bluuebunny/crossref_metadata_2025 huggingface dataset:
A bioinspired neuromuscular system enabled by flexible electro-optical N2200 nanowire synaptic transistor
Authors: Hu Jiahe , Qu Shangda , Xu Honghuan , Sun Lin , Jiang Chengpeng , Yang Lu , Du Yi , Xu Wentao
Published: June 2024

Mimicking the functional traits of the muscle system evolves the development of the neuromorphic prosthetic limbs. Herein, a bioinspired neuromuscular system was constructed by connecting an information processor that uses a flexible electro-optical synaptic transistor (FNST) to an effector that uses artificial muscle fibers. In this system, the response of artificial muscle fibers, which imitate the movement of biological muscle fibers, is manipulated by neuromorphic synaptic devices. The FNST is regulated by light pulses and electrical spikes to emulate biological synaptic functions, and thereby applied in secure communication. The feasibility of n-type organic nanowires acting as the channels for neuromorphic devices was demonstrated. Attributing to the flexibility of the n-type organic semiconductor N2200 nanowires, the current of the FNST retains >85% of its initial value after the 5000 bending cycles to radius = 1 cm. The tolerance of bending of the FNST implies its potential applications in wearable electronics. This work offers an approach to potentially advancing electronic skin, neuro-controlled robots, and neuromorphic prosthetic limbs.
A minimal completion theorem and almost everywhere equivalence for completely positive maps
Authors: Bhat B. , Chongdar Arghya
Published: June 2024

A problem of completing a linear map on

C
∗

C^*

-algebras to a completely positive map is analyzed. It is shown that whenever such a completion is feasible there exists a unique minimal completion. This theorem is used to show that under some very general conditions a completely positive map almost everywhere equivalent to a quasi-pure map is actually equal to that map.
On the analyticity of the maximal extension of a number field with prescribed ramification and splitting
Authors: Lim Donghyeok , Maire Christian
Published: June 2024

We determine all the

p
p

-adic analytic groups that are realizable as Galois groups of the maximal pro-

p
p

extensions of number fields with prescribed ramification and splitting under an assumption which allows us to move away from the Tame Fontaine-Mazur conjecture.
Time-dependent uniform upper semicontinuity of pullback attractors for non-autonomous delay dynamical systems: Theoretical results and applications
Authors: Zhang Qiangheng , Caraballo Tomás , Yang Shuang
Published: June 2024

In this paper we provide general results on the uniform upper semicontinuity of pullback attractors with respect to the time parameter for non-autonomous delay dynamical systems. Namely, we establish a criteria in terms of the multi-index convergence of solutions for the delay system to the non-delay one, locally pointwise convergence and local controllability of pullback attractors. As an application, we prove the upper semicontinuity of pullback attractors for a non-autonomous delay reaction-diffusion equation to the corresponding nondelay one over any bounded time interval as the delay parameter tends to zero.
Alienation
Authors: Wills Vanessa Christina
Published: June 2024

Chapter 4 argues that human beings are essentially social beings who produce their own existence through conscious, purposive activity in the labor process. In alienation, this process is frustrated. Human products—material, social, and intellectual—take on a foreign and hostile character. Instead of furthering human aims, alienated products of human labor thwart their creators’ intentions. The fact that these ideal and material creations have been produced through human activity, and can be controlled and directed through that activity, is partly or entirely obscured. This chapter addresses a long-standing debate in Marx interpretation as to whether Marx abandons the “alienation” concept in his later work. It argues that Marx does not do so; while there are terminological changes, the “alienation” concept continues to play a substantive role in Marx’s theory. Alienation is contrary to, and impedes the development of, essential human nature; this is a central tenet of Marx’s ethical perspective.
Radical Chains (Marx on Freedom and Determinism)
Authors: Wills Vanessa Christina
Published: June 2024

This chapter introduces the term “dialectical compatibilism” to highlight how Marx’s approach to freedom and determinism enters into conversation with traditional analyses of this pairing. Much confusion surrounding Marx’s positions on freedom and determinism stems from the fact that for Marx this is an evolving, historically contingent relationship. One cannot issue timeless, universal statements about the degree to which external determining factors influence human behavior, or concerning the extent to which this behavior is the free and voluntary action of human beings. Marx’s picture is not of a compatibility between freedom and determinism that holds true in precisely the same way for all humans across time and space, but rather of a human freedom that grows, spurred in part by the operation of deterministic laws. In human activity, freedom and determinism are mutually conditioned in ways that produce their ever greater dialectical compatibility, unfolding across time.
Should the negated conditional entail its antecedent?
Authors: Omori Hitoshi
Published: June 2024

We show that there is a simple derivation of triviality with very few assumptions involving the formula that the negated conditional entails the antecedent of the conditional.
Evaluation of the HANDOC Score and the 2023 International Society of Cardiovascular Infectious Diseases and European Society of Cardiology Duke Clinical Criteria for the Diagnosis of Infective Endocarditis Among Patients With Streptococcal Bacteremia
Authors: Fourré Nicolas , Zimmermann Virgile , Senn Laurence , Monney Pierre , Tzimas Georgios , Caruana Giorgia , Tozzi Piergiorgio , Kirsch Matthias , Guery Benoit , Papadimitriou-Olivgeris Matthaios
Published: June 2024

Background

Streptococci are a common cause of infective endocarditis (IE). We aimed to evaluate the performance of the HANDOC score to identify patients at high risk for IE and the Duke clinical criteria of the European Society of Cardiology (ESC; 2015 and 2023 versions) and the 2023 version from the International Society of Cardiovascular Infectious Diseases (ISCVID) in diagnosing IE among patients with streptococcal bacteremia.

Methods

This retrospective study included adult patients with streptococcal bacteremia hospitalized at Lausanne University Hospital. Episodes were classified as IE by the Endocarditis Team. A HANDOC score >2 classified patients as high risk for IE.

Results

Among 851 episodes with streptococcal bacteremia, IE was diagnosed in 171 episodes (20%). Among 607 episodes with non-β-hemolytic streptococci, 213 (35%) had HANDOC scores >2 points; 132 (22%) had IE. The sensitivity of the HANDOC score to identify episodes at high risk for IE was 95% (95% confidence interval [CI], 90%–98%), the specificity 82% (95% CI, 78%–85%), and the negative predictive value (NPV) 98% (95% CI, 96%–99%). 2015 Duke-ESC, 2023 Duke-ISCVID, and 2023 Duke-ESC clinical criteria classified 114 (13%), 145 (17%), and 126 (15%) episodes as definite IE, respectively. Sensitivity (95% CI) for the 2015 Duke-ESC, 2023 Duke-ISCVID, and 2023 Duke-ESC clinical criteria was calculated at 65% (57%–72%), 81% (74%–86%), and 73% (65%–79%), respectively, with specificity (95% CI) at 100% (98%–100%), 99% (98%–100%), and 99% (98%–100%), respectively.

Conclusions

The HANDOC score showed an excellent NPV to identify episodes at high risk for IE. Among the different versions of the Duke criteria, the 2023 Duke-ISCVID version fared better for the diagnosis of IE among streptococcal bacteremia.
Functional modularity and mechanical stress shape plastic responses during fish development
Authors: Lofeu Leandro , Montefeltro Felipe , Simon Monique Nouailhetas , Kohlsdorf Tiana
Published: June 2024

The adaptive potential of plastic phenotypes relies on combined developmental responses. We investigated how manipulation of developmental conditions related to foraging mode in the fish Megaleporinus macrocephalus induces plastic responses at different levels: (a) functional modularity of skull bones, (b) biomechanical properties of the chondrocranium using finite element models, (c) bmp4 expression levels, used as a proxy for molecular pathways involved in bone responses to mechanical load. We identified new modules in experimental groups, suggesting increased integration in specific head bone elements associated with the development of subterminal and upturned mouths, which are major features of Megaleporinus plastic morphotypes released in the lab. Plastic responses in head shape involved differences in the magnitude of mechanical stress, which seem restricted to certain chondrocranium regions. Three bones represent a “mechanical unit” related to changes in mouth position induced by foraging mode, suggesting that functional modularity might be enhanced by the way specific regions respond to mechanical load. Differences in bmp4 expression levels between plastic morphotypes indicate associations between molecular signaling pathways and biomechanical responses to load. Our results offer a multilevel perspective of epigenetic factors involved in plastic responses, expanding our knowledge about mechanisms of developmental plasticity that originate novel complex phenotypes.
The Assessment of Patent Validity by the Unified Patent Court
Authors: Meier-Beck Peter
Published: June 2024

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

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

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

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

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.
Horizontal Agreements—Cartels and Collusion
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter examines how EU competition law applies both to undertakings operating cartels and to undertakings that tacitly coordinate their behaviour on a market. It starts by looking at the difference between ‘explicit’ and ‘tacit’ collusion. The chapter then deals with cartels and other agreements akin to cartels, or which may facilitate explicit or tacit collusion on a market. Next, it considers the problem of tacit collusion and whether, in particular, Articles 101 and 102 operate as effective mechanisms for dealing with the oligopoly problem. The chapter also considers other options that EU competition law might offer to deal with tacit collusion, either ex ante or ex post, such as the use of the concept of collective dominance and sector inquiries under Regulation 1/2003, Article 17.
EU Competition Law and Policy in the Digital Economy
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter considers the application of the EU competition rules specifically within the digital economy. It considers: the competition dynamics that typically arise in digital markets; examples of competition enforcement in digital markets at EU level to date; and some of the enforcement challenges that arise, including the limited scope of application of the EU competition rules, the prevalence of novel or controversial theories of harm, and the speed of intervention and effectiveness of remedies that can be imposed. The chapter also explores efforts to augment the ordinary competition law framework in the digital context. In particular, it considers the provisions and implications of the Digital Markets Act, which imposes a series of prescriptive ex ante obligations on large digital gatekeepers.
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

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

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

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

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.

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

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

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.
Differential expression of NAT1 pharmacogene in hormone receptor positive vs. negative female breast tumors may affect drug treatment
Authors: Ivanova Desislava , Fakis Giannoulis , Boukouvala Sotiria
Published: June 2024

Studies have reported overexpression of NAT1 gene for xenobiotic metabolizing arylamine N-acetyltransferase type 1 in estrogen receptor positive breast tumors, and this association has been linked to patient chemoresistance and response to tamoxifen. We probed the expression of NAT1, using quantitative reverse transcription PCR to screen clinically characterized breast cancer tissue cDNA arrays. Primers detecting all NAT1 alternative transcripts were used, and the protocol and results are reported according to consensus guidelines. The clinical information about 166 tumor samples screened is provided, including tumor stage, estrogen and progesterone receptor status and HER2 expression. NAT1 was found to be significantly (P < 0.001) upregulated in hormone receptor positive vs. negative tumors. No correlation was apparent between NAT1 and tumor stage or HER2 expression. Our findings demonstrate a strong correlation between the expression of NAT1 and steroid hormone receptors in breast tumors, supporting its possible utility as a pharmacogenetic biomarker or drug target. Of the two polymorphic NAT genes, NAT1 is the one primarily expressed in breast tissue, and is subjected to regulation by two differential promoters and more than one polyadenylation signal. Hormonal factors may enhance NAT1 gene expression at the transcriptional or epigenetic level, and tamoxifen has additionally been shown to inhibit NAT1 enzymatic activity. The outcome of tamoxifen treatment is also more favorable in patients with NAT1 overexpressing tumors. The study adds to the growing body of evidence implicating NAT1 in breast cancer and its pharmacological treatment.
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.
Association between leisure-time physical activity and arterial stiffness in adults of the ELSA-Brasil study: a mediation analysis
Authors: Baldo Marcelo P. , Zaniqueli Divanei A. , Cunha Roberto S. , Griep Rosane H. , Barreto Sandhi M. , Bensenor Isabela , Lotufo Paulo A. , Mill José Geraldo
Published: June 2024

Objectives:

We aimed at defining the direct and the mediated pathways for the association between leisure-time physical activity (LTPA) and carotid-to-femoral pulse wave velocity (cf-PWV), and also to identify whether these effects are influenced by sex and age.

Methods:

Cross-sectional data from 13 718 adults (35–74 years) were obtained at the baseline of the ELSA-Brasil study. The cf-PWV was obtained by measuring the pulse transit time and the distance traveled by the pulse between the carotid and the femoral, as well as clinical and anthropometric parameters were measured. The levels of LTPA were determined by applying the long form of the International Physical Activity Questionnaire (IPAQ).

Results:

Classical cardiovascular risk factors were independently associated with cf-PWV. Path analysis showed that increased levels of LTPA were directly associated with lower cf-PWV in both men and women (β: −0.123 ± 0.03 vs. 0.065 ± 0.029, P for sex = 0.165), except for diabetes. Also, the mediated effect of LTPA on SBP and DBPs, heart rate, BMI, and fasting glucose, was associated with lower cf-PWV in men and women (β: −0.113 ± 0.016 vs. −0.104 ± 0.016, P for sex = 0.692), except for diabetes. When age was tested as a moderator, the direct effect did not change significantly according to participants’ age, regardless of sex. However, the mediated effect increases in both men and women over 50 years.

Conclusion:

Our findings support that LTPA in adults reduces cf-PWV by acting in different ways according to age. Physical activity in older individuals improves cardiometabolic risk factors and thus mitigates the stiffening of large arteries.
Unraveling the neuroimmune interface in chronic pain—the association between cytokines in the cerebrospinal fluid and pain in patients with lumbar disk herniation or degenerative disk disease
Authors: Rosenström Alexander H.C. , Ahmed Aisha Siddiqah , Kultima Kim , Freyhult Eva , Berg Svante , Bersellini Farinotti Alex , Palada Vinko , Svensson Camilla I. , Kosek Eva
Published: June 2024

Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity.
Vitamin C for all?
Authors: de Man Angelique , Long Micah T. , Stoppe Christian
Published: June 2024

Purpose of review

Vitamin C can be a potential adjunctive treatment option for critically ill individuals due to its pleiotropic effects as electron donor in many enzymatic reactions throughout the body. Recently, several important randomized controlled trials (RCTs) investigating vitamin C in critically ill patients have been published.

Recent findings

Two recent large RCTs administering high-dose vitamin C to patients with sepsis and COVID-19 showed signs of harm. Though performed at high standard, these trials had several limitations. Recent studies in cardiac surgery and burns showed decreased cardiac enzymes and improved clinical outcomes after cardiac surgery, and decreased fluid requirements, reduced wound healing time and in-hospital mortality after burns. Vitamin C may hold benefit in the management of other ischemia/reperfusion injury populations, including postcardiac arrest patients and after solid organ transplantation. Currently, covering basal vitamin C requirements during critical illness is recommended, though the exact dose remains to be determined.

Future work should address optimal vitamin C timing, since early versus late drug administration are likely distinct, and duration of therapy, where withdrawal-induced injury is possible. Additionally accurate assessment of body stores with determination of individual vitamin requirements is crucial to ascertain patient and subgroups most likely to benefit from vitamin C.
Understanding the complexity of cardiogenic shock management: the added value of advanced computational modeling
Authors: Meuwese Christiaan L. , van Loon Lex M. , Donker Dirk W.
Published: June 2024

Purpose of review

The purpose of this review is to explain the value of computational physiological modeling for in-depth understanding of the complex derangements of cardiopulmonary pathophysiology during cardiogenic shock, particularly when treated with temporary mechanical circulatory support (tMCS) devices.

Recent findings

Computational physiological models have evolved in recent years and can provide a high degree of clinical realism in the simulation of cardiogenic shock and related conservative and interventional therapies. These models feature a large spectrum of practically relevant hemodynamic and respiratory parameters tunable to patient-specific disease states as well as adjustable to medical therapies and support device settings. Current applications work in real-time and can operate on an ordinary computer, laptop or mobile device.

The use of computational physiological models is increasingly appreciated for educational purposes as they help to understand the complexity of cardiogenic shock, especially when sophisticated management of tMCS is involved in addition to multimodal critical care support. Practical implementation of computational models as clinical decision support tools at the bedside is at the horizon but awaits rigorous clinical validation.
Sex differences in the presentation and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock: a critical review of contemporary data and a look towards future directions
Authors: Smith Emily , Tamis-Holland Jacqueline E.
Published: June 2024

Purpose of review

Cardiogenic shock (CS) is a devasting complicating of acute myocardial infarction (AMI), associated with significant mortality. Prior studies have reported sex differences in the presentation, management and outcomes of patients with AMI and CS. These differences are likely due to a variety of factors influencing therapeutic decision-making and impacting survival. This review highlights the more contemporary studies exploring differences in women and men with AMI-CS, providing a critical perspective towards understanding the factors that might lead to these differences and outlining potential opportunities to reduce disparities in treatment and improve survival for women with AMI-CS.

Recent findings

Recent reports demonstrate that women with AMI-CS are older than men and have more cardiovascular comorbidities. When examining an unselected population of patients with AMI-CS, women receive less aggressive treatment compared to men and have poorer outcomes. However, when examining a selected population of patients with AMI-CS treated with mechanical circulatory support (MCS) and/or admitted to centers that implement CS protocols to manage AMI-CS, these sex-based differences in outcomes are largely mitigated.

Standardizing protocols for the diagnosis and treatment of patients with AMI-CS, with an emphasis on early revascularization and appropriate invasive therapies, can improve outcomes in women and narrow the gender gap.
A practical approach to preparing your ICU for epidemics and pandemics
Authors: Maves Ryan C. , Cawcutt Kelly A.
Published: June 2024

Purpose of review

Major outbreaks of infectious diseases, including epidemics and pandemics, are increasing in scope and frequency, threatening public health and straining the capacity of health systems worldwide. High-consequence infectious diseases (HCIDs), including highly pathogenic respiratory viruses and viral hemorrhagic fevers, are both contagious and virulent, and these pathogens thus are topics of special concern for pandemic planning.

Recent findings

The COVID-19 pandemic demonstrated how a major disease outbreak can negatively impact all aspects of hospital functioning. Identification of patients with HCIDs needs careful clinical evaluation and coordination with public health authorities. Staff safety and patient care require appropriate infection prevention precautions, including personal protective equipment. Surges of ill patients may lead to significant strain, with increased ICU patient mortality. Strategies to reduce the impact of surge appear to reduce mortality, such as tiered staffing models and load-leveling across health systems.

Pandemics and HCIDs are a significant threat to global health, and ICUs play a major role in the care of affected patients. Critical care professionals must work to ensure that our hospitals are prepared to identify and care for these patients in advance of the next emergency.
Clonal hematopoiesis: a shared risk factor for cardiovascular diseases and tumors
Authors: Zha Ling-Feng , Cheng Xiang
Published: June 2024

Clonal hematopoiesis (CH) is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation. Genes integral to critical cellular processes such as epigenetic regulation, DNA damage response, and inflammation frequently carry these mutations. Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions. Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis. Here, we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH, as well as look forward to future related studies, so as to provide valuable references for future research and clinical practice.