bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Assessment of Patent Validity by the Unified Patent Court
Authors: Meier-Beck Peter 
Published: June 2024

Abstract
A little more than six months after the Unified Patent Court commenced its work, the judgment of the Court of Appeal in 10x Genomics v. NanoString is the first final decision of the new court to deal in detail with the interpretation of an asserted patent claim and, based on this, with the assessment of the patentability of the subject-matter of a European patent. On the basis of this patent, a preliminary injunction was requested and issued by the Munich Local Division of the Court of First Instance. This fact alone shows that the significance of the decision can hardly be overestimated. A closer analysis of the decision confirms that it provides a wealth of insights into the way in which the UPC will deal with the questions of novelty and inventive step, which are at the centre of the examination of the validity of a patent in proceedings for interim measures, but also in proceedings on the merits. This article attempts to summarise the most important findings on substantive patent law and its application that can be derived from the decision of the UPC Court of Appeal.
Clinical characteristics and genome epidemiology of Stenotrophomonas maltophilia in Japan
Authors: Hase Ryota , Sakurai Aki , Suzuki Masahiro , Itoh Naoya , Hayakawa Kayoko , Uemura Kohei , Matsumura Yasufumi , Kato Hideaki , Ishihara Takuma , van Duin David , Ohmagari Norio , Doi Yohei , Saito Sho 
Published: June 2024

Abstract

Background
Stenotrophomonas maltophilia is a carbapenem-resistant Gram-negative pathogen increasingly responsible for difficult-to-treat nosocomial infections.

Objectives
To describe the contemporary clinical characteristics and genome epidemiology of patients colonized or infected by S. maltophilia in a multicentre, prospective cohort.

Methods
All patients with a clinical culture growing S. maltophilia were enrolled at six tertiary hospitals across Japan between April 2019 and March 2022. The clinical characteristics, outcomes, antimicrobial susceptibility and genomic epidemiology of cases with S. maltophilia were investigated.

Results
In total, 78 patients were included representing 34 infection and 44 colonization cases. The median age was 72.5 years (IQR, 61–78), and males accounted for 53 cases (68%). The most common comorbidity was localized solid malignancy (39%). Nearly half of the patients (44%) were immunosuppressed, with antineoplastic chemotherapy accounting for 31%. The respiratory tract was the most common site of colonization (86%), whereas bacteraemia accounted for most infection cases (56%). The 30 day all-cause mortality rate was 21%, which was significantly higher in infection cases than colonization cases (35% versus 9%; adjusted HR, 3.81; 95% CI, 1.22–11.96). Susceptibility rates to ceftazidime, levofloxacin, minocycline and sulfamethoxazole/trimethoprim were 14%, 65%, 87% and 100%, respectively. The percentage of infection ranged from 13% in the unclassified group to 86% in genomic group 6A. The percentage of non-susceptibility to ceftazidime ranged from 33% in genomic group C to 100% in genomic groups 6 and 7 and genomic group geniculate.

Conclusions
In this contemporary multicentre cohort, S. maltophilia primarily colonized the respiratory tract, whereas patients with bacteraemia had the highest the mortality from this pathogen. Sulfamethoxazole/trimethoprim remained consistently active, but susceptibility to levofloxacin was relatively low. The proportions of cases representing infection and susceptibility to ceftazidime differed significantly based on genomic groups.
The prevalence and mechanisms of heteroresistance to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae
Authors: Zhang Xiaotuan , Zeng Weiliang , Kong Jingchun , Huang Zeyu , Shu Hongyun , Tang Miran , Qian Changrui , Xu Chunquan , Zhou Tieli , Ye Jianzhong 
Published: June 2024

Abstract

Objectives
To investigate the prevalence and mechanisms of ceftazidime/avibactam heteroresistance in KPC-producing Klebsiella pneumoniae (KPC-KP) isolates, as well as the role of heteroresistance in the transition of ceftazidime/avibactam susceptibility to resistance.

Methods
Clinical KPC-KP isolates were obtained from a tertiary hospital in China from 2016 to 2017 and 2019 to 2020. Antimicrobial susceptibility was determined by the broth microdilution method. Population analysis profiles were used to assess ceftazidime/avibactam heteroresistance. WGS and molecular cloning were conducted to reveal heteroresistance mechanisms and molecular characteristics.

Results
The findings indicated that the transition of ceftazidime/avibactam susceptibility to resistance during the treatment of KPC-KP infection is primarily attributed to the heteroresistance exhibited by KPC-KP isolates towards ceftazidime/avibactam. Among 355 ceftazidime/avibactam-susceptible KPC-KP isolates (indicating a resistance rate of 0%), 41 (11.55%) exhibited ceftazidime/avibactam heteroresistance, with the primary mechanism being the presence of KPC mutant subpopulations. These KPC variants, arising from point mutations, deletions and insertions, significantly increased ceftazidime/avibactam resistance while alongside enhanced carbapenem susceptibility. Notably, 11 new KPC variants were identified. Furthermore, four heteroresistant isolates were caused by mixed infection involving subpopulations carrying NDM-1 or NDM-5. Phylogenetic analysis indicated that the clonal spread of ST11-KL64 KPC-KP may be correlated with the prevalence of heteroresistance.

Conclusions
Ceftazidime/avibactam heteroresistance, primarily driven by pre-existing KPC variants, underscores the importance of considering heteroresistance in ceftazidime/avibactam therapeutics. Awareness of these dynamics is crucial for the effective and sustainable clinical application of ceftazidime/avibactam.
Shared genetic basis connects smoking behaviors and bone health: insights from a genome-wide cross-trait analysis
Authors: Qin Chenjiarui , Zhang Wenqiang , Xiao Changfeng , Qu Yang , Xiao Jinyu , Wu Xueyao , Zhang Li , Wang Yutong , He Lin , Zhu Jingwei , Wang Wenzhi , Li Yun , Sun Lei , Jiang Xia 
Published: June 2024

Abstract
Although the negative association of tobacco smoking with osteoporosis is well-documented, little is known regarding the shared genetic basis underlying these conditions. In this study, we aim to investigate a shared genetic architecture between smoking and heel estimated bone mineral density (eBMD), a reliable proxy for osteoporosis. We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci and causal relationship of smoking with eBMD, leveraging summary statistics of the hitherto largest genome-wide association studies conducted in European ancestry for smoking initiation (Nsmoker = 1 175 108, Nnonsmoker = 1 493 921), heaviness (cigarettes per day, N = 618 489), cessation (Ncurrent smoker = 304 244, Nformer smoker = 843 028), and eBMD (N = 426 824). A significant negative global genetic correlation was found for smoking cessation and eBMD (${r}_g$ = −0.051, P = 0.01), while we failed to identify a significant global genetic correlation of smoking initiation or heaviness with eBMD. Partitioning the whole genome into independent blocks, we observed 6 significant shared local signals for smoking and eBMD, with 22q13.1 showing the strongest regional genetic correlation. Such a genetic overlap was further supported by 71 pleiotropic loci identified in the cross-trait meta-analysis. Mendelian randomization identified no causal effect of smoking initiation (beta = −0.003 g/cm2, 95% CI = −0.033 to 0.027) or heaviness (beta = −0.017 g/cm2, 95% CI = −0.072 to 0.038) on eBMD, but a putative causal effect of genetic predisposition to being a current smoker was associated with a lower eBMD compared to former smokers (beta = −0.100 g/cm2, 95% CI = −0.181 to −0.018). Our study demonstrates a pronounced biological pleiotropy as well as a putative causal link between current smoking status and eBMD, providing novel insights into the primary prevention and modifiable intervention of osteoporosis by advocating individuals to avoid, reduce or quit smoking as early as possible.
Acute hemolytic transfusion reaction caused by anti-M antibodies: a case report and literature review
Authors: He Yanjing , Li Yang , Wang Qiushi 
Published: June 2024

Abstract

Objective
We report a rare case of acute hemolytic reactions caused by immunoglobulin (Ig)M anti-M antibody and present a literature review.

Case Report
A 61-year-old male patient who underwent blood transfusion developed fever, chills, soy sauce–colored urine, and changes in laboratory test results, including persistently decreased hemoglobin levels, neutrophilia, elevated lactate dehydrogenase level, acute kidney injury, mild acute liver injury, and activation of the coagulation system, indicating acute hemolytic transfusion reaction (AHTR). Antibody screening and major crossmatching results indicated weak positive at 37°C for both posttransfusion and pretransfusion sample. Subsequent serological examinations indicated the presence of IgM anti-M antibodies in plasma but the direct antiglobulin and elution tests were negative. Antibody hemolytic activity assay confirmed AHTR caused by anti-M. The transfused red blood cells were MM and the patient is NN. These signs and symptoms disappeared rapidly and required no additional interventions before discharge.

Conclusion
The accurate diagnosis of anti-M antibody–mediated acute hemolysis is essential for guiding treatment decisions.
Entropy-based syntactic tree analysis for text classification: a novel approach to distinguishing between original and translated Chinese texts
Authors: Wang Zhongliang , Cheung Andrew K F , Liu Kanglong 
Published: June 2024

Abstract
This research focuses on classifying translated and non-translated Chinese texts by analyzing syntactic rule features, using an integrated approach of machine learning and entropy analysis. The methodology employs information entropy to gauge the complexity of syntactic rules in both text types. The methodology is based on the concept of information entropy, which serves as a quantitative measure for the complexity inherent in syntactic rules as manifested from tree-based annotations. The goal of the study is to explore whether translated Chinese texts demonstrate syntactic characteristics that are significantly different from those of non-translated texts, thereby permitting a reliable classification between the two. To do this, the research calculates information entropy values for syntactic rules in two comparable corpora, one of translated and the other of non-translated Chinese texts. Then, various machine learning models are applied to these entropy metrics to identify any significant differences between the two groups. The results show significant differences in the syntactic structures. Translated texts have a higher degree of entropy, indicating more complex syntactic constructs compared to non-translated texts. These findings contribute to our understanding of the effect of translation on language syntax, with implications for text classification and translation studies.
Low CI/CO abundance ratio revealed by HST UV spectroscopy of CO-rich debris discs
Authors: Brennan Aoife , Matrà Luca , Marino Sebastián , Wilner David , Qi Chunhua , Hughes A Meredith , Roberge Aki , Hales Antonio S , Redfield Seth 
Published: June 2024

ABSTRACT
The origin and evolution of CO gas in debris discs has been debated since its initial detection. The gas could have a primordial origin, as a remnant of the protoplanetary disc or a secondary exocometary origin. This paper investigates the origin of gas in two debris discs, HD110058 and HD131488, using Hubble Space Telescope (HST) observations of CI and CO, which play critical roles in the gas evolution. We fitted several electronic transitions of CI and CO rovibronic bands to derive column densities and temperatures for each system, revealing high CO column densities (∼3–4 orders of magnitude higher than β Pictoris), and low CI/CO ratios in both. Using the exogas model, we simulated the radial evolution of the gas in the debris disc assuming a secondary gas origin. We explored a wide range of CO exocometary release rates and α viscosities, which are the key parameters of the model. Additionally, we incorporated photodissociation due to stellar ultraviolet (UV) to the exogas model and found that it is negligible for typical CO-rich discs and host stars, even at a few au due to the high radial optical depths in the Extreme ultraviolet radiation (EUV). We find that the current steady-state secondary release model cannot simultaneously reproduce the CO and CI HST-derived column densities, as it predicts larger CI/CO ratios than observed. Our direct UV measurement of low CI/CO ratios agrees with results derived from recent Atacama Large Millimetre/submillimetre Array findings and may point to vertical layering of CI, additional CI removal, CO shielding processes, or different gas origin scenarios.
Liam tackles complex multimodal single-cell data integration challenges
Authors: Rautenstrauch Pia , Ohler Uwe 
Published: June 2024

Abstract
Multi-omics characterization of single cells holds outstanding potential for profiling the dynamics and relations of gene regulatory states of thousands of cells. How to integrate multimodal data is an open problem, especially when aiming to combine data from multiple sources or conditions containing both biological and technical variation. We introduce liam, a flexible model for the simultaneous horizontal and vertical integration of paired single-cell multimodal data and mosaic integration of paired with unimodal data. Liam learns a joint low-dimensional representation of the measured modalities, which proves beneficial when the information content or quality of the modalities differ. Its integration accounts for complex batch effects using a tunable combination of conditional and adversarial training, which can be optimized using replicate information while retaining selected biological variation. We demonstrate liam’s superior performance on multiple paired multimodal data types, including Multiome and CITE-seq data, and in mosaic integration scenarios. Our detailed benchmarking experiments illustrate the complexities and challenges remaining for integration and the meaningful assessment of its success.
YjgA plays dual roles in enhancing PTC maturation
Authors: Du Mengtan , Deng Chenke , Yu Ting , Zhou Qixin , Zeng Fuxing 
Published: June 2024

Abstract
Ribosome biogenesis is a highly regulated cellular process that involves the control of numerous assembly factors. The small protein YjgA has been reported to play a role in the late stages of 50S assembly. However, the precise molecular mechanism underlying its function remains unclear. In this study, cryo-electron microscopy (cryo-EM) structures revealed that depletion of YjgA or its N-terminal loop in Escherichia coli both lead to the accumulation of immature 50S particles with structural abnormalities mainly in peptidyl transferase center (PTC) and H68/69 region. CryoDRGN analysis uncovered 8 and 6 distinct conformations of pre50S for ΔyjgA and YjgA-ΔNloop, respectively. These conformations highlighted the role of the N-terminal loop of YjgA in integrating uL16 and stabilizing H89 in PTC, which was further verified by the pull-down assays of YjgA and its mutants with uL16. Together with the function of undocking H68 through the binding of its C-terminal CTLH-like domain to the base of the L1 stalk, YjgA facilitates the maturation of PTC. This study identified critical domains of YjgA contributing to 50S assembly efficiency, providing a comprehensive understanding of the dual roles of YjgA in accelerating ribosome biogenesis and expanding our knowledge of the intricate processes governing cellular protein synthesis.
Why sedative hypnotics often fail in development
Authors: Sneyd J. Robert 
Published: June 2024

Purpose of review
Drug development to support anaesthesia and sedation has been slow with few candidates emerging from preclinical discovery and limited innovation beyond attempted reformulation of existing compounds.

Recent findings
The market is well supported by low-cost generic products and development compounds have not been shown to improve patient outcomes or possess other distinctive characteristics to justify the cost of development.

Summary
To make progress in a large-volume, low margin and highly competitive environment requires meaningful advances in relevant basic science. Opportunities exist, but probably require bolder initiatives than further attempts at reformulation or fiddling with the structure of propofol. Extending development ambitions to include nonanaesthesiologist providers challenges professional boundaries but may facilitate cost-effective changes in patterns of care.
Granulomatous Panniculitis as an Initial Manifestation of Sjögren Syndrome
Authors: Méndez-Flores Silvia , Méndez-Pérez R. Angélica , Saeb-Lima Marcela , Hernández-Molina Gabriela 
Published: June 2024

Abstract:
A 65-year-old woman presented with unexplained weight loss, recurrent fever, and a dermatosis with painful nodules on the extremities. Biopsies showed focal lobular panniculitis with neutrophilic microgranulomas. Comprehensive investigations ruled out infection and hematologic and solid organ neoplasms. Laboratory results showed anti-Ro/SSA and anti-La/SSB antibody positivity, and elevated inflammatory markers. Dry mouth and eye were confirmed. The diagnosis of Sjögren syndrome with cutaneous panniculitis was established. Prednisone treatment with 30 mg/d resulted in remission of fever and pain improvement. This case emphasizes Sjögren syndrome as an autoimmune disease with multiple cutaneous manifestations and highlights its association with granulomatous panniculitis.
Histopathologic Features of Drug Reaction With Eosinophilia and Systemic Symptoms
Authors: Ehsan Emily , Wei Erin X. , Georgesen Corey 
Published: June 2024

Importance:
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous adverse reaction occurring 2 to 8 weeks after medication initiation. Diagnosis is clinical; RegiSCAR scoring includes biopsy “suggestive of DRESS,” undefined in the literature.

Objective:
This study correlates DRESS dermatopathology, culprit drugs, disease course, and outcome severity compared with maculopapular drug reactions (MDR).

Methods:
Between 2014 and 2023, a retrospective cohort study at a tertiary care institute reviewed 55 patients with DRESS, assessing demographics, culprit drug, illness course, and histopathology. Biopsies of 15 patients with DRESS and 15 MDR patients were graded by a predefined histopathological scoring system. Statistical analysis (significant P-value<0.05) included the Fisher exact probability, ANOVA, and correlation tests.

Results:
Among 55 patients with DRESS (mean age 50.13, 28 female/27 male), 15 (mean age 50.4, 7 female/8 male) had diagnostic biopsies. Compared with MDR patients, patients with DRESS exhibited significantly more interface dermatitis (P = 0.04), lichenoid dermatitis (P = 0.0007), pigment incontinence (P = 0.04), and periadnexal interface dermatitis (P = 0.002). MDR biopsies displayed perivascular inflammation and higher eosinophils than DRESS, trending toward significance.

Conclusions:
Key histopathologic features are interface dermatitis, periadnexal interface dermatitis, lichenoid dermatitis, pigment incontinence, and neutrophils dominance over eosinophils indicate DRESS clinically.
Enfortumab Vedotin Drug Eruption: Cutaneous Adverse Events and Histopathologic Findings
Authors: Casale Fiore , Roth Gretchen , Wanat Karolyn , Saab-Chalhoub Mario 
Published: June 2024

Abstract:
Enfortumab is a monoclonal antibody directed against nectin-4 and, when combined with vedotin, is an antibody–drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancers. A 75-year-old woman with stage IV papillary urothelial carcinoma of the bladder who completed cycle 2 of enfortumab vedotin (EV) infusions presented to our dermatology department for new-onset symmetric and painful dusky erythematous patches on the extremities and trunk without mucosal involvement. Two biopsies were obtained, which revealed an interface dermatitis with notable ring mitoses within the basal and suprabasal layers of the epidermis without epidermal necrosis. The patient was diagnosed with toxic erythema of chemotherapy and improved with application of triamcinolone 0.1% ointment twice daily without discontinuation of her EV infusions. Although a targeted therapy, EV commonly exhibits cutaneous side effects due to the expression of nectin-4 in the skin. Most cutaneous side effects are mild and can be managed symptomatically. However, severe drug-induced eruptions, such as toxic epidermal necrolysis, have been described. The histologic findings of EV associated skin eruptions can aid in correctly identifying the culprit drug and assist in management. This case provides insights for dermatologists by highlighting the common cutaneous side effects of EV and the associated histologic findings as this targeted therapy becomes increasingly utilized in the treatment of refractory neoplasms.
Efficacy and Safety of Programmed Death 1/Programmed Death-Ligand 1 Plus Cytotoxic T-Lymphocyte–Associated Antigen 4 Inhibitors for Advanced or Metastatic Non–Small Cell Lung Cancer: A Meta-analysis Based on Randomized Controlled Trials
Authors: Ren Wei , Fang Yingying , He Yujing , Ren Yifeng , Wang Minfang , Xu Anyi , Ruan Jiale , Tao Qinghua 
Published: June 2024

Background:
This meta-analysis aims to investigate the efficacy and safety of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) combined with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors for patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Methods:
Authors conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Medline for randomized controlled trials comparing the prognosis and safety of PD-1/PD-L1 plus CTLA-4 inhibitors with other therapies for advanced or metastatic NSCLC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used as effect sizes. The primary outcomes of this study were overall survival (OS) and progression-free survival.

Results:
A total of 4943 patients diagnosed with stage III/IV advanced or metastatic NSCLC were included in the analysis of the 6 randomized controlled trials. The results showed that patients receiving dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors had a longer survival time compared with the control group (HR = 0.88, P = 0.044). However, no statistically significant difference was observed in progression-free survival (HR = 0.95, P = 0.579). Subgroup analysis revealed better OS in the interventional group for patients aged >65 years (HR = 0.88, P = 0.076), smokers (HR = 0.81, P = 0.036), and those with a tumor mutational burden (TMB) ≥20 mut/Mb (HR = 0.66, P < 0.001). Conversely, the control group demonstrated superior OS in patients with TMB <20 mut/Mb (HR = 1.14, P = 0.048). In addition, the statistical results indicated a lower incidence rate of any-grade anemia in the dual immunotherapy group compared with the control group (RR = 0.32, P = 0.04).

Conclusions:
This meta-analysis demonstrates the effectiveness and safety of dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors for treating advanced or metastatic NSCLC. Its efficacy is influenced by certain clinical and pathological factors, such as age, smoking status, and TMB.