bluuebunny/crossref_metadata_2025 huggingface dataset:
Farm characteristics determine why a large share of organically produced wine is not labelled as organic
Authors: Zachmann Lucca , McCallum Chloe , Finger Robert
Published: November 2024

Organic agricultural production is increasing globally and is of high policy relevance, particularly in Europe. Various measures incentivize farmers to adopt organic practices, such as direct payments and labelling. We here address a rarely considered aspect of organic production, that not all organic producers in Europe opt for organic labelling for their products at the point of sale. We investigate the discrepancy between organic production and labelling in Swiss viticulture. Out of 115 grapevine growers who adhere to organic principles in production, 43.5% do not use organic labelling when marketing their wines. We find that especially farms using alternative labelling strategies (e.g. for fungus-resistant varieties), smaller farms and farms less specialized in viticulture to be more likely to forgo organic labelling. We draw conclusions for policy and science. For example, our findings show that there may be, for some crops, more organic products on shelves than indicated from sales statistics of organically labelled products. The use of statistics that indicate the share of sales of organic products for specific products and food sales at large may thus be misleading.
Enhancing regeneration and functionality of excitable tissues via integrating bioelectronics and bioengineered constructs
Authors: Meng Zijie , Gu Bingsong , Yao Cong , Li Jiaxin , Yu Kun , Ding Yi , He Pei , Jiang Nan , Li Dichen , He Jiankang
Published: November 2024

The inherent complexities of excitable cardiac, nervous, and skeletal muscle tissues pose great challenges in constructing artificial counterparts that closely resemble their natural bioelectrical, structural, and mechanical properties. Recent advances have increasingly revealed the beneficial impact of bioelectrical microenvironments on cellular behaviors, tissue regeneration, and therapeutic efficacy for excitable tissues. This review aims to unveil the mechanisms by which electrical microenvironments enhance the regeneration and functionality of excitable cells and tissues, considering both endogenous electrical cues from electroactive biomaterials and exogenous electrical stimuli from external electronic systems. We explore the synergistic effects of these electrical microenvironments, combined with structural and mechanical guidance, on the regeneration of excitable tissues using tissue engineering scaffolds. Additionally, the emergence of micro/nanoscale bioelectronics has significantly broadened this field, facilitating intimate interactions between implantable bioelectronics and excitable tissues across cellular, tissue, and organ levels. These interactions enable precise data acquisition and localized modulation of cell and tissue functionalities through intricately designed electronic components according to physiological needs. The integration of tissue engineering and bioelectronics promises optimal outcomes, highlighting a growing trend in developing living tissue construct-bioelectronic hybrids for restoring and monitoring damaged excitable tissues. Furthermore, we envision critical challenges in engineering the next-generation hybrids, focusing on integrated fabrication strategies, the development of ionic conductive biomaterials, and their convergence with biosensors.
Impact of data bias on machine learning for crystal compound synthesizability predictions
Authors: Davariashtiyani Ali , Wang Busheng , Hajinazar Samad , Zurek Eva , Kadkhodaei Sara
Published: November 2024

Machine learning models are susceptible to being misled by biases in training data that emphasize incidental correlations over the intended learning task. In this study, we demonstrate the impact of data bias on the performance of a machine learning model designed to predict the likelihood of synthesizability of crystal compounds. The model performs a binary classification on labeled crystal samples. Despite using the same architecture for the machine learning model, we showcase how the model’s learning and prediction behavior differs once trained on distinct data. We use two data sets for illustration: a mixed-source data set that integrates experimental and computational crystal samples and a single-source data set consisting of data exclusively from one computational database. We present simple procedures to detect data bias and to evaluate its effect on the model’s performance and generalization. This study reveals how inconsistent, unbalanced data can propagate bias, undermining real-world applicability even for advanced machine learning techniques.
An efficient Wasserstein-distance approach for reconstructing jump-diffusion processes using parameterized neural networks
Authors: Xia Mingtao , Li Xiangting , Shen Qijing , Chou Tom
Published: November 2024

We analyze the Wasserstein distance (W-distance) between two probability distributions associated with two multidimensional jump-diffusion processes. Specifically, we analyze a temporally decoupled squared W
2-distance, which provides both upper and lower bounds associated with the discrepancies in the drift, diffusion, and jump amplitude functions between the two jump-diffusion processes. Then, we propose a temporally decoupled squared W
2-distance method for efficiently reconstructing unknown jump-diffusion processes from data using parameterized neural networks. We further show its performance can be enhanced by utilizing prior information on the drift function of the jump-diffusion process. The effectiveness of our proposed reconstruction method is demonstrated across several examples and applications.
The paradox of safe milk supply by small-scale dairy farmers in Sub-Saharan Africa: insights based on current practices in Malawi
Authors: Njombwa Chunala A , Chisambi Cornellius , Chris McCarthy
Published: November 2024

This research paper aimed to assess milking and milk handling practices among small-scale dairy farmers and to determine the presence of Escherichia coli (E. coli) in raw and processed liquid milk in Malawi. A total of 113 dairy farmers were interviewed across three agroecological zones of Malawi. Eighty-seven (87) processed and raw milk samples were collected from selected food stores and dairy farms and tested for E. coli. Ninety-five percent of small-scale dairy farmers had at most 2 milking cows, with a daily average milk production of less than 10 l. Sixty-nine percent cleaned milking utensils using untreated water, and the farmers had no refrigerators. Eighty-eight percent held raw milk for over 6 h at room temperature. E. coli was found to be widely distributed in raw milk (76%) and pasteurized milk (75%), averaging 5.38 ± 1.82 and 2.47 ± 1.02 log cfu ml−1, respectively. In conclusion, this study demonstrates that Malawian small-scale dairy farmers employ poor milking and post-milking practices, which compromise the socioeconomic environment of small-scale dairy farmers.
Source-specific acute cardio-respiratory effects of ambient coarse particulate matter exposure in California’s Salton Sea region
Authors: Miao Yaning , Porter William C , Benmarhnia Tarik , Lowe Catherine , Lyons Timothy W , Hung Caroline , Diamond Charles
Published: November 2024

Windblown dust is an ongoing air quality and public health concern among residents living around California’s Salton Sea, a region characterized by critical socioeconomic and health outcome disparities. Dropping water levels and unique biogeochemistry at the Salton Sea have raised concerns regarding the human health impacts of drying sediments exposed on shrinking shorelines, as well as potential lake spray emissions from the water surface itself. As particles emitted from different surface types can differ greatly in terms of composition, size distribution, and other properties, variability in the resulting health impacts of windblown particulates reaching communities in the region may likewise be source dependent. However, these potential effects remain understudied. Here we use observed coarse particulate matter (PMc) concentrations and modeled atmospheric back trajectories along with land surface data to estimate individual source region contributions to particulates observed at long term surface air quality monitoring sites in the Salton Sea region. We then apply these data products to an analysis of source-specific acute cardio-respiratory impacts using a time-stratified case crossover design with conditional logistic regression based on 171 465 hospitalizations cases recorded from 2008 to 2019. To assess source-specific health impacts, we quantify and compare the acute health effects of dust arriving from different directions and from over different source surfaces on daily respiratory and cardiovascular hospitalizations. Using a remote sensing chlorophyll-a data product, we further investigate the possible influence of periodic bloom events—a result of ongoing nutrient loading into the Salton Sea—on those hospitalizations. Results suggest that a 10 μg m−3 increase in coarse PM coming from over the Salton Sea is associated with an 8.6% (Risk Ratio, RR = 1.086, 95% CI: 1.028–1.147) increased risk of respiratory hospital admissions; increases that are greater than those for dust likely originating from other surface types. Furthermore, we find even higher RR values for dust associated with Salton Sea back trajectories during bloom events: a 24.9% (RR = 1.249 95% CI: 1.031–1.514) increased risk in respiratory hospitalization. Our findings suggest that exposure to dust and aerosols potentially originating from the Salton Sea or surrounding surfaces is associated with increased respiratory hospitalizations, especially during observed bloom events. Further research is needed to determine the underlying mechanisms responsible for these health impacts, as well as possible primary or secondary preventive strategies.
Natural assets, changes, and variations of the socioeconomic-environmental systems along the Asian drylands belt
Authors: Chen Jiquan , John Ranjeet , Kolluru Venkatesh , Mack Elizabeth A , Fan Peilei , Yuan Jing , Ouyang Zutao , Chen Jingyan , Groisman Pavel , Shao Changliang , Amartuvshin Amarjargal , Gutman Garik
Published: November 2024

The amount of and changes in a country’s natural assets are crucial for developing national strategic plans and policies due to their foundational role in determining the resilience of social-environmental systems (SES), especially under a changing climate. Many integrated metrics on natural assets have been proposed based on individual measures to provide insights into the state of national natural resources. This is particularly true for countries experiencing extreme environmental stresses. Drawing on longitudinal data spanning from 1980 to 2020, the objective of this study is to analyze nuanced distinctions across 23 political entities (PEs) in the dryland regions of mid-latitudinal Asia, investigating their interannual variabilities over the four-decade study period and discerning potential driving forces. We examined three key integrated measures of the SES: ecosystem water use efficiency, human appropriation of net primary production, and human appropriation of water resources. We found increased variability as well as spikes in extreme values in each of these three measures of SES function among the 23 PEs over the study period. Water stress played an increasing and more important role than temperature in influencing the magnitude and variations of the three measures. Our results also indicate that human interventions may help increase the efficiency of water use in this dryland region of the world.
Stable behavior of Frobenius powers over a general hypersurface
Authors: Miller Claudia , Rahmati Hamidreza , R. G. Rebecca
Published: November 2024

The main goal of this paper is to prove, in positive characteristic

p
p

, stability behavior for the graded Betti numbers in the periodic tails of the minimal resolutions of Frobenius powers of the homogeneous maximal ideals for very general choices of hypersurface in three variables whose degree has the opposite parity to that of

p
p

. We also find some of the structure of the matrix factorization giving the resolution. We achieve this by developing a method for obtaining the degrees of the generators of the defining ideal of an

c

\mathfrak {c}

-compressed Gorenstein Artinian graded algebra from its socle degree, where

c

\mathfrak {c}

is a Frobenius power of the homogeneous maximal ideal. As an application, we also obtain the Hilbert–Kunz function of the hypersurface ring, as well as the Castelnuovo–Mumford regularity of the quotients by Frobenius powers of the homogeneous maximal ideal.
Portraits of Religious Conversions
Authors: John Aruthuckal Varughese
Published: November 2024

Chapter 4 analyses the interreligious strife that has become common in India, focusing on the issue of religious conversion. The chapter argues that the conflicts related to conversion are manifestations of the cross-pressures within the condition of secularity in India. In particular, opposition to religious conversions reveals the way Christianity and the secular are seen as allies, even conflated, by many Hindus, based in part on the association of Christian missions with colonialism. In addition, though, religious conversions, which assume individual volition and threaten social hierarchy, can be perceived by orthodox Hindus as a betrayal of culture and a danger to a social fabric infused with the sacred.
Religious Freedom, Truth-Predicates, and the Ghent School
Authors: John Aruthuckal Varughese
Published: November 2024

Chapter 5 examines one prominent attempt to relieve the cross-pressures surrounding religious freedom: the Ghent School’s challenge to the classical notion of religious freedom as freedom to convert. S. N. Balagangadhara, Jakob De Roover, and some others have argued that the Indian Constitution’s definition of freedom of religion results from Judaeo-Christian religious doctrine rather than from the Hindu tradition. Underlying this argument is the assumption that conceptions of religious freedom function as subsets of religious doctrine. This, in their view, entails a conflict, in which the Constitution’s conception of religious freedom conflicts with the Hindu conception of religious freedom. However, the central assumption of the Ghent School’s argument, that truth-predicates are unique to Semitic religious beliefs and therefore alien to Hinduism, is false. By using Śivapurāṇa as a case in point, this chapter illustrates that Hinduism has a robust idea of truth. It also argues that all human beliefs, religious or otherwise, possess truth-predicates. If truth-predicates are tied to religious beliefs, contrary to the Ghent School’s claim, then the secularism of India’s Constitution cannot be dismissed as alien to Indian culture on these grounds. Religious freedom grounded in the equality of individuals rather than the equality of religious beliefs does not entail a privileging of Semitic religions over Hinduism.
Clinical biomarker–based biological ageing and the risk of adverse outcomes in patients with chronic kidney disease
Authors: Xiang Hao , Huang Yu , Zhang Yuanyuan , He Panpan , Ye Ziliang , Yang Sisi , Zhang Yanjun , Gan Xiaoqin , Hou Fan Fan , Qin Xianhui
Published: November 2024

Objective

Patients with chronic kidney disease (CKD) show features of premature ageing. We aimed to evaluate the association between biological ageing and adverse outcomes, including end-stage kidney disease (ESKD), cardiovascular diseases (CVD) and all-cause mortality, in patients with CKD.

Methods

23 435 participants with CKD and free of related adverse outcomes at baseline from the UK Biobank were included. Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction assay. Clinical biomarker–based biological ages were quantified using Klemera–Doubal method biological age (KDM-BA) and PhenoAge algorithms.

Results

During a median follow-up of 12 years, 3417 incident CVD, 383 incident ESKD and 3195 all-cause mortality were recorded. Per SD increment of KDM-BA acceleration was associated with a 56% [95% confidence interval (CI): 41%–73%], 26% (95% CI: 21%–31%) and 39% (95% CI: 34%–44%) increase in the risk of incident ESKD, incident CVD and all-cause mortality, respectively. Similar results were found for PhenoAge acceleration. LTL (per SD increment) was inversely associated with the risk of incident CVD [hazard ratio (HR): 0.96, 95% CI: 0.92–0.99] and all-cause mortality (HR: 0.94, 95% CI: 0.91–0.98) and was not significantly associated with the risk of incident ESKD (HR: 0.96, 95% CI: 0.86–1.06). Adding KDM-BA acceleration or PhenoAge acceleration, but not LTL, to the traditional validated clinical prediction models significantly improved the predictive performance for incident ESKD, all-cause mortality and CVD.

Conclusion

In patients with CKD, both KDM-BA acceleration and PhenoAge acceleration were associated with an increased risk of ESKD, CVD and all-cause mortality, and KDM-BA or PhenoAge may be a better predictor on adverse outcomes than LTL.
Social Media and the Unmediated in Early African Americanist Scholarship
Authors: Saillant John
Published: November 2024

The Odyssey of Phillis Wheatley: A Poet’s Journeys through American Slavery and Independence (2023), by David Waldstreicher, analyzes Wheatley in her context in Revolutionary America. Waldstreicher provides reasonable interpretation of her poetry, especially fine for his understanding of her classical allusions. An added bonus is an appendix of anonymous poems that he argues should be attributed to her. His book is guided by a conviction that Wheatley must have been—and must be recognized today as—important. By this, he means influential in her time. His definition of influence seems to draw from early twenty-first-century social media, finding power in touching many people through words and images. Print was, he writes, “the internet of the eighteenth century” (41). Reading Pleasures: Everyday Black Living in Early America (2023), by Tara A. Bynum, expresses a parallel relationship to social media. She discusses #BlackLivesMatter, while her scholarship itself is often discussed in social media. The immediacy and ubiquity of social media in our lives give us a sense of unmediated access to those we encounter in it. In this, Bynum shines on and with the printed page. Her focus is Black pleasure in scenes in which scholars have slighted it—friendship, religion, revolution, even the talking book.
Orchid phylogenetics and evolution: history, current status and prospects
Authors: Freudenstein John V
Published: November 2024

Background

Orchidaceae are one of the two largest families of angiosperms; they exhibit a host of changes – morphological, ecological and molecular – that make them excellent candidates for evolutionary study. Such studies are most effectively performed in a phylogenetic context, which provides direction to character change. Understanding of orchid relationships began in the pre-evolutionary classification systems of the 1800s, which were based solely on morphology, and now is largely based on genomic analysis. The resulting patterns have been used to update family classification and to test many evolutionary hypotheses in the family.

Scope

Recent analyses with dense sampling and large numbers of nuclear loci have yielded well-supported trees that have confirmed many longstanding hypotheses and overturned others. They are being used to understand evolutionary change and diversification in the family. These include dating the origination of the family, analysis of change in ecological habit (from terrestrial to epiphytic and back again in some cases), revealing significant plastid genome change in leafless holomycotrophs, studying biogeographic patterns in various parts of the world, and interpreting patterns of fungal associations with orchids.

Conclusions

Understanding of orchid relationships has progressed significantly in recent decades, especially since DNA sequence data have been available. These data have contributed to an increasingly refined classification of orchids and the pattern has facilitated many studies on character evolution and diversification in the family. Whole-genome studies of the family are just beginning and promise to reveal fine-level details underlying structure and function in these plants, and, when set in a phylogenetic context, provide a much richer understanding of how the family has been so successful in diversification.
Source–sink manipulations through shading, crop load and water deficit affect plant morphogenesis and carbon sink priorities leading to contrasted plant carbon status in grapevine
Authors: Poupard Magali , Gallo Agustina , Boulord Romain , Guillem Pablo , Rolland Gaëlle , Simonneau Thierry , Christophe Angélique , Pallas Benoît
Published: November 2024

Background and Aims

Shading, water deficit and crop load shape plant development in a very plastic way. They directly influence the plant’s carbon supply and demand to and from the different organs via metabolic, hydraulic and hormonal mechanisms. However, how the multiple environmental factors combine through these mechanisms and how they interplay with carbon status, vegetative and reproductive development and carbon assimilation of the plant needs to be investigated in the context of current climatic and technological constraints.

Methods

With this aim, two experiments were conducted on potted grapevines, subjected to ten combinations of treatments. Leaf area growth rates, berry characteristics at harvest (weight, number and total soluble content) and a series of leaf traits (gas exchanges, non-structural carbohydrate contents, water potential and SPAD [Soil–Plant Analysis Development] values) were measured.

Key Results

Grapevine development showed different responses corresponding to different sink priorities: under shade, vegetative development was maintained at the expense of berries, whereas under high crop load and water deficit, berry growth was the priority sink. These responses were accompanied by changes in specific leaf area in agreement with the shade avoidance syndrome. These different strategies affected plant carbon status as estimated through starch content in leaves. Leaf starch content was not affected by shade, while it decreased under water deficit and crop load conditions. Carbon assimilation was decreased under water deficit, low crop load and shading conditions. Hydraulic properties and leaf nitrogen content correlated with this decrease while plant carbon status had a very low impact. Finally, no major interaction between the different types of constraint was observed on both morphological and functional variables.

Conclusions

Depending on the type of abiotic constraints, grapevine exhibits specific morphogenetic responses at plant and leaf levels. The absence of interaction between the different constraints showed that grapevine is able to exhibit independent responses to shade and water deficit. This result is of major importance for the further design of new agricultural systems facing multiple abiotic constraints, such as those in agroforestry and agrivoltaic systems.
Ripples in the Historiography: Harlem Studio Photographer James Van Der Zee and Cecil Beaton’s New York, 1938
Authors: Chesnutt Boone Emilie
Published: November 2024

In 1938, the well-known British photographer Cecil Beaton published his travelogue Cecil Beaton’s New York for American and British audiences. The book was the first to publish and consider works by the African American studio photographer James Van Der Zee. Yet this account of Van Der Zee has been overlooked by scholars and relegated to footnotes, feasibly because of Beaton’s dismissive and tactless consideration of the now highly regarded photographer. With commitments to exploring the overlooked and unexpected moments in Van Der Zee’s historiography, this essay approaches Cecil Beaton’s New York as an opportunity to begin thinking about Van Der Zee in ways that transgress established narratives. It does so by inserting Van Der Zee within an avant-garde circle in which he is rarely considered, and attending to the possibility of an early-twentieth century-critical Black readership of Beaton’s book. With the aim of centring Van Der Zee, this essay demonstrates his relevance to a multitude of interwar contexts animated by the practice of photography. As a result, it becomes conceivable to shift the very terms through which we interpret the early account of Van Der Zee’s work, and the transatlantic contexts that scholars may choose to consider.
Is Vibration Anesthesia Effective and Safe for Pain Reduction in Botulinum Toxin Injection? A Randomized Split-Face Controlled Trial and Cadaver Experiment
Authors: Hua Tianzhen , Li Huan , Liang Chun , Zhang Guangliang , Luo Libo , Jia Haoran , Liu Xin , Chi Yuan , An Yang , Chen Youbai
Published: November 2024

Background

Pain is an important issue in botulinum toxin injection. Vibration anesthesia is a noninvasive method for pain alleviation, but few studies have reported its use during botulinum toxin injection.

Objectives

The aim of this study was to investigate whether vibration anesthesia was effective and safe for pain reduction during botulinum toxin injection for masseter reduction.

Methods

A randomized split-face controlled trial was performed in patients who required masseter reduction. Vibration anesthesia was randomly administered on either side. Study outcomes were pain scores on a visual analog scale, duration of effect, satisfaction, and complications. Intergroup comparison and linear regression analyses were performed.

Results

In a total of 216 patients, the pain score on the vibration side (2.97 ± 1.44) was significantly lower than that on the nonvibration side (4.72 ± 2.13) (P < .0001), with a higher proportion of mild pain. Linear regression showed that a history of injection and more injection points and doses increased the pain, whereas a 2-mL syringe reduced the pain compared to a 1-mL syringe. Side effects were found in 19 patients and 21 sides (7%), but were not associated with vibration. High satisfaction was reported. A cadaver experiment confirmed that vibration did not alter the diffusion radius and depth of injection.

Conclusions

Vibration anesthesia significantly relieved pain during botulinum toxin injection for masseter reduction, and it did not cause adverse effects and or affect duration of effect. Therefore, we recommend vibration anesthesia, a larger syringe size, and fewer injection points to improve patient experience and satisfaction.

Level of Evidence: 3 (Therapeutic)
Optimizing multi-omics data imputation with NMF and GAN synergy
Authors: Ansari Md Istiaq , Ahmed Khandakar Tanvir , Zhang Wei
Published: November 2024

Motivation

Integrating multiple omics datasets can significantly advance our understanding of disease mechanisms, physiology, and treatment responses. However, a major challenge in multi-omics studies is the disparity in sample sizes across different datasets, which can introduce bias and reduce statistical power. To address this issue, we propose a novel framework, OmicsNMF, designed to impute missing omics data and enhance disease phenotype prediction. OmicsNMF integrates Generative Adversarial Networks (GANs) with Non-Negative Matrix Factorization (NMF). NMF is a well-established method for uncovering underlying patterns in omics data, while GANs enhance the imputation process by generating realistic data samples. This synergy aims to more effectively address sample size disparity, thereby improving data integration and prediction accuracy.

Results

For evaluation, we focused on predicting breast cancer subtypes using the imputed data generated by our proposed framework, OmicsNMF. Our results indicate that OmicsNMF consistently outperforms baseline methods. We further assessed the quality of the imputed data through survival analysis, revealing that the imputed omics profiles provide significant prognostic power for both overall survival and disease-free status. Overall, OmicsNMF effectively leverages GANs and NMF to impute missing samples while preserving key biological features. This approach shows potential for advancing precision oncology by improving data integration and analysis.

Availability and implementation

Source code is available at: https://github.com/compbiolabucf/OmicsNMF.
Protein structure alignment by Reseek improves sensitivity to remote homologs
Authors: Edgar Robert C
Published: November 2024

Motivation

Recent breakthroughs in protein fold prediction from amino acid sequences have unleashed a deluge of new structures, presenting new opportunities and challenges to bioinformatics.

Results

Reseek is a novel protein structure alignment algorithm based on sequence alignment where each residue in the protein backbone is represented by a letter in a “mega-alphabet” of 85 899 345 920 (∼1011) distinct states. Reseek achieves substantially improved sensitivity to remote homologs compared to state-of-the-art methods including DALI, TMalign, and Foldseek, with comparable speed to Foldseek, the fastest previous method. Scaling to large databases of AI-predicted folds is analyzed. Foldseek E-values are shown to be under-estimated by several orders of magnitude, while Reseek E-values are in good agreement with measured error rates.

Availability and implementation

https://github.com/rcedgar/reseek.
Topical application of the Hedgehog inhibitor patidegib in patients with Gorlin syndrome: a phase II trial
Authors: Lear John T , Harwood Catherine A , Hasan Zeeshaan , Kentley Jonathan , Thomson Jason , Khoo Andre , Alderman Alix , DeSouza Mark , Epstein Ervin H , Kochendoerfer Gerd G , Tang Jean Y
Published: November 2024

Background

Patients with Gorlin (basal cell naevus) syndrome (GS) have numerous phenotypic abnormalities due to overactivity of the hedgehog (HH) signalling pathway, most commonly caused by a heritable mutation in PTCH1, which encodes a major inhibitor of this pathway. Oral HH inhibitors (HHi) can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit–risk ratio, we developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop oral HHi treatment.

Objectives

To determine whether or not patidegib topical gel 2% or 4% can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects typical of oral HHi treatment.

Methods

We conducted a small randomized double-blinded phase IIA trial at two sites in the UK, to assess the clinical and molecular efficacy and adverse effects of 6 months of twice-daily application of patidegib topical gel to the entire face, as well as to treatment-targeted surgically eligible BCCs at other anatomical sites.

Results

Post hoc analyses suggested that patidegib topical gel reduced the number of new, surgically eligible BCCs and the level of HH signalling, with minimal adverse effects.

Conclusions

Patidegib topical gel warrants further clinical development.
Exploring the genetic driver events of eccrine poromas and porocarcinomas: a retrospective, cross-institutional study of 54 cases
Authors: Arends Mark J , Del Castillo Velasco-Herrera Martin , Cheema Saamin , Wong Kim , Boccacino Jacqueline M , Vermes Ian , Roberts Kirsty , Anderson Elizabeth , van der Horst Michiel P J , de Saint Aubain Nicolas , Alomari Ahmed K , Monteagudo Carlos , Billings Steven D , Frew Derek , Clarke Emily , Merchant William , Rajan Neil , Ferguson Peter , Mogler Carolin , Ferreira Ingrid , Brenn Thomas , van der Weyden Louise , Adams David J
Published: November 2024

We have comprehensively characterized the mutational landscape of eccrine poroma (EP) and eccrine porocarcinoma (EPC), uncovering novel molecular events and delineating different pathways of tumorigenesis underlying these tumours. EPs are driven largely by oncogenic fusion genes, whereas EPCs are driven largely by somatic mutations affecting various pathways, with a subset driven by fusion genes as the first oncogenic driver, and somatic mutations representing secondary events contributing to progression of the tumour. Fusion genes in EP predominantly involve YAP1, while those in EPC preferentially involve PAK gene family members.
Localized multiple spiradenomas are caused by somatic mosaicism in an ALPK1 hotspot mutation
Authors: Hirano-Lotman Yui , Ishida Yoshihiro , Doi Hiromi , Ogawa Seishi , Kabashima Kenji
Published: November 2024

Spiradenocarcinoma, a rare skin adnexal tumour, is linked to an ALPK1 hotspot mutation. This study reveals that spiradenocarcinoma, accompanied by multiple localized spiradenomas, is caused by somatic mosaicism in the ALPK1 mutation hotspot.
Mapping sentence comprehension and syntactic complexity: evidence from 131 stroke survivors
Authors: Biondo Nicoletta , Ivanova Maria V , Pracar Alexis L , Baldo Juliana , Dronkers Nina F
Published: November 2024

Understanding and interpreting how words are organized in a sentence to convey distinct meanings is a cornerstone of human communication. The neural underpinnings of this ability, known as syntactic comprehension, are far from agreed upon in current neurocognitive models of language comprehension. Traditionally, left frontal regions (e.g. left posterior inferior frontal gyrus) were considered critical, while more recently, left temporal regions (most prominently, left posterior middle temporal gyrus) have been identified as more indispensable to syntactic comprehension. Syntactic processing has been investigated by using different types of non-canonical sentences i.e. those that do not follow prototypical word order and are considered more syntactically complex. However, non-canonical sentences can be complex for different linguistic reasons, and thus, their comprehension might rely on different neural underpinnings. In this cross-sectional study, we explored the neural correlates of syntactic comprehension by investigating the roles of left hemisphere brain regions and white matter pathways in processing sentences with different levels of syntactic complexity. Participants were assessed at a single point in time using structural MRI and behavioural tests. Employing lesion–symptom mapping and indirect structural disconnection mapping in a cohort of 131 left hemisphere stroke survivors, our analysis revealed the following left temporal regions and underlying white matter pathways as crucial for general sentence comprehension: the left mid-posterior superior temporal gyrus, middle temporal gyrus and superior temporal sulcus and the inferior longitudinal fasciculus, the inferior fronto-occipital fasciculus, the middle longitudinal fasciculus, the uncinate fasciculus and the tracts crossing the most posterior part of the corpus callosum. We further found significant involvement of different white matter tracts connecting the left temporal and frontal lobes for different sentence types. Spared connections between the left temporal and frontal regions were critical for the comprehension of non-canonical sentences requiring long-distance retrieval (spared superior longitudinal fasciculus for both subject and object extraction and spared arcuate fasciculus for object extraction) but not for comprehension of non-canonical passive sentences and canonical declarative sentences. Our results challenge traditional language models that emphasize the primary role of the left frontal regions, such as Broca’s area, in basic sentence structure comprehension. Our findings suggest a gradient of syntactic complexity, rather than a clear-cut dichotomy between canonical and non-canonical sentence structures. Our findings contribute to a more nuanced understanding of the neural architecture of language comprehension and highlight potential directions for future research.
Development and Validation of Rapid and Cost-Effective RP-HPLC/UV Method for Determination of Cetirizine/Levocetirizine in Blood Plasma of Smokers and Non Smokers: a Two Cohort Comparative Study
Authors: Khattak Mashal , Iqbal Zafar , Jan Asif , Ali Niaz , Nasir Fazli , Shahbaz Naila
Published: November 2024

In this research study, a simple, rapid, sensitive, and cost-effective Reverse Phase High Performance Liquid Chromatography method was developed and validated for determination of Cetirizine and Levocetirizine in human plasma. The drugs were separated on an ACE Generix100–5 C18 RP (250 × 4.6 mm, 5 μm) column, using Acetonitrile and Distilled water pH 7 (59:41 v/v) as mobile phase with a flow rate of 1.5 mL/min, retention time of 3.39 ± 0.02 min, detection wavelength of 230 nm, and column oven temperature at 26°C. The drug was extracted from human plasma using Methanol, the percent recovery was 97%. The LOD and LOQ for Cetirizine and Levocetirizine were 0.5 ng and 1 ng. The method was linear over the concentration range of 0.5–1000 ng /mL for Cetirizine and Levocetirizine. The method was applied for analysis of drugs in plasma following oral administration of Cetirizine (10 mg) and Levocetirizine (5 mg) in smokers and nonsmokers of Pashtun ethnicity belonging from different districts of Khyber Pakhtunkhwa, Pakistan. The difference between Cetirizine plasma levels in smokers and non-smokers was significant with p -value 0.0279.
Impact of arteriovenous fistula formation on trajectory of kidney function decline: a target trial emulation
Authors: Loureiro Harrison Luis , Fu Edouard L , Thomson Peter C , Traynor Jamie P , Mark Patrick B , Stoumpos Sokratis
Published: November 2024

Background

Prior nonrandomized studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases.

Methods

We studied patients attending nephrology clinics in the West of Scotland during 2010–22 with an estimated glomerular filtration rate (eGFR) ≤15 mL/min/1.73 m2 and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomize patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first 6 months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen–Johansen and Kaplan–Meier estimators respectively.

Results

A total of 1364 unique patients (mean age 51.1 years, 55.7% male) contributed 3125 person-trials, with 561 in the AVF and 2564 in the no AVF group. Mean eGFR was 12.6 mL/min/1.73 m2 and the median number of eGFR measurements per person-trial was 7 (interquartile range 4–12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between-group difference –0.67 mL/min/1.73 m2/year, 95% CI –1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95% CI 84, 91) in the AVF group and 75% (95% CI 73, 77) in the no AVF group, and the 5-year survival probability was 77% (95% CI 70, 83) in the AVF group and 67% (95% CI 64, 69) in the no AVF group.

Conclusions

In this study of patients with advanced chronic kidney disease, there was no evidence of a nephroprotective effect of AVF formation.
Prospective and External Validation of an Ensemble Learning Approach to Sensitively Detect Intravenous Fluid Contamination in Basic Metabolic Panels
Authors: Spies Nicholas C , Militello Leah , Farnsworth Christopher W , El-Khoury Joe M , Durant Thomas J S , Zaydman Mark A
Published: November 2024

Background

Intravenous (IV) fluid contamination within clinical specimens causes an operational burden on the laboratory when detected, and potential patient harm when undetected. Even mild contamination is often sufficient to meaningfully alter results across multiple analytes. A recently reported unsupervised learning approach was more sensitive than routine workflows, but still lacked sensitivity to mild but significant contamination. Here, we leverage ensemble learning to more sensitively detect contaminated results using an approach which is explainable and generalizable across institutions.

Methods

An ensemble-based machine learning pipeline of general and fluid-specific models was trained on real-world and simulated contamination and internally and externally validated. Benchmarks for performance assessment were derived from in silico simulations, in vitro experiments, and expert review. Fluid-specific regression models estimated contamination severity. SHapley Additive exPlanation (SHAP) values were calculated to explain specimen-level predictions, and algorithmic fairness was evaluated by comparing flag rates across demographic and clinical subgroups.

Results

The sensitivities, specificities, and Matthews correlation coefficients were 0.858, 0.993, and 0.747 for the internal validation set, and 1.00, 0.980, and 0.387 for the external set. SHAP values provided plausible explanations for dextrose- and ketoacidosis-related hyperglycemia. Flag rates from the pipeline were higher than the current workflow, with improved detection of contamination events expected to exceed allowable limits for measurement error and reference change values.

Conclusions

An accurate, generalizable, and explainable ensemble-based machine learning pipeline was developed and validated for sensitively detecting IV fluid contamination. Implementing this pipeline would help identify errors that are poorly detected by current clinical workflows and a previously described unsupervised machine learning-based method.
Egg shape in an obligate brood parasite stabilizes temperature variation during incubation
Authors: Magdaleno Francisco R , Hawkins Lyndon R , Salinas Isaac Quintanilla , Peer Brian D
Published: November 2024

The brood-parasitic brown-headed cowbird (Molothrus ater) has one of the shortest incubation periods of any bird. Brown-headed cowbird eggs, and those of other avian brood parasites, tend to be more spherical due to their greater relative width. The traditional explanation for this egg shape is that it, combined with the thicker eggshells, resists host puncture-ejection. However, very few North American hosts of the brown-headed cowbird actually engage in puncture-ejection and therefore wider eggs may instead provide greater contact with a host’s brood patch during incubation, especially in large host nests. We tested whether greater egg width increased mean temperature and reduced temperature variation in brown-headed cowbirds by inserting temperature probes into brown-headed cowbird and house sparrow (Passer domesticus) eggs and placing them into red-winged blackbird (Agelaius phoeniceus) nests. House sparrow eggs are similar in appearance and in length to cowbird eggs, but are not as wide. We found no significant relationship between brown-headed cowbird egg width and mean incubation temperature. However, brown-headed cowbird eggs experienced less temperature variation than house sparrow eggs, and within brown-headed cowbird eggs, more spherical eggs experienced less temperature variation when accounting for differences in width. These results suggest that brown-headed cowbirds may have short incubation periods in part because their eggs exhibit less temperature variation over the course of incubation. The brown-headed cowbird’s egg shape may contribute to its accelerated embryonic development rate relative to host eggs of similar size, which explains its ability to hatch in a variety of host nests.
Fulminant eosinophilic myocarditis and doxycycline administration: a case report
Authors: Salaûn Alexandre , Tarris Georges , Bonnotte Bernard , Cottin Yves
Published: November 2024

Background

Eosinophilic myocarditis is a life-threatening condition with a heterogeneous clinical presentation and aetiology. Cases of drug-induced or parasitic myocarditis have been reported but there is scant literature on the involvement of treatments, such as doxycycline, and eosinophil degranulation due to parasitic lysis.

Case summary

Here, we report the case of a 59-year-old man without a relevant past medical history who developed a skin rash with hepatic cytolysis and mild eosinophilia. No aetiology was found despite an exhaustive work-up, but a parasitic infestation was suspected in view of the patient’s daily contact with freshwater environments. A few days after doxycycline administration, the patient’s clinical state worsened rapidly leading to a ventricular electrical storm-related cardiogenic shock requiring mechanical support. After initiation of high-dose corticosteroid therapy, cardiac function normalized promptly allowing for withdrawal of the mechanical support. An endomyocardial biopsy led to the diagnosis of eosinophilic myocarditis, which was congruent with the cardiac magnetic resonance imaging data.

Discussion

The main aetiologies reported for eosinophilic myocarditis are often allergic reactions, such as DRESS syndrome in developed countries, or infections, especially due to parasites in other countries. Drugs such as tuberculosis medications, antipsychotics, and antiepileptics have been implicated, as well as antibiotics, e.g. minocycline, but there has been no case of doxycycline-related eosinophilic myocarditis reported to date. Parasitic lysis is known to induce the activation of eosinophils and their on-site degranulation but no case has been reported on myocarditis due to parasitic lysis after administration of antiparasitic drugs.
Globalization and Conflicts: the Good, the Bad, and the Ugly of Corporations in Africa
Authors: Sonno Tommaso
Published: November 2024

Using a novel georeferenced datataset on the affiliates and headquarters of multinational enterprises between 2007 and 2018 together with georeferenced conflict data for the African continent, this work establishes a causal link between the activities of multinational enterprises and violent conflicts: multinationals’ activity increases the number of conflicts. This applies particularly to sectors intense in scarce resources, especially land. As farming is the primary source of food and income for Africans, land-intensive activity on the part of the multinationals increases local grievance, escalating to violent actions. These effects are magnified in areas targeted for large-scale land acquisitions.
High-quality genome assembly and annotation of the crested gecko (Correlophus ciliatus)
Authors: Huang Ruyi , Zhang Jinghang , Lu Liang , Huang Song , Li Chenhong
Published: November 2024

Correlophus ciliatus, or the crested gecko, is widely kept as a pet in many countries around the world due to its ease to care and bred and its high survival rate. However, there is limited number of genomic studies on the crested gecko. In this study, we generated a high-quality chromosome-level genome assembly of the crested gecko by combining Nanopore, Illumina, and Hi-C data. The genome assemble has a size of 1.66 Gb, with scaffold N50 of 109.97 Mb, and 99.52% of the scaffold anchored on 19 chromosomes. The BUSCO analysis indicated a gene completeness of 90.3% (n = 7,480), including 6,673 (89.2%) single-copy genes and 84 (1.1%) duplicated genes. Additionally, we identified 21,065 protein-coding genes using the MAKER3 annotation toolkit, with 41.98% (697.51 Mb) consisting of repetitive elements. Among these, 21,037 genes were validated through InterProScan5. Our study is the first to report a chromosome-level genome for the crested gecko. It provides valuable genomic resources for understanding molecular mechanisms under many interesting traits of the species.