinical applications have been constrained by limitations in antibody engineering, conjugation chemistries, and optical technologies. However, recent advances in antibody–drug conjugate (ADC) research and the emergence of sophisticated laser technologies have greatly benefited the broader applicability of PIT. Notably, the first near-infrared photoimmunotherapy (NIR-PIT) treatment for head and neck cancer has been approved in Japan and is currently in phase III clinical trials in the USA. A significant advantage of PIT over traditional ADCs in cancer management is the agnostic nature of PDT, making it more adaptable to different tumor types. Specifically, PIT can act on cancer stem cells and cancer cells displaying treatment resistance and aggressive phenotypes—a capability beyond the scope of ADCs alone. This review provides an overview of the mechanism of action of NIR-PIT, highlighting its adaptability and application in cancer therapeutics, and concludes by exploring the potential of PIT in advancing cancer treatments.
A new phylogenetic framework for the genus Kalanchoe (Crassulaceae) and implications for infrageneric classification
Authors: Rodewald Seraina E , Klein David-Paul , Shtein Ronen , Smith Gideon F , Joyce Elizabeth , Morales Briones Diego F , Bernhard Sven , Letsara Rokiman , Mertes Hannah , Hühn Philipp , Kadereit Gudrun
Published: January 2025

Background and Aims

Kalanchoe is a diverse genus in the Crassulaceae, with centres of diversity in Madagascar and sub-Saharan Africa. The genus is known for its popularity in horticulture, its use as a model system for research on CAM photosynthesis and vegetative reproduction, its high invasive potential, and its use in traditional medicine. The genus-rank circumscription and infrageneric classification of Kalanchoe have been the subject of debate for centuries, especially regarding the status and rank of what is now treated as K. subg. Bryophyllum and K. subg. Kitchingia. We aim to generate a densely sampled phylogeny of Kalanchoe s.l. and evaluate the current infrageneric classification system.

Methods

We inferred a phylogenetic tree for Kalanchoe using a ddRAD sequencing approach, covering 70% of taxa and four out of five subgenera currently recognised in the genus.

Key Results

We recovered four well-supported clades, partially corresponding to the current subgeneric classification. Kalanchoe subg. Calophygia resolves as sister to the rest of the genus. The relationships among the three remaining clades, however, receive less support. The predominantly mainland African K. subg. Kalanchoe forms a strongly supported clade that resolves as sister to K. subg. Bryophyllum. These two clades are together sister to a clade containing mainly species from K. subg. Kitchingia and K. sect. Pubescentes.

Conclusions

The current subgeneric classification of Kalanchoe is partially backed up by our phylogenetic tree but requires further refinement. The tree topology suggests a Malagasy origin of the genus and one dispersal event to the African mainland, with subsequent dispersal from continental Africa to the Arabian Peninsula and Southeast Asia. The formation of bulbils on the leaf margin is restricted to a larger clade within K. subg. Bryophyllum and thus only evolved once. Our tree provides a framework for further taxonomic, evolutionary, and physiological research on the genus.
Mapping Longitudinal Psychiatric Signatures in Huntington’s Disease
Authors: De Paepe Audrey E , Giannoula Alexia , Garcia-Gorro Clara , Rodriguez-Dechicha Nadia , Vaquer Irene , Calopa Matilde , Sanz Ferran , Furlong Laura I , de Diego-Balaguer Ruth , Camara Estela
Published: January 2025

Objective

Although Huntington’s disease is characterized by motor onset, psychiatric disturbances may present years prior and affect functioning. However, there is inter-individual variability in psychiatric expression and progression. This study therefore strives to stratify longitudinal psychiatric signatures that may inform Huntington’s disease prognosis, with potential clinical applications.

Methods

Forty-six Huntington’s disease gene carriers (21 premanifest, 25 manifest; 31 female; age range 25–69) underwent short-Problem Behavior Assessment for depression, irritability, apathy, and dysexecutive behaviors for up to six longitudinal visits. The Disease Trajectories software, a machine-learning approach, was employed to perform unsupervised clustering of psychiatric trajectories. Linear fits were calculated for each cluster. Lastly, the main clusters of shared trajectories were assessed for group differences in demographic and clinical characteristics.

Results

The Disease Trajectories analysis software identified two main psychiatric patterns comprising premanifest and manifest patients that explained 54% of the sample. These two clusters evinced a dissociation in the development of depression and irritability; the first cluster was defined by increasing irritability with no depression and the second by a rise-and-fall in depression with no irritability. Both clusters showed a longitudinal increase in clinically relevant apathy and dysexecutive behaviors.

Conclusions

Ultimately, through the detection of individual-level psychiatric trajectories with machine-learning, this exploratory study reveals that a dissociation of depression and irritability is apparent even in premanifest stages. These findings underscore individual differences in the severity of longitudinal multivariate clinical characteristics for real-world patient stratification, with implications for precision medicine.
3D Technology for Autologous Breast Reconstruction: Increased Aesthetic Outcomes and Quality of Life Utilizing Patient-Specific Templates
Authors: Zaussinger Maximilian , Schwaiger Karl , Schwarzbauer Jürgen , Schwartz Bernhard , Holzbauer Matthias , Bachleitner Kathrin , Ehebruster Gudrun , Schmidt Manfred
Published: January 2025

Background

In autologous breast reconstruction accomplishing aesthetically pleasing outcomes represents an integral challenge. Three-dimensional (3D) technology may aid in accurate flap shaping and subsequent breast appearance.

Objectives

The aim of this study was to evaluate the applicability of 3-dimensional technology for surgical planning and its influence on outcomes for breast reconstruction.

Methods

Outcomes of 50 female patients who underwent deep epigastric artery perforator flap breast reconstruction were analyzed. The patient population was divided into 2 study groups (with 3D technology vs without), including 25 patients each. Based on individual 3D scans and simulations, patient-specific templates were utilized intraoperatively in the 3D group. Quality of life assessment and aesthetic evaluations of breast appearance were statistically evaluated and compared.

Results

Various scales of the BREAST-Q showed statistically significantly better values in the 3D group (P < .05). Concerning breast appearance, patients with 3D technology rated their breast shape and projection statistically significantly higher compared to the control group (P < .05). In addition, blinded ratings of external plastic surgeons were statistically significantly higher related to shape, symmetry, and projection of breasts with 3D technology (P < .05). All patients treated with 3D technology–assisted breast reconstruction strongly recommended this approach.

Conclusions

Patient-specific templates represent a practical method for facilitating personalized flap planning and shaping. Results demonstrated that 3D technology significantly enhances breast reconstruction outcomes concerning aesthetics and postoperative quality of life.

Level of Evidence: 3 (Therapeutic)
Evaluating Real-world Use and Adverse Events From 3262 Patients Treated With 18,203 Cycles of Cryolipolysis for Localized Fat Reduction: A Multilocation Practice Retrospective Chart Review
Authors: Friedmann Daniel P , Kommera Jatin , Durga Prishita , Shashidhar Amogh , Verma Kritin K
Published: January 2025

Background

Cryolipolysis is an established method for noninvasive focal subcutaneous fat reduction.

Objectives

The aim of this study was to highlight the safety and real-world use of this technology.

Methods

The electronic medical records of all patients treated with a commercially available cryolipolysis technology (CoolSculpting and CoolSculpting Elite, Allergan Aesthetics, Irvine, CA) between January 2016 and June 2023 at a multilocation group practice were retrospectively reviewed. Extracted procedure-related data included number of total sessions and cycles, number of sessions and cycles per body area, and treatment-related adverse events. A cycle was defined as 1 applicator treating 1 body area.

Results

In total, 3262 patients (2797 female, 465 male) treated with 18,203 cycles across 6245 sessions were included. The mean [standard deviation] age at first treatment was 45.0 [12.8] years (range, 15-83 years). The mean number of cycles per patient was 5.6 [6.5] (range, 1-177), with a median of 4 cycles per patient. The mean number of sessions per patient was 1.9 [1.7] (range, 1-38), with a median of 1 session per patient. The most commonly treated area was the lower abdomen (n = 1761, 4734 cycles), and the most frequently treated body area combination was the upper/mid + lower abdomen (n = 937, 5140 cycles). Dual submental treatment was more common than single applicator therapy. Eighty-seven patients exhibited 180 adverse events (2.05% of cycles), including 3 body areas (n = 2) with paradoxical adipose hyperplasia.

Conclusions

This retrospective chart review of cryolipolysis treatment, among the largest to date, demonstrates its overall safety and broad use across numerous body areas. The paradoxical adipose hyperplasia risk per cycle is between 0.018% (1 in 5501) and 0.048% (1 in 2063), depending on the calculation method.

Level of Evidence: 4 (Therapeutic)
Multi-view multi-level contrastive graph convolutional network for cancer subtyping on multi-omics data
Authors: Yang Bo , Cui Chenxi , Wang Meng , Ji Hong , Gao Feiyue
Published: January 2025

Cancer is a highly diverse group of diseases, and each type of cancer can be further divided into various subtypes according to specific characteristics, cellular origins, and molecular markers. Subtyping helps in tailoring treatment and prognosis accuracy. However, the existing studies are more concerned with integrating different omics data to discover potential connections, but ignoring the relationships between consensus information and individual information within each omics level during the integration process. To this end, we propose a novel fusion-free method called multi-view multi-level contrastive graph convolutional network (M$^{2}$CGCN) for cancer subtyping. M$^{2}$CGCN learns multi-level features, i.e. high-level and low-level features, respectively. The low-level features from each view capture the intrinsic information in each omics by reconstruction of node attribute and graph structures. The high-level features achieve cancer subtyping via contrastive learning. Comprehensive experiments were performed on 34 multi-omics cancer datasets. The findings indicate that M$^{2}$CGCN achieves results comparable to or surpassing many state-of-the-art methods.
Assessment of the functionality and usability of open-source rare variant analysis pipelines
Authors: Riccio Cristian , Jansen Max L , Thalén Felix , Koliopanos Georgios , Link Vivian , Ziegler Andreas
Published: January 2025

Sequencing of increasingly larger cohorts has revealed many rare variants, presenting an opportunity to further unravel the genetic basis of complex traits. Compared with common variants, rare variants are more complex to analyze. Specialized computational tools for these analyses should be both flexible and user-friendly. However, an overview of the available rare variant analysis pipelines and their functionalities is currently lacking. Here, we provide a systematic review of the currently available rare variant analysis pipelines. We searched MEDLINE and Google Scholar until 27 November 2023, and included open-source rare variant pipelines that accepted genotype data from cohort and case–control studies and group variants into testing units. Eligible pipelines were assessed based on functionality and usability criteria. We identified 17 rare variant pipelines that collectively support various trait types, association tests, testing units, and variant weighting schemes. Currently, no single pipeline can handle all data types in a scalable and flexible manner. We recommend different tools to meet diverse analysis needs. STAARpipeline is suitable for newcomers and common applications owing to its built-in definitions for the testing units. REGENIE is highly scalable, actively maintained, regularly updated, and well documented. Ravages is suitable for analyzing multinomial variables, and OrdinalGWAS is tailored for analyzing ordinal variables. Opportunities remain for developing a user-friendly pipeline that provides high degrees of flexibility and scalability. Such a pipeline would enable researchers to exploit the potential of rare variant analyses to uncover the genetic basis of complex traits.
Adult phenotypes of genetic developmental and epileptic encephalopathies
Authors: Vakrinou Angeliki , Pagni Susanna , Mills James D , Clayton Lisa M , Balestrini Simona , Sisodiya Sanjay M
Published: January 2025

Developmental and epileptic encephalopathies constitute a group of severe epilepsies, with seizure onset typically occurring in infancy or childhood, and diverse clinical manifestations, including neurodevelopmental deficits and multimorbidities. Many have genetic aetiologies, identified in up to 50% of individuals. Whilst classically considered paediatric disorders, most are compatible with survival into adulthood, but their adult phenotypes remain inadequately understood. This cross-sectional study presents detailed phenotypes of 129 adults (age range 17–71 years), with genetic developmental and epileptic encephalopathies involving causal variants in 42 genes. We describe diverse disease aspects, and we sought genetic insights from the age-related trends of expression of the genes involved. Most developmental and epileptic encephalopathies (69.7%) are epileptic encephalopathies in adulthood, with the presence of epileptic encephalopathy correlating with worse cognitive phenotypes (P = 0.0007). However, phenotypic variability was observed, ranging from those with epileptic encephalopathy to seizure-free individuals with normal EEG or intermediate clinical and EEG phenotypes. This variability was found across individual genes and age-related gene expression trends, suggesting that other influential factors are likely at play. Mobility, feeding and communication impairments were common, with significant dependence on others for activities of daily living. Neurological and psychiatric comorbidities were most prevalent, along with additional systemic comorbidities observed, particularly musculoskeletal, cardiac and gastrointestinal conditions, highlighting the need for comprehensive and multisystemic monitoring. Despite an average diagnostic delay of 25.2 years, aetiology-based therapeutic interventions were feasible for 54.8% of the cohort, underscoring the critical need for genome-wide genetic testing for adults with these phenotypes. Optimizing seizure control remains necessary, but it may not be sufficient to ensure good outcomes, which may differ significantly from childhood metrics, like cognitive function and independence in daily living. Therapies addressing additional aspects beyond seizures are necessary for improving overall outcomes. Understanding the intricate relationship between molecular pathways and the age-related trends of gene expression is crucial for development of appropriate gene-specific therapies and timely intervention. Whilst prospective data are also needed to define these complexities, such studies of necessity take years to acquire: insights from adults can inform care strategies for both paediatric and adult populations now.
Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial
Authors: Luetkemeyer Anne F , Chew Kara W , Lacey Stuart , Hughes Michael D , Harrison Linda J , Daar Eric S , Eron Joseph , Fletcher Courtney V , Greninger Alexander L , Hessinger Diane , Li Jonathan Z , Mailhot David , Wohl David , Chayakulkeeree Methee , Mendoza Jose Luis Accini , Elistratova Polina , Makinde Oluwaseun , Morgan Gareth , Portsmouth Simon , Uehara Takeki , Smith Davey , Currier Judith S
Published: January 2025

Background

Ensitrelvir, a severe acute respiratory syndrome coronavirus-2 main protease inhibitor, has demonstrated clinical and virologic efficacy in previous studies.

Methods

In this global phase 3 trial, nonhospitalized adults with mild-to-moderate coronavirus disease 2019 (COVID-19) and symptom onset within 5 days were randomized (1:1) to receive once-daily ensitrelvir (375 mg day 1, 125 mg days 2–5) or blinded matching placebo. The primary endpoint was the restricted mean time to sustained (≥2 days) resolution of 15 COVID-19 symptoms, recorded in participant daily diaries, through day 29 in participants starting treatment within 3 days after symptom onset. Virologic efficacy and safety were assessed.

Results

Of 2093 participants, 1888 started treatment within 3 days after symptom onset. Mean time to symptom resolution was 12.5 and 13.1 days with ensitrelvir and placebo, respectively (difference, −0.6 days; 95% confidence interval, −1.38 to 0.19; P = .14). On day 4, ensitrelvir reduced least-squares mean RNA by 0.72 log10 copies/mL more than placebo (95% confidence interval, 0.55–0.90). Among those with positive viral cultures at enrollment, 274/287 (95.5%) ensitrelvir-treated versus 210/280 (75.0%) placebo-treated participants had negative cultures on day 4. RNA rebound was similar (<1.5%) between groups. The proportion of participants with ≥1 adverse event was similar with ensitrelvir (61.5%) and placebo (60.6%). No treatment-related serious adverse events or deaths occurred. Three (0.3%) ensitrelvir-treated and 1 (0.1%) placebo-treated participants had COVID-19–related hospitalizations by day 29.

Conclusions

Despite the evidence of antiviral activity with ensitrelvir, this trial did not demonstrate a significant difference in time to sustained symptom resolution.
Living Beyond IBD: A Patient’s Experience With EIMs and the Case for Multidisciplinary Care
Authors: Castrillon Rocio
Published: January 2025

This editorial explores the complex relationship between inflammatory bowel disease (IBD) and extra-intestinal manifestations (EIMs) and underscores the clinician’s critical need for comprehensive EIM care, as well as the physical and emotional burden imposed on the patient. The editorial concludes with actionable steps for clinicians and a call to advance IBD care with a comprehensive multidisciplinary approach that acknowledges the various challenges faced by patients. Together, we can transform the IBD journey into a partnership built on understanding, support, and shared hope.
Mapping the DeFi crime landscape: an evidence-based picture
Authors: Carpentier-Desjardins Catherine , Paquet-Clouston Masarah , Kitzler Stefan , Haslhofer Bernhard
Published: January 2025

Decentralized finance (DeFi) has been the target of numerous profit-driven crimes, but the prevalence and cumulative impact of these crimes have not yet been assessed. This study provides a comprehensive assessment of profit-driven crimes targeting the DeFi sector. We collected data on 1141 crime events from 2017 to 2022. Of these, 1036 were related to DeFi (the main focus of this study) and 105 to centralized finance (CeFi). The findings show that the entire cryptoasset industry has suffered a minimum loss of US$30B, with two-thirds related to CeFi and one-third to DeFi. Focusing on DeFi, a taxonomy was developed to clarify the similarities and differences among these crimes. All events were mapped onto the DeFi stack to assess the impacted technical layers, and the financial damages were quantified to gauge their scale. The results highlight that during an attack, a DeFi actor (an entity developing a DeFi technology) can serve as a direct target (due to technical vulnerabilities or exploitation of human risks), as a perpetrator (through malicious uses of contracts or market manipulations), or as an intermediary (by being imitated through, for example, phishing scams). The findings also show that DeFi actors are the first victims of crimes targeting the DeFi industry: 52% of events targeted them, primarily due to technical vulnerabilities at the protocol layer, and these events accounted for 83% of all financial damages. Alternatively, in 41% of events, DeFi actors were themselves malicious perpetrators, predominantly misusing contracts at the cryptoasset layer (e.g. rug pull scams). However, these events accounted for only 17% of all financial damages. The study offers a preliminary assessment of the size and scope of crime events within the DeFi sector and highlights the vulnerable position of DeFi actors in the ecosystem.
Methods for assessing peri-implant marginal bone levels on digital periapical radiographs: a meta-research
Authors: dos Reis Isabella Neme Ribeiro , Vilela Nathalia , Naenni Nadja , Jung Ronald Ernest , Schwarz Frank , Romito Giuseppe Alexandre , Spin-Neto Rubens , Pannuti Claudio Mendes
Published: January 2025

Objectives

This meta-research assessed methodologies used for evaluating peri-implant marginal bone levels on digital periapical radiographs in randomized clinical trials published between 2019 and 2023.

Methods

Articles were searched in four databases. Data on methods for assessing peri-implant marginal bone levels were extracted. Risk of bias assessment was performed.

Results

During full-text reading, 108 out of 162 articles were excluded. Methodological issues accounted for these exclusions, including the absence of radiograph-type information, the lack of radiographic positioners, the missing anatomical references, and the use of panoramic radiographs or tomography. Fifty-four articles were included, most from Europe (70%) and university-based (74%). Radiographic positioners were specified in 54% of articles. Examiner calibration was unreported in 54%, with 69% lacking details. In 59%, no statistical measure assessed examiner agreement. Blinding was unreported or unused in 50%. Marginal bone level changes were the primary outcome of 61%. Most articles (59.3%) raised “some concerns” regarding bias, while 37% showed a high risk of bias, and only two articles (3.7%) demonstrated a low risk of bias.

Conclusions

Several limitations and areas for improvement were identified. Future studies should prioritize protocol registration, standardize radiographic acquisitions, specify examiner details, implement calibration and statistical measures for agreement, introduce blinding protocols, and maintain geometric calibration standards.
Gasdermin B modulates intestinal epithelial homeostasis via regulating hyperactive unfolded protein response in Crohn’s disease
Authors: Gong Wenbin , Liu Peizhao , Liu Juanhan , Li Yangguang , Jiang Haiyang , Li Weizhen , Kang Jiaqi , Jiao Fan , Wu Xiuwen , Zhao Yun , Ren Jianan
Published: January 2025

Background

Impaired intestinal epithelial barrier has been considered to be associated with an increasing variety of gastrointestinal diseases, especially inflammatory bowel disease (IBD) encompassing Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to investigate the role of Gasdermin B (GSDMB) in modulating intestinal epithelial barrier integrity and proposed a promising therapeutic strategy.

Methods

Gasdermin B expression was evaluated in adult CD samples by molecular biology means and single-cell transcriptomes. We generated GSDMB (Rosa26-lsl/lsl-GSDMB;Villin-Cre) and one of its functional missense variant rs2305480 (Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre) intestinal epithelial-specific knock in mice to observe the functions of GSDMB in intestinal epithelial barrier. RNA-seq analysis as well as human and murine intestine-derived organoids were used to determine the pathogenic mechanism of GSDMB.

Results

The expression of GSDMB was increased during active intestinal inflammation and principally localized in intestinal epithelial cells (IECs). Rosa26-lsl/lsl-GSDMB;Villin-Cre mice developed enterocolitis and exhibited aberrant intestinal barrier integrity. Mechanistically, epithelial GSDMB modulated hyperactive unfolded protein response of IECs by up-regulating BHLHA15 to mediate intestinal barrier injury. Rosa26-lsl/lsl-GSDMB-MU;Villin-Cre mice with the mutant rs2305480 of GSDMB aggravated such inflammatory effects.

Conclusion

We have uncovered an important and previously unrecognized role of GSDMB in intestinal homeostasis, which represents a potential therapeutic target for intestinal inflammation.
Revisiting ascending aortic resection in the elective valve-sparing root replacement: assessing the benefits and necessity of hemiarch replacement at three centres
Authors: Yildiz Murat , Schoenhoff Florian , Werdecker Victoria , Nucera Maria , Mosbahi Selim , Zhao Yu , Goel Nicholas , Berezowski Mikolaj , Lawrence Kendall , Kapoor Sankrit , Kreibich Maximillian , Berger Tim , Kletzer Joseph , Bavaria Joseph , Szeto Wilson Y , Siepe Matthias , Czerny Martin , Desai Nimesh D
Published: January 2025

OBJECTIVE

The aim of this study was to determine the indication and optimal timing for performing a hemiarch procedure in patients undergoing valve-sparing root replacement (VSRR).

METHODS

We conducted a retrospective study on 986 patients undergoing VSRR at three tertiary care centres. Inclusion criteria were all patients undergoing elective VSRR. Exclusion criteria were age <18 years, Stanford type A dissection, dissection in the arch, total aortic arch replacement or previous aortic arch replacement. We performed propensity score matching in a 1:1 ratio. The primary end-point is a composite outcome that includes mortality, aortic arch reintervention, new aortic dissection during follow-up and cerebrovascular incidents within the first 30 days.

RESULTS

A total of 401 patients (41%) had a hemiarch replacement, while 585 (59%) did not. Root phenotype was present in 565 (57%). The mean follow-up time was 4.7 years (SD ± 4.6). In the matched population, there was no significant difference in the 10-year freedom from the composite outcome between the non-hemiarch and hemiarch groups (87.3% vs 85.0%, P > 0.999). Similarly, no difference was found for aortic reinterventions (P = 0.13) or survival (P = 0.5). This was also true for patients with heritable thoracic aortic disease. However, in patients with a bicuspid aortic valve, the intervention rate was significantly higher in the hemiarch group (10.8% vs 0%, P = 0.016). There was no significant difference in the 30-day incidence of cerebrovascular accidents between the groups (5% vs 2.7% in the hemiarch group, P = 0.117). Only the distal ascending diameter showed a tendency with better outcome over 45 mm for the hemiarch procedure; otherwise, we found no reliable cut-off values based on ascending length, diameter-to-height index or ascending length-to-height index.

CONCLUSIONS

Our findings conclusively demonstrate that concomitant hemiarch replacement does not increase the perioperative risk in young patients undergoing VSRR. However, concomitant replacement does not seem to protect from aortic reinterventions during medium-term follow-up.
Mild autonomous cortisol secretion in patients with aldosterone-producing adenoma and risk for cardiac remodeling and diastolic dysfunction
Authors: Tsai Cheng-Hsuan , Liao Che-Wei , Wu Xue-Ming , Chen Zheng-Wei , Pan Chien-Ting , Chang Yi-Yao , Lee Bo-Ching , Chou Chia-Hung , Chang Chin-Chen , Wu Vin-Cent , Hung Chi-Sheng , Vaidya Anand , Lin Yen-Hung
Published: January 2025

Background

Mild autonomous cortisol secretion (MACS) is common in adrenal adenomas, including patients with primary aldosteronism (PA) with aldosterone-producing adenomas (APA). This study investigated the impact of MACS on cardiac remodeling and diastolic dysfunction in patients with APA.

Methods

We prospectively enrolled 483 patients with APA. MACS was defined as a cortisol level >1.8 μg/dL after an overnight dexamethasone-suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and one-year following targeted treatments.

Results

In this prospective cohort, 21% of patients with APA had concurrent MACS. Patients with MACS were older, had a higher prevalence of diabetes, larger adrenal tumor size, higher left ventricular mass index (LVMI), and worse diastolic function (E/e′). Multivariable linear regression analysis showed that concurrent MACS with APA was an independent risk factor for higher LVMI and worse E/e′. Among patients who underwent adrenalectomy, both those with and without MACS showed significant improvements in LVMI and E/e′. In contrast, among patients who received mineralocorticoid receptor antagonist (MRA) treatment, significant LVMI improvement was only observed in patients without MACS. MRA therapy did not improve E/e′ regardless of the presence or absence of MACS.

Conclusions

The presence of MACS in patients with PA was associated with worse cardiac hypertrophy and diastolic dysfunction. Surgical adrenalectomy was able to effectively reverse cardiac remodeling in patients with PA and concurrent MACS; however, MRA therapy was not associated with significant improvements in cardiac function. These findings highlight the independent deleterious effects of cortisol on cardiovascular disease in PA.
Hypertrophic cardiomyopathy: prevalence of disease-specific red flags
Authors: Maurizi Niccolò , Monda Emanuele , Biagini Elena , Field Ella , Passantino Silvia , Dall' Aglio Gabriella , Fumagalli Carlo , Antiochos Panagiotis , Skalidis Ioannis , Pieroni Maurizio , Argirò Alessia , Girolami Francesca , Cecchi Franco , Barbey Frederic , Monney Pierre , Elliott Perry M , Kaski Juan Pablo , Limongelli Giuseppe , Olivotto Iacopo
Published: January 2025

Background and Aims

The European Society of Cardiology guidelines recommend a systematic search for diagnostic clues or ‘red flags’ (RFs) in patients with hypertrophic cardiomyopathy (HCM) to better tailor disease management. To date, the prevalence and clinical significance of RF associated with HCM phenotypes in different clinical settings are unknown.

Methods

The study cohort comprised 818 patients with a clinical diagnosis of HCM [479 (62%) males, mean age 49 ± 21 years] referred to four European centres. Pre-specified RFs were categorized into one of five domains: (i) family history; (ii) physical examination; (iii) electrocardiography; (iv) echocardiography; and (v) laboratory.

Results

A total of 318 (39%) patients had a pathogenic or likely pathogenic sarcomere gene variant; 240 (29%) a TTR and GLA variant; 154 (19%) a syndromic cause; and 106 (13%) no identifiable cause. In the overall cohort, 2979 RFs were identified. Of these, 1018 (34%) were identifiable from clinical history and examination alone (generalist setting) and 1961 (66%) by 12-lead electrocardiogram and echocardiography (cardiologist’s office). Non-sarcomeric patients were diagnosed more often aged <20 and after 60 years (476/500, 95%). Syndromic diseases such as Rasopathies, inherited metabolic disorders, and mitochondrial disorders were diagnosed in neonatal/early childhood (mean age 3 ± 2 years), whereas patients with Danon disease, Friedreich’s ataxia, Noonan syndrome, and PRKAG2 cardiomyopathy were identified mostly during adolescence (mean age 16 ± 8 years). Non-cardiac RFs identified by clinical history, physical examination, and routine laboratory testing were most frequent in patients with HCM caused by Rasopathies, inherited metabolic disorders, and mitochondrial disorders (48%, 47%, and 57%, respectively). Physical RFs were almost exclusively observed in patients with a definite non-sarcomeric aetiology [348/350 (99%)]. On the contrary, most RFs associated with geno-positive and geno-negative HCM were derived from electrocardiogram and echocardiography [692/990 (70%) and 332/375 (88%), respectively].

Conclusions

Red flags are a common finding in patients presenting with HCM, most commonly non-cardiac in non-sarcomeric aetiology and cardiac in sarcomeric HCM. Over 34% of RF, most relevant to rare HCM phenocopies, can be potentially detected in a generalist setting. Investing in high-touch-low tech, widespread awareness for HCM-related RF may provide substantial advantage in terms of diagnostic yield and appropriate use of resources.
Effects of changes to income tax and devolved benefits in Scotland on health inequalities: a modelling study
Authors: Richardson Elizabeth , Walsh David , McCartney Gerry , Pulford Andrew , Robinson Mark
Published: January 2025

There is a well-understood relationship between inequalities in income and health. We assessed how changes to income tax and social security—options recently devolved to the Scottish Government—could affect income and life expectancy inequalities. We used the microsimulation model UKMOD to estimate policies’ effects on household income distribution by socioeconomic deprivation, compared to baseline (Scottish income tax schedule for 2022/23). We then used the ‘Triple I’ (Informing Interventions to reduce health Inequalities) scenario modelling approach to estimate mortality effects for the income changes and calculated inequalities in life expectancy at birth. Scenario health impacts were determined largely by how much money they gave or took from households in the most deprived areas. Policies that increased incomes for households in deprived areas tended to reduce inequalities in life expectancy. Although we found this also applied to tax-cutting policies that increased income inequality, our estimates did not account for the public spending cuts that these costly policies would necessitate and their likely widening effect on health inequalities. Combining the best-performing (i.e. greatest positive impact) revenue-generating and revenue-spending policies we modelled—tax increases targeted at high earners and a doubling the value of social security benefits—would generate net revenue while reducing income inequality by approximately 10% and inequalities in life expectancy by 8% to 9%, but sizeable inequalities would remain. A multifaceted approach based on combinations of policies—including, but not limited to, bolder income tax measures—is required to achieve meaningful reductions in inequalities.
Reference genome of Calochortus tolmiei Hook. & Arn. (Liliaceae), a cat's ear mariposa lily
Authors: Landis Jacob B , Harden Julianna J , Eifler Evan , Buttelman Gretta L , Hernández Adriana I , Givnish Thomas J , Strickler Susan R , Specht Chelsea D
Published: January 2025

Calochortus tolmiei Hook. & Arn., a bulbous monocot with cat's ear flowers in the angiosperm family Liliaceae, is a perennial herb native to northern California, Oregon, and Washington. Calochortus exhibits substantial morphological and karyotype diversity with multiple floral forms and a haploid chromosome number varying from 6 to 10. Here, we present the first high-quality reference assembly in Liliaceae for C. tolmiei, with a scaffolded assembly of 2.9 Gb with an N50 of 296 Mb. Notably, 92% of the assembled genome is scaffolded into 10 pseudomolecules, matching the documented chromosome count of C. tolmiei. The genome contains 31,049 protein-coding genes, with 86.2% being functionally annotated. The closest reference-quality genome assembly to C. tolmiei is from Chionographis japonica (Willd.) Maxim. (Melianthiaceae), which diverged ∼83 Mya, providing a valuable genomic resource in the Liliales, an order which lacks genomic resources.
Disentangling Selection Into Mode From Mode Effects
Authors: O’Muircheartaigh Colm , Schumm L Philip , English Ned , Curtis Becki
Published: January 2025

Objectives

We investigate the impact of data collection mode on responses to variables in the National Social Life, Health, and Aging Project (NSHAP) Round 4 and discuss how potential mode differences should (and should not) be addressed in substantive analyses.

Methods

Among the set of respondents who were eligible to be contacted remotely in Round 4, we randomly selected 398 to be contacted instead for an in-person interview. We compare response rates and the distributions of selected key outcomes among those 398 respondents to those among the control group who were initially approached remotely. In contrast, we compared all R4 respondents according to the mode in which they completed the interview, including those not part of the randomized experiment.

Results

Among those included in the experiment, there was no evidence of systematic differences in responses to physical and mental health questions between remote and in-person modes, nor in responses to number recall measures. In-person respondents scored moderately lower on cognitive function measures requiring careful attention to a figure and/or task, though this difference became less with each similar item. Remote respondents named fewer social network members. Comparing all respondents according to their final mode yielded substantially different results in all cases.

Discussion

Mode did not appear to affect reports of physical and mental health based on a randomized comparison, though it did moderately affect other items in predictable ways. Naïve estimates of mode effects based on comparing all respondents according to mode yielded misleading results, and should not be used to adjust for mode differences in analyses.
Interleukin 6 Is Significantly Increased in Severe Pneumonia After Allo-Hematopoietic Stem Cell Transplantation and Might Induce Lung Injury via IL-6/sIL-6R/JAK1/STAT3 Pathway
Authors: Zhou Jing-Rui , Liao Yi , Cao Le-Qing , Ma Rui , He Yun , Li Na , Zhu Dan-Ping , Zhao Xiao-Su , Huang Xiao-Jun , Sun Yu-Qian
Published: January 2025

Background

Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokines, including interleukin 6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe coronavirus disease 2019 (COVID-19), we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia after allo-HSCT and explore its underlying mechanism.

Methods

Serum cytokine levels were prospectively measured in patients with severe and nonsevere pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiments using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI.

Results

Serum IL-6 and soluble IL-6 receptor (sIL-6R) levels were higher in the severe pneumonia group than in the nonsevere group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses.

Conclusions

IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.
Estimation for Nearest Neighbor Imputed Survey Data
Authors: Xia Xintao , Zhang Xiaofei , Fuller Wayne A
Published: January 2025

Nearest neighbor imputation is a popular procedure used to complete missing records. However, the nearest neighbor imputation estimator suffers from a bias that increases as the dimension of the matching variable increases. We study estimators that are model unbiased and have the hot-deck property. Estimation for domains is discussed. In the simulation study for the population mean, a proposed estimator is less biased and more efficient than the nearest neighbor estimator. The suggested replication variance estimator does not require repeated imputation and is appropriate for vectors with different missing patterns. In the simulation, the variance estimator gives confidence intervals with coverage rates close to the nominal level.
Engineered initiator tRNAs can effectively start translation at non-AUG start codons and diversify N-terminal amino acids for mRNA Display
Authors: Helmling Christina , Chan Alix I , Cunningham Christian N
Published: January 2025

mRNA display is an effective tool to identify high-affinity macrocyclic binders for challenging protein targets. The success of an mRNA display selection is dependent on generating highly diverse libraries with trillions of peptides. While translation elongation can canonically accommodate the 61 proteinogenic triplet codons, translation initiation is restricted to the native start codon AUG. Here, we investigate the ability of the Escherichia coli ribosome to initiate translation for 31 initiator tRNA (tRNAini) anticodon mutants at their respective cognate start codon using a NanoBiT translation assay. We show that the ability of those anticodon mutant tRNAsini to initiate translation is highly variable and is, in part, inhibited by tRNA misfolding induced by the anticodon mutations. We demonstrate based on two distinct misfolding patterns that translation efficiency can be effectively restored by introducing additional mutations that restore the active tRNA fold. We then used 10 of the engineered tRNAsini in a mutational analysis experiment for three reported macrocyclic peptides binding to Ubiquitin Specific Protease 7 (USP7). The observed enrichment of peptides correlates strongly with dissociation constants measured by surface plasmon resonance, and provides insights into the structure–activity relationship of the N-terminal amino acid without the requirement for peptide synthesis.