bluuebunny/crossref_metadata_2025 huggingface dataset:
E-value: a superior alternative toP-value and its adjustments in DNA methylation studies
Authors: Yang Yifan , Liu Haoyuan , Liu Yi , Zhou Liyuan , Zheng Xiaoqi , Yue Rongxian , Mattson David L , Kidambi Srividya , Liang Mingyu , Liu Pengyuan , Pan Xiaoqing
Published: June 2023

DNA methylation plays a crucial role in transcriptional regulation. Reduced representation bisulfite sequencing (RRBS) is a technique of increasing use for analyzing genome-wide methylation profiles. Many computational tools such as Metilene, MethylKit, BiSeq and DMRfinder have been developed to use RRBS data for the detection of the differentially methylated regions (DMRs) potentially involved in epigenetic regulations of gene expression. For DMR detection tools, as for countless other medical applications, P-values and their adjustments are among the most standard reporting statistics used to assess the statistical significance of biological findings. However, P-values are coming under increasing criticism relating to their questionable accuracy and relatively high levels of false positive or negative indications. Here, we propose a method to calculate E-values, as likelihood ratios falling into the null hypothesis over the entire parameter space, for DMR detection in RRBS data. We also provide the R package ‘metevalue’ as a user-friendly interface to implement E-value calculations into various DMR detection tools. To evaluate the performance of E-values, we generated various RRBS benchmarking datasets using our simulator ‘RRBSsim’ with eight samples in each experimental group. Our comprehensive benchmarking analyses showed that using E-values not only significantly improved accuracy, area under ROC curve and power, over that of P-values or adjusted P-values, but also reduced false discovery rates and type I errors. In applications using real RRBS data of CRL rats and a clinical trial on low-salt diet, the use of E-values detected biologically more relevant DMRs and also improved the negative association between DNA methylation and gene expression.
Sialylation: fate decision of mammalian sperm development, fertilization, and male fertility
Authors: Yi Shiqi , Feng Ying , Wang Yan , Ma Fang
Published: June 2023

Sperm development, maturation, and successful fertilization within the female reproductive tract are intricate and orderly processes that involve protein translation and post-translational modifications. Among these modifications, sialylation plays a crucial role. Any disruptions occurring throughout the sperm’s life cycle can result in male infertility, yet our current understanding of this process remains limited. Conventional semen analysis often fails to diagnose some infertility cases associated with sperm sialylation, emphasizing the need to comprehend and investigate the characteristics of sperm sialylation. This review reanalyzes the significance of sialylation in sperm development and fertilization and evaluates the impact of sialylation damage on male fertility under pathological conditions. Sialylation serves a vital role in the life journey of sperm, providing a negatively charged glycocalyx and enriching the molecular structure of the sperm surface, which is beneficial to sperm reversible recognition and immune interaction. These characteristics are particularly crucial during sperm maturation and fertilization within the female reproductive tract. Moreover, enhancing the understanding of the mechanism underlying sperm sialylation can promote the development of relevant clinical indicators for infertility detection and treatment.
Mogamulizumab-induced bone granuloma: a multicentre nationwide case series
Authors: Amatore Florent , Darbord Delphine , Franck Nathalie  , Carlotti Agnes , Gillet Baptiste  , Haffner Aurelie , Coze Stephanie , Delaporte Emmanuel  , Carrasquilla-Capilla Ana  , Dalle Stephane , Dereure Olivier
Published: June 2023

Our case series reports a new immune-related adverse event and highlights three important facts. Firstly, granulomatous reactions not only occur in the skin, but can also affect bones. Secondly, although possibly transient and spontaneously regressive, such lesions may result in protracted functional disabilities owing to their location and the interest of systemic steroids in this setting remains to be established. Finally, they should not be mistaken with an unfavourable evolution of the underlying disease and seem instead to be associated with protracted responses.
Myeloid Cell-Specific Deletion of PDGFR-α Promotes Dysbiotic Intestinal Microbiota and thus Increased Colitis Susceptibility
Authors: Dörk Ronja , Pelczar Penelope , Shiri Ahmad M , Volmari Annika , Zierz Elisabeth , Giannou Anastasios , Böttcher Marius , Bosurgi Lidia , Huber Samuel , Manthey Carolin F
Published: June 2023

Background and Aims

The incidence of inflammatory bowel diseases [IBD] is steadily increasing, and thus the identification of new targets to improve therapy is a major goal. Growth factors of the PDGF family and their receptors are expressed early in intestinal development and are found in mononuclear cells and macrophages in adult tissues. Macrophages play a distinct role in the pathogenesis of IBD since their function is crucial to maintaining tolerance.

Methods

We aimed to study the role of myeloid expression of PDGFR-α in mediating intestinal homeostasis in mouse IBD and infectious models.

Results

Our results show that loss of myeloid PDGFR-α increases susceptibility to dextran saline sulphate-induced colitis. Accordingly, LysM-PDGFR-α-/- mice showed higher colitis scores, and reduced levels of anti-inflammatory macrophages compared to control mice. This effect was mediated via a pro-colitogenic microbiota, which developed in the absence of myeloid PDGFR-α and caused increased colitis susceptibility in gnotobiotic mice upon faecal microbiota transplantation compared to controls. Furthermore, LysM-PDGFR-α-/- mice had a leaky gut, accompanied by impaired phagocytosis, resulting in a severe barrier defect.

Conclusions

Taken together, our results indicate a protective role for myeloid PDGFR-α in maintaining gut homeostasis by promoting a protective intestinal microbiota and providing an anti-inflammatory macrophage phenotype.
Acute pulmonary tumour embolism and right systolic dysfunction in a hidden intrahepatic cholangiocarcinoma: case report
Authors: Portillo-Romero Alejandra , Cuevas-Medina Eric , Santa Ana-Bayona Maria Jose , Saenz-Ancira Santiago
Published: June 2023

Background

Pulmonary tumour embolism is a rare entity that can arise from a wide variety of neoplasms. It can initially manifest as a pulmonary embolism with right heart failure and be refractory to thrombolytic therapy. Cholangiocarcinoma is a rare malignancy that arises from the epithelium of the biliary tree, representing 3% of all the gastrointestinal malignancies, being the intrahepatic cholangiocarcinoma the second most common liver tumour after hepatocellular carcinoma.

Case summary

This case regards a patient that presented to our centre with acute pulmonary embolism, deep vein thrombosis, and unrevealing previous medical history. Imaging studies revealed pulmonary embolism, an ovarian mass, and multiple hepatic hypodensities. Throughout the hospitalization, the patient’s haemodynamic state and right heart failure worsened, eventually leading to multi-organ failure and death. Post-mortem evaluation revealed cholangiocarcinoma cells on the pulmonary arteries.

Discussion

Pulmonary tumour embolism is a rare pathology that can present with acute right heart failure. The diagnosis of occult cancer can be challenging, and the appropriate treatment for this entity remains an unexplored subject.
Mendelian randomisation reveals Sodium-glucose Cotransporter-1 inhibition's potential in reducing Non-Alcoholic Fatty Liver Disease risk
Authors: Dobbie Laurence J , Cuthbertson Daniel J , Hydes Theresa J , Alam Uazman , Zhao Sizheng Steven
Published: June 2023

Non-alcoholic fatty liver disease (NAFLD) has no approved pharmacological treatments. Sodium-glucose cotransporter (SGLT)-1 is a glucose transporter that mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344 182) to proxy SGLT-1i. Outcome genetic data comprised 1483 NAFLD cases and 17 781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; P = .023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD.
Proportions of taxa belonging to the gut core microbiome change throughout the life cycle and season of the bark beetleIps typographus
Authors: Veselská Tereza , Švec Karel , Kostovčík Martin , Peral-Aranega Ezequiel , Garcia-Fraile Paula , Křížková Barbora , Havlíček Václav , Saati-Santamaría Zaki , Kolařík Miroslav
Published: June 2023

The European spruce bark beetle, Ips typographus, is a serious pest of spruce forests in Europe, and its invasion and development inside spruce tissues are facilitated by microorganisms. We investigated the core gut bacterial and fungal microbiomes of I. typographus throughout its life cycle in spring and summer generations. We used cultivation techniques and molecular identification in combination with DNA and RNA metabarcoding. Our results revealed that communities differ throughout their life cycle and across generations in proportion of dominantly associated microbes, rather than changes in species composition. The bacteriome consisted mostly of the phylum Gammaproteobacteria, with the most common orders and genera being Enterobacteriales (Erwinia and Serratia), Pseudomonadales (Pseudomonas), and Xanthomonadales. The fungal microbiome was dominated by yeasts (Saccharomycetes—Wickerhamomyces, Kuraishia, and Nakazawaea), followed by Sordariomycetes (Ophiostoma bicolor and Endoconidiophora polonica). We did not observe any structure ensuring long-term persistence of microbiota on any part of the gut epithelium, suggesting that microbial cells are more likely to pass through the beetle’s gut with chyme. The most abundant taxa in the beetle’s gut were also identified as dominant in intact spruce phloem. Therefore, we propose that these taxa are acquired from the environment rather than specifically vectored between generations.
Characterization of direct and/or indirect genetic associations for multiple traits in longitudinal studies of disease progression
Authors: Brossard Myriam , Paterson Andrew D , Espin-Garcia Osvaldo , Craiu Radu V , Bull Shelley B
Published: June 2023

When quantitative longitudinal traits are risk factors for disease progression and subject to random biological variation, joint model analysis of time-to-event and longitudinal traits can effectively identify direct and/or indirect genetic association of single nucleotide polymorphisms (SNPs) with time-to-event. We present a joint model that integrates: (1) a multivariate linear mixed model describing trajectories of multiple longitudinal traits as a function of time, SNP effects, and subject-specific random effects and (2) a frailty Cox survival model that depends on SNPs, longitudinal trajectory effects, and subject-specific frailty accounting for dependence among multiple time-to-event traits. Motivated by complex genetic architecture of type 1 diabetes complications (T1DC) observed in the Diabetes Control and Complications Trial (DCCT), we implement a 2-stage approach to inference with bootstrap joint covariance estimation and develop a hypothesis testing procedure to classify direct and/or indirect SNP association with each time-to-event trait. By realistic simulation study, we show that joint modeling of 2 time-to-T1DC (retinopathy and nephropathy) and 2 longitudinal risk factors (HbA1c and systolic blood pressure) reduces estimation bias in genetic effects and improves classification accuracy of direct and/or indirect SNP associations, compared to methods that ignore within-subject risk factor variability and dependence among longitudinal and time-to-event traits. Through DCCT data analysis, we demonstrate feasibility for candidate SNP modeling and quantify effects of sample size and Winner's curse bias on classification for 2 SNPs identified as having indirect associations with time-to-T1DC traits. Joint analysis of multiple longitudinal and multiple time-to-event traits provides insight into complex traits architecture.
Hydrodynamic Diversity of Jets Mediated by Giant and Non-Giant Axon Systems in Brief Squid
Authors: Li Diana H , Bartol Ian K , Gilly William F
Published: June 2023

Synopsis

Neural input is critical for establishing behavioral output, but understanding how neuromuscular signals give rise to behaviors remains a challenge. In squid, locomotion through jet propulsion underlies many key behaviors, and the jet is mediated by two parallel neural pathways, the giant and non-giant axon systems. Much work has been done on the impact of these two systems on jet kinematics, such as mantle muscle contraction and pressure-derived jet speed at the funnel aperture. However, little is known about any influence these neural pathways may have on the hydrodynamics of the jet after it leaves the squid and transfers momentum to the surrounding fluid for the animal to swim. To gain a more comprehensive view of squid jet propulsion, we made simultaneous measurements of neural activity, pressure inside the mantle cavity, and wake structure. By computing impulse and time-averaged forces from the wake structures of jets associated with giant or non-giant axon activity, we show that the influence of neural pathways on jet kinematics could extend to hydrodynamic impulse and force production. Specifically, the giant axon system produced jets with, on average, greater impulse magnitude than those of the non-giant system. However, non-giant impulse could exceed that of the giant system, evident by the graded range of its output in contrast to the stereotyped nature of the giant system. Our results suggest that the non-giant system offers flexibility in hydrodynamic output, while recruitment of giant axon activity can provide a reliable boost when necessary.
Cephalopod-omics: Emerging Fields and Technologies in Cephalopod Biology
Authors: Baden Tom , Briseño John , Coffing Gabrielle , Cohen-Bodénès Sophie , Courtney Amy , Dickerson Dominick , Dölen Gül , Fiorito Graziano , Gestal Camino , Gustafson Taryn , Heath-Heckman Elizabeth , Hua Qiaz , Imperadore Pamela , Kimbara Ryosuke , Król Mirela , Lajbner Zdeněk , Lichilín Nicolás , Macchi Filippo , McCoy Matthew J , Nishiguchi Michele K , Nyholm Spencer V , Otjacques Eve , Pérez-Ferrer Pedro Antonio , Ponte Giovanna , Pungor Judit R , Rogers Thea F , Rosenthal Joshua J C , Rouressol Lisa , Rubas Noelle , Sanchez Gustavo , Santos Catarina Pereira , Schultz Darrin T , Seuntjens Eve , Songco-Casey Jeremea O , Stewart Ian Erik , Styfhals Ruth , Tuanapaya Surangkana , Vijayan Nidhi , Weissenbacher Anton , Zifcakova Lucia , Schulz Grace , Weertman Willem , Simakov Oleg , Albertin Caroline B
Published: June 2023

Synopsis

Few animal groups can claim the level of wonder that cephalopods instill in the minds of researchers and the general public. Much of cephalopod biology, however, remains unexplored: the largest invertebrate brain, difficult husbandry conditions, and complex (meta-)genomes, among many other things, have hindered progress in addressing key questions. However, recent technological advancements in sequencing, imaging, and genetic manipulation have opened new avenues for exploring the biology of these extraordinary animals. The cephalopod molecular biology community is thus experiencing a large influx of researchers, emerging from different fields, accelerating the pace of research in this clade. In the first post-pandemic event at the Cephalopod International Advisory Council (CIAC) conference in April 2022, over 40 participants from all over the world met and discussed key challenges and perspectives for current cephalopod molecular biology and evolution. Our particular focus was on the fields of comparative and regulatory genomics, gene manipulation, single-cell transcriptomics, metagenomics, and microbial interactions. This article is a result of this joint effort, summarizing the latest insights from these emerging fields, their bottlenecks, and potential solutions. The article highlights the interdisciplinary nature of the cephalopod-omics community and provides an emphasis on continuous consolidation of efforts and collaboration in this rapidly evolving field.
Military spending and innovation: learning from 19th-century world fair exhibition data
Authors: Danzer Alexander M , Danzer Natalia , Feuerbaum Carsten
Published: June 2023

We provide quantitative evidence on the relationship between military spending and innovation in the 19th century. Combining innovation data from world fairs and historical military data across Europe, we show that national military spending is associated with national innovation toward war logistics such as food processing, but less toward war technology such as guns. This innovation pattern reflects differences in the historical markets for war supplies: while the armed forces sourced weapons globally, the food market remained local.
Grooming and agonistic behaviors in the semi-terrestrial crabsOcypode quadrata(Fabricius, 1787) andMinuca(Uca) burgersi(Holthuis, 1967) (Decapoda: Brachyura: Ocypodidae)
Authors: Dakin Maggie , Wortham Jen L
Published: June 2023

Grooming behaviors reduce body fouling and are well documented in crustaceans. There are more detailed laboratory-based grooming studies on fully aquatic crabs compared to semi-terrestrial crabs. By contrast, semi-terrestrial crabs are predicted to have different grooming time budgets than fully aquatic crabs because semi-terrestrial crabs are not constantly submerged in water that can mechanically remove sedimentary fouling, whereas fully aquatic crustaceans have increased fouling from algae and epibionts. We studied the grooming behaviors of two semi-terrestrial crab species. Crabs (N = 50 ghost crabs, Ocypode quadrata (Fabricius, 1787); N = 50 fiddler crabs, Minuca (Uca) burgersi (Holthuis, 1967)) were observed in isolation for 45-min trials. We recorded grooming frequency, location, appendage, and time. Ghost crabs were also observed in agonistic encounters to determine how grooming varied in the presence of a conspecific individual. Ghost crabs and fiddler crabs have different grooming time budgets, (0.526 and 0.895%, respectively) with both species having lower grooming time budgets than fully aquatic crustaceans. Some similarities and differences in grooming between the two semi-terrestrial crabs exist, with both species frequently grooming their eyes and maxillipeds using a brush or scrape mechanism, but with fiddler crabs using their eyes as a grooming appendage more frequently than ghost crabs. Ghost crab males groom less than females, whereas fiddler crab males and females groom equally. In agonistic interactions in ghost crabs, the grooming time budget decreased compared with isolated observations and individuals engaged in a “playing dead” behavior (thanatosis) after engaging in a fight. Semi-terrestrial crabs were found to groom significantly less than fully aquatic crustaceans.
Protection of Biocultural Heritage in the Anthropocene: Towards Reconciling Natural, Cultural, Tangible and Intangible Heritage
Authors: Bhati Harsh Vardhan , Epstein Yaffa
Published: June 2023

This article examines the effectiveness, legitimacy, and fairness of heritage conservation outcomes under the 1972 World Heritage Convention (1972 WHC), with a focus on recognising and respecting the rights of Indigenous Peoples in heritage nomination, protection, and management. Examining conflicts surrounding World Heritage sites in Kenya and Sweden, this article argues that recognition of biocultural heritage and biocultural rights can promote environmental justice and help meet global environmental challenges. To promote the conservation of both built and natural landscapes, the article recommends expanding protection for the relationship between humans and their environment. Recognising biocultural heritage under UNESCO conventions could promote Indigenous sovereignty, protect cultural and natural heritage, and contribute to global efforts to address climate change. The article calls for further research mapping biocultural heritage in natural and mixed heritage sites and advocates for fuller engagement with Indigenous Peoples to increase the ability of the 1972 WHC to promote sustainability as it enters its second half-century.
Symptomatic acinar cell cystadenoma of the pancreas
Authors: Sergi William , D’Ugo Stefano , Libia Annarita , Depalma Norma , Marchese Tiziana , Garritano Stefano , Vadrucci Stefania , Stasi Elisa , Botrugno Ivan , Manoochehri Farshad , Spampinato Marcello , Sergi William
Published: June 2023

Acinar cystic transformation (ACT), also known as ‘acinar cell cystadenoma’, is an uncommon cystic neoplasm of pancreas with unknown malignant potential. This case regards a woman with symptomatic pancreatic head ACT, revealed with pathological exam of specimen after pancreaticoduodenectomy. A 57-years-old patient presented mild hyperbilirubinemia and recurrent cholangitis; she underwent to ERCP, EUS and MRI, and these exams revealed a large cyst of the pancreatic head that caused biliary compression. The discussion of the case by the multidisciplinary group indicated surgical resection. Pancreatic ACT is so rare, and its preoperative diagnosis is difficult. The symptoms of the patients and the features of the cyst are the criteria to choose a surgical resection.
First case of primary appendiceal tuberculosis presented as stump appendicitis
Authors: Mathew Midhun , Mathew Tony , Joseph Elizabeth
Published: June 2023

Tuberculosis (TB) remains as a significant global public health issue, especially in developing and underdeveloped nations. Extrapulmonary TB comprises 20% of the TB cases; of which 34.4% were in the lymphatics, 25.2% pleural, followed by 12.8% gastrointestinal and 9.4% in the central nervous system. Ileocecal involvement is the most common among gastrointestinal TB. Although it can cause secondary damage to the appendix, primary type of appendicular TB is rare and can occur with no other signs of the disease. A high index of suspicion is necessary for early diagnosis and treatment of TB. Similarly, stump appendicitis (SA) is a rare and delayed complication of appendectomy. Here we report a case of primary appendicular TB in a patient presented to a multi-specialty hospital in Kerala, India, with SA.
Wooded streets, but not streetlight dimming, favour bat activity in a temperate urban setting
Authors: Stanley Christopher , Bagniewska Joanna Maria , Grabowska-Zhang Ada , Hesselberg Thomas
Published: June 2023

Urbanization damages biodiversity, reducing people’s connection to nature and negatively impacting the survivability of local species. However, with small adjustments, the damage could be mitigated. In temperate regions, several bat species inhabit urban areas, and with urbanization set to increase, adapting urban areas to improve their suitability for bats is imperative. Therefore, we investigated if wooded streets and streetlight dimming in an urban setting influenced bat activity. Static bat detectors were used to compare wooded versus non-wooded, and bright versus dim streets in Leicester, UK, on predominantly residential streets. The collected calls were quantified into bat activity (passes per night). Six species were identified, but the common pipistrelle (Pipistrellus pipistrellus) was dominant, making up 94.1% of all calls, so it was the sole species included in the statistical model. Wooded streets had significantly higher bat activity than non-wooded streets, but bright and dim streets were not significantly different. The results suggest that wooded streets were being used as green corridors, with common pipistrelles possibly following them to conceal themselves from predators, such as the tawny owl, and the proliferation of wooded streets in urban areas could allow the formation of better-connected populations. Streetlight dimming did not affect bat activity, but no light-averse bats were detected, likely because even the most dimmed streets deterred them despite street lighting increasing food availability by attracting insects. Therefore, an alternate solution, such as part-night lighting, may be required to increase the suitability of urban areas to light-averse species.
Synchrotron science for sustainability: life cycle of metals in the environment
Authors: Smieska Louisa , Guerinot Mary Lou , Olson Hoal Karin , Reid Matthew , Vatamaniuk Olena
Published: June 2023

The movement of metals through the environment links together a wide range of scientific fields: from earth sciences and geology as weathering releases minerals; to environmental sciences as metals are mobilized and transformed, cycling through soil and water; to biology as living things take up metals from their surroundings. Studies of these fundamental processes all require quantitative analysis of metal concentrations, locations, and chemical states. Synchrotron X-ray tools can address these requirements with high sensitivity, high spatial resolution, and minimal sample preparation. This perspective describes the state of fundamental scientific questions in the lifecycle of metals, from rocks to ecosystems, from soils to plants, and from environment to animals. Key X-ray capabilities and facility infrastructure for future synchrotron-based analytical resources serving these areas are summarized, and potential opportunities for future experiments are explored.
ViCloD, an interactive web tool for visualizing B cell repertoires and analyzing intraclonal diversities: application to human B-cell tumors
Authors: Jeusset Lucile , Abdollahi Nika , Verny Thibaud , Armand Marine , De Septenville Anne Langlois , Davi Frédéric , Bernardes Juliana Silva
Published: June 2023

High throughput sequencing of adaptive immune receptor repertoire (AIRR-seq) has provided numerous human immunoglobulin (IG) sequences allowing specific B cell receptor (BCR) studies such as the antigen-driven evolution of antibodies (soluble forms of the membrane-bound IG part of the BCR). AIRR-seq data allows researchers to examine intraclonal differences caused primarily by somatic hypermutations in IG genes and affinity maturation. Exploring this essential adaptive immunity process could help elucidate the generation of antibodies with high affinity or broadly neutralizing activities. Retracing their evolutionary history could also clarify how vaccines or pathogen exposition drive the humoral immune response, and unravel the clonal architecture of B cell tumors. Computational methods are necessary for large-scale analysis of AIRR-seq properties. However, there is no efficient and interactive tool for analyzing intraclonal diversity, permitting users to explore adaptive immune receptor repertoires in biological and clinical applications. Here we present ViCloD, a web server for large-scale visual analysis of repertoire clonality and intraclonal diversity. ViCloD uses preprocessed data in the format defined by the Adaptive Immune Receptor Repertoire (AIRR) Community. Then, it performs clonal grouping and evolutionary analyses, producing a collection of useful plots for clonal lineage inspection. The web server presents diverse functionalities, including repertoire navigation, clonal abundance analysis, and intraclonal evolutionary tree reconstruction. Users can download the analyzed data in different table formats and save the generated plots as images. ViCloD is a simple, versatile, and user-friendly tool that can help researchers and clinicians to analyze B cell intraclonal diversity. Moreover, its pipeline is optimized to process hundreds of thousands of sequences within a few minutes, allowing an efficient investigation of large and complex repertoires.
Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome
Authors: Kolodziejczak Anna S , Guerrini-Rousseau Lea , Planchon Julien Masliah , Ecker Jonas , Selt Florian , Mynarek Martin , Obrecht Denise , Sill Martin , Autry Robert J , Stutheit-Zhao Eric , Hirsch Steffen , Amouyal Elsa , Dufour Christelle , Ayrault Olivier , Torrejon Jacob , Waszak Sebastian M , Ramaswamy Vijay , Pentikainen Virve , Demir Haci Ahmet , Clifford Steven C , Schwalbe Ed C , Massimi Luca , Snuderl Matija , Galbraith Kristyn , Karajannis Matthias A , Hill Katherine , Li Bryan K , Walsh Mike , White Christine L , Redmond Shelagh , Loizos Loizou , Jakob Marcus , Kordes Uwe R , Schmid Irene , Hauer Julia , Blattmann Claudia , Filippidou Maria , Piccolo Gianluca , Scheurlen Wolfram , Farrag Ahmed , Grund Kerstin , Sutter Christian , Pietsch Torsten , Frank Stephan , Schewe Denis M , Malkin David , Ben-Arush Myriam , Sehested Astrid , Wong Tai-Tong , Wu Kuo-Sheng , Liu Yen-Lin , Carceller Fernando , Mueller Sabine , Stoller Schuyler , Taylor Michael D , Tabori Uri , Bouffet Eric , Kool Marcel , Sahm Felix , von Deimling Andreas , Korshunov Andrey , von Hoff Katja , Kratz Christian P , Sturm Dominik , Jones David T W , Rutkowski Stefan , van Tilburg Cornelis M , Witt Olaf , Bougeard Gaëlle , Pajtler Kristian W , Pfister Stefan M , Bourdeaut Franck , Milde Till
Published: June 2023

Background

The prognosis for Li–Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients.

Methods

In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated.

Results

The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup “SHH_3” (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively).

Conclusions

LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.
Phase separation-based visualization of protein–protein interactions and kinase activities in plants
Authors: Safi Alaeddine , Smagghe Wouter , Gonçalves Amanda , Wang Qing , Xu Ke , Fernandez Ana Ibis , Cappe Benjamin , Riquet Franck B , Mylle Evelien , Eeckhout Dominique , De Winne Nancy , Van De Slijke Eveline , Persyn Freya , Persiau Geert , Van Damme Daniël , Geelen Danny , De Jaeger Geert , Beeckman Tom , Van Leene Jelle , Vanneste Steffen
Published: June 2023

Protein activities depend heavily on protein complex formation and dynamic posttranslational modifications, such as phosphorylation. The dynamic nature of protein complex formation and posttranslational modifications is notoriously difficult to monitor in planta at cellular resolution, often requiring extensive optimization. Here, we generated and exploited the SYnthetic Multivalency in PLants (SYMPL)-vector set to assay protein–protein interactions (PPIs) (separation of phases-based protein interaction reporter) and kinase activities (separation of phases-based activity reporter of kinase) in planta, based on phase separation. This technology enabled easy detection of inducible, binary and ternary PPIs among cytoplasmic and nuclear proteins in plant cells via a robust image-based readout. Moreover, we applied the SYMPL toolbox to develop an in vivo reporter for SNF1-related kinase 1 activity, allowing us to visualize tissue-specific, dynamic SnRK1 activity in stable transgenic Arabidopsis (Arabidopsis thaliana) plants. The SYMPL cloning toolbox provides a means to explore PPIs, phosphorylation, and other posttranslational modifications with unprecedented ease and sensitivity.
First Provider Seen for an Acute Episode of Low Back Pain Influences Subsequent Health Care Utilization
Authors: Bise Christopher G , Schneider Michael , Freburger Janet , Fitzgerald G Kelley , Switzer Galen , Smyda Garry , Peele Pamela , Delitto Anthony
Published: June 2023

Objective

Costs associated with low back pain (LBP) continue to rise. Despite numerous clinical practice guidelines, the evaluation and treatments for LBP are variable and largely depend on the individual provider. As yet, little attention has been given to the first choice of provider. Early research indicates that the choice of first provider and the timing of interventions for LBP appear to influence utilization. We sought to examine the association between the first provider seen and health care utilization.

Methods

Using 2015–2018 data from a large insurer, this retrospective analysis focused on patients (29,806) seeking care for a new episode of LBP. The study identified the first provider chosen and examined the following year of medical utilization. Cox proportional hazards models were calculated using inverse probability weighting on propensity scores to evaluate the time to event and the relationship to the first choice of provider.

Results

The primary outcome was the timing and use of health care resources. Total health care use was lowest in those who first sought care with chiropractic care or physical therapy. Highest health care use was seen in those patients who chose the emergency department.

Conclusion

Overall, there appears to be an association between the first choice of provider and future health care use. Chiropractic care and physical therapy provide nonpharmacologic and nonsurgical, guideline-based interventions. The use of physical therapists and chiropractors as entry points into the health system appears related to a decrease in immediate and long-term use of health resources. This study expands the existing body of literature and provides a compelling case for the influence of the first provider on an acute episode of LBP.

Impact

The first provider seen for an acute episode of LBP influences immediate treatment decisions, the trajectory of a specific patient episode, and future health care choices in the management of LBP.
China’s use of formal science and technology agreements as a tool of diplomacy
Authors: Wagner Caroline S , Simon Denis F
Published: June 2023

China’s government uses a variety of diplomatic tools to pursue its foreign policy aims including negotiating and signing formal bilateral science and technology agreements (STAs). These agreements have been signed with at least fifty-two countries. We identified agreements with an additional sixty-four countries with science and technology (S&T), among other topics such as education, as subjects for cooperation. The Ministry of Science and Technology reports having signed 115 intergovernmental science and technology agreements (STAs) and established ties with 161 countries and regions, although we were not able to identify all these agreements. The earliest of China’s STAs were signed in the 1950s with communist countries, but, in the late 1970s, China began signing agreements with scientifically-advanced nations, which opened opportunities for S&T cooperation. More recently, China has negotiated and signed scientific and technological cooperation agreements with dozens of middle- and lower-income countries, possibly to establish political goodwill. While building political ties clearly remains an important Chinese objective, access to the latest know-how in S&T has become a critical part of China’s priorities in establishing formal relationships.
IVChaucer
Authors: Menmuir Rebecca , Buchanan Peter , Kask Pamela
Published: June 2023

This chapter has four sections: 1. General; 2. The Canterbury Tales; 3. Other Works; 4. Reception. Section 1 is by Peter Buchanan and Pamela Kask; section 2 is by Rebecca Menmuir and Pamela Kask; section 3 is by Peter Buchanan; section 4 is by Rebecca Menmuir.
Recognition and Treatment of Wounds in Persons Using Xylazine: A Case Report From New Haven, Connecticut
Authors: Dowton Anne , Doernberg Molly , Heiman Erica , Barelli Peter , Golden Marjorie , Wang He , Leventhal Jonathan , Morford Kenneth L. , Sue Kimberly L.
Published: June 2023

Background

Xylazine is an α2-adrenergic agonist that is commonly used as a veterinary tranquilizer and is increasingly present in the unregulated US drug supply since at least 2019. There are many suspected clinical complications of xylazine use, including unusual skin wounds, atypical overdose presentations, and possible dependence and withdrawal syndromes. However, there are few reports of cutaneous manifestations of xylazine in patients who inject drugs that can guide diagnosis and management in patients with confirmed xylazine toxicology.

Case Summary

We present the cases of 3 stably housed patients in Connecticut with opioid use disorder and intravenous use of fentanyl who presented with atypical, chronic wounds at the site of injection drug use. Xylazine toxicology sent on all 3 patients was positive. All patients were seen by wound care and dermatology, and 1 patient was followed by infectious diseases. Wound care management strategies are discussed as well as harm reduction strategies. For all patients, the dose of their medication for opioid use disorder was increased to decrease frequency of drug use given concern that patients were exposed to a drug supply containing xylazine.

Clinical Significance

This case report presents wound characteristics that raise the index of suspicion for xylazine-involved injection wounds and might assist in their diagnosis and management. There is urgent need for more reporting of such cases as well as rigorous research to understand the potential impact of xylazine on people who use drugs. Multidisciplinary best practices should be established.
Do Neuroprognostic Studies Account for Self-Fulfilling Prophecy Bias in Their Methodology? The SPIN Protocol for a Systematic Review
Authors: Teixeira Fernanda J. P. , Ahmad Bakhtawar , Gibatova Viktoriya , Ameli Pouya A. , Silva Ivan da , Carneiro Thiago , Roth William , Ford Jenna L. , Selfe Terry Kit , Greer David M. , Busl Katharina M. , Maciel Carolina B.
Published: June 2023

Background:

Self-fulfilling prophecy bias occurs when a perceived prognosis leads to treatment decisions that inherently modify outcomes of a patient, and thus, overinflate the prediction performance of prognostic methods. The goal of this series of systematic reviews is to characterize the extent to which neuroprognostic studies account for the potential impact of self-fulfilling prophecy bias in their methodology by assessing their adequacy of disclosing factors relevant to this bias.

Methods:

Studies evaluating the prediction performance of neuroprognostic tools in cardiac arrest, malignant ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, and spontaneous intracerebral hemorrhage will be identified through PubMed, Cochrane, and Embase database searches. Two reviewers blinded to each other’s assessment will perform screening and data extraction of included studies using Distiller SR and following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We will abstract data pertinent to the methodology of the studies relevant to self-fulfilling prophecy bias.

Results:

We will conduct a descriptive analysis of the data. We will summarize the reporting of mortality according to timing and mode of death, rates of exposure to withdrawal of life-sustaining therapy, reasoning behind limitations of supportive care, systematic use of standardized neuroprognostication algorithms and whether the tool being investigated is part of such assessments, and blinding of treatment team to results of neuroprognostic test being evaluated.

CONCLUSIONS:

We will identify if neuroprognostic studies have been transparent in their methodology to factors that affect the self-fulfilling prophecy bias. Our results will serve as the foundation for standardization of neuroprognostic study methodologies by refining the quality of the data derived from such studies.
Epidermal growth factor receptor compound and concomitant mutations: advances in precision treatment strategies
Authors: Li Wenqian , Bai Rilan , Guo Hanfei , Cui Jiuwei
Published: June 2023

Epidermal growth factor receptor (EGFR) mutations are common oncogenic driver mutations in patients with non-small cell lung cancer (NSCLC). The application of EGFR-tyrosine kinase inhibitors (TKIs) is beneficial for patients with advanced and early-stage NSCLC. With the development of next-generation sequencing technology, numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation; however, the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown. Thus, we review the incidence, prognosis, and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.
Clinicopathologic Features of Noninvasive Inverted Urothelial Papillary Tumor
Authors: Liu Ziyu , Wei Shumei , Tang Jinlong
Published: June 2023

Objectives:

Clinicopathologic features and recurrence rates of inverted noninvasive urothelial papillary tumors have been poorly characterized to date with few larger studies evaluating long-term outcomes. The spectrum of histomorphology, clinical features, and prognosis of inverted lesions of the urinary bladder are retrospectively reviewed.

Methods:

Archived paraffin-embedded urothelial tumor samples from patients diagnosed with inverted urothelial papillary lesions between January 2005 and June 2020 were collated. A matched control population of patients with exophytic papillary lesions of the urothelium diagnosed during the same time period was randomly selected. The conventional clinicopathologic features of inverted urothelial papillary tumor were evaluated retrospectively and patient demographics, tumor characteristics, recurrence, and survival information were recorded.

Results:

Lower recurrence rates were observed for inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP) relative to papillary urothelial neoplasms of low malignant potential and for low-grade papillary urothelial carcinoma with an inverted growth pattern (LG-PUCI) relative to low-grade papillary urothelial carcinomas. No recurrence was found among the inverted urothelial papilloma cases. The 2- and 5-year disease-free survival rates were 100.0% and 85.2% for IPUNLMP patients; 94.4% and 80.4% for papillary urothelial neoplasms of low malignant potential; 89.5% and 82.0% for LG-PUCI; 73.7% and 54.6% for low-grade papillary urothelial carcinoma; 40.0% and 20.0% for high-grade papillary urothelial carcinoma with an inverted growth pattern patients and 26.7% and 26.7% for high-grade papillary urothelial carcinoma. Multivariate Cox regression analysis of IPUNLMP and LG-PUCI/high-grade papillary urothelial carcinoma with an inverted growth pattern indicated that tumor number (hazard ratio=4.356; 95% CI: 1.145-16.570; P=0.031) was a powerful prognostic factor for disease-free survival.

Conclusion:

Noninvasive, papillary urothelial lesions of the bladder tend to have lower recurrence and a better outcome if an inverted growth pattern is shown.
Don't Go Breaking My Heart: Not Your Ordinary Tattoo Reaction
Authors: McKenna Brian , Lee Jack , Raghavan Shyam , Zlotoff Barrett
Published: June 2023

Necrobiosis lipoidica (NL) is a rare, chronic idiopathic granulomatous dermatitis with a somewhat controversial association with diabetes and other systemic diseases. We report a case of NL developing within a polychromic tattoo on the lower leg of a 53-year-old woman. Characteristic histopathologic findings of both active and chronic “burnt-out” NL appeared to originate from the tattoo where red ink was used 13 years prior. To the best of our knowledge, only 3 other cases of tattoo-associated NL have been reported.
Self-Healing Juvenile Cutaneous Mucinosis: A Report of Two Cases With Differing Evolution
Authors: Rodríguez-Cuadrado Francisco José , Reneses-Prieto Elvira , Silvestre-Egea Gala , López-López Agustín , Nájera-Botello Laura , Alfonso-Alberola Remedios , Moragón-Gordón Manuel , Roustan-Gullón Gaston , Onrubia-Pintado José , López-Negrete-Arenal Elena
Published: June 2023

Self-healing juvenile cutaneous mucinosis is a rare entity, characterized by the presence of subcutaneous nodules together with frequent nonspecific systemic symptoms, which occurs in the pediatric age and characteristically resolves spontaneously. Although the diagnostic criteria do not require a biopsy to be performed, it is frequently performed, and an abundant dermal mucin deposition will be observed together with other features such as fibroblastic proliferation. Although the prognosis is benign, follow-up is required for the eventual development of a rheumatologic disease.

We present 2 clinical cases, describing the clinical findings and their histopathologic correlation. Comparatively, the outcome in both cases was different: in one case, the mucinosis resolved without any related event in the follow-up, and in the other case, the resolution was accompanied by the subsequent development of idiopathic juvenile arthritis.