bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radical cure for Plasmodium vivax malaria after G6PD qualitative testing in four provinces in Cambodia, results from Phase I implementation
Authors: Lek Dysoley , Tsai Yu-Cheng , Hirano Jillian , Sovannaroth Siv , Bunreth Voeurng , Vonn Prak , Vannthen Or , Bunkea Tol , Samphornarann Top , Sokomar Nguon , Sarath Mak , Kheang Soy Ty , Wong Evelyn , Burbach Michelle K. , Hughes Jayme , Rekol Huy 
Published: February 2024

Abstract
Background
Cambodia aims to eliminate all forms of malaria by 2025. In 2020, 90% of all malaria cases were Plasmodium vivax. Thus, preventing P. vivax and relapse malaria is a top priority for elimination. 14-day primaquine, a World Health Organization-recommended radical cure treatment regimen, specifically targets dormant hypnozoites in the liver to prevent relapse. Cambodia introduced P. vivax radical cure with primaquine after glucose-6-phosphate dehydrogenase (G6PD) qualitative testing in 2019. This paper presents Cambodia’s radical cure Phase I implementation results and assesses the safety, effectiveness, and feasibility of the programme prior to nationwide scale up.

Methods
Phase I implementation was carried out in 88 select health facilities (HFs) across four provinces. Males over 20kgs with confirmed P. vivax or mixed (P. vivax and Plasmodium falciparum) infections were enrolled. A descriptive analysis evaluated the following: successful referral to health facilities, G6PD testing results, and self-reported 14-day treatment adherence. P. vivax incidence was compared before and after radical cure rollout and a controlled interrupted time series analysis compared the estimated relapse rate between implementation and non-implementation provinces before and after radical cure.

Results
In the 4 provinces from November 2019 to December 2020, 3,239 P. vivax/mixed infections were reported, 1,282 patients underwent G6PD deficiency testing, and 959 patients received radical cure, achieving 29.6% radical cure coverage among all P. vivax/mixed cases and 98.8% coverage among G6PD normal patients. Among those who initiated radical cure, 747 patients (78%) completed treatment. Six patients reported side effects. In implementation provinces, an average 31.8 relapse cases per month were estimated signaling a 90% (286 cases) reduction in relapse compared to what would be expected if radical cure was not implemented.

Conclusions
Plasmodium vivax radical cure is a crucial tool for malaria elimination in Cambodia. The high coverage of radical cure initiation and adherence among G6PD normal patients demonstrated the high feasibility of providing radical cure at point of care in Cambodia. Incomplete referral from community to HFs and limited capacity of HF staff to conduct G6PD testing in high burden areas led to lower coverage of G6PD testing. Phase I implementation informed approaches to improve referral completion and patient adherence during the nationwide expansion of radical cure in 2021.
Improving access to HIV care among people who inject drugs through tele-harm reduction: a qualitative analysis of perceived discrimination and stigma
Authors: Scaramutti Carolina , Hervera Belén , Rivera Yanexy , Chueng Teresa A. , Forrest David W. , Suarez Edward , Serota, David P. , Alkamli Hatoun , Ciraldo Katrina , Bartholomew Tyler S. , Tookes Hansel E. 
Published: February 2024

AbstractBackgroundTele-harm reduction (THR) is a telehealth-enhanced, peer-led, harm reduction intervention delivered within a trusted syringe services program (SSP) venue. The primary goal of THR is to facilitate linkage to care and rapid, enduring virologic suppression among people who inject drugs (PWID) with HIV. An SSP in Miami, Florida, developed THR to circumvent pervasive stigma within the traditional healthcare system.MethodsDuring intervention development, we conducted in-depth interviews with PWID with HIV (n = 25) to identify barriers and facilitators to care via THR. We employed a general inductive approach to transcripts guided by iterative readings of the raw data to derive the concepts, themes, and interpretations of the THR intervention.ResultsOf the 25 PWID interviewed, 15 were in HIV care and adherent to medication; 4 were in HIV care but non-adherent; and 6 were not in care. Themes that emerged from the qualitative analysis included the trust and confidence PWID have with SSP clinicians as opposed to professionals within the traditional healthcare system. Several barriers to treatment were reported among PWID, including perceived and actual discrimination by friends and family, negative internalized behaviors, denial of HIV status, and fear of engaging in care. Facilitators to HIV care included empathy and respect by SSP staff, flexibility of telehealth location, and an overall destigmatizing approach.ConclusionPWID identified barriers and facilitators to receipt of HIV care through the THR intervention. Interviews helped inform THR intervention development, centered on PWID in the destigmatizing environment of an SSP.
The Prader-Willi syndrome Profile: validation of a new measure of behavioral and emotional problems in Prader-Willi syndrome
Authors: Dykens Elisabeth M. , Roof Elizabeth , Hunt-Hawkins Hailee 
Published: February 2024

Abstract
Background
Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder caused by the lack of expression of paternally imprinted genes on chromosome 15q11-13. PWS features a complex behavioral phenotype, including hyperphagia, anxiety, compulsivity, rigidity, repetitive speech, temper outbursts, aggressivity, and skin-picking. Questionnaires exist for measuring hyperphagia, but not for the aggregation of other problems that are distinctive to PWS. A PWS-specific tool is needed for phenotypic research, and to help evaluate treatment efficacy in future clinical trials aimed at attenuating PWS’s hyperphagia and related problems. In this 4-phase study, we leveraged our expertise in PWS with feedback from families and specialists to validate the PWS Profile, a novel, informant-based measure of behavioral and emotional problems in this syndrome.

Results
The authors developed a bank of 73 items that tapped both common and less frequent but clinically significant problems in PWS (Phase 1). An iterative feedback process with families and stakeholders was used to ensure content and construct validity (Phase 2). After adding, omitting, or revising items, in Phase 3, we pilot tested the measure in 112 participants. Results were reviewed by an international team of PWS specialists and revised again (Phase 3). The final, 57-item Profile was then administered to 761 participants (Phase 4). Principal component factor analyses (n = 873) revealed eight conceptually meaningful factors, accounting for 60.52% of test variance, and were readily interpretated as: Rigidity, Insistence; Aggressive Behaviors; Repetitive Questioning, Speech; Compulsive Behaviors; Depression, Anxiety; Hoarding; Negative Distorted Thinking; and Magical Distorted Thinking. Factors were internally consistent and showed good test-retest reliability and convergent validity with existent measures of behavioral problems. Profile factors were not related to IQ, BMI, or parental SES. Three Profile factors differed across PWS genetic subtypes. Age and gender differences were found in only one Profile factor, Hoarding.

Conclusions
The PWS Profile is a valid, psychometrically-sound questionnaire that already has shown responsivity to treatment in a previous clinical trial. The Profile can extend the reach of future clinical trials by evaluating the impact of novel agents not only on hyperphagia, but also on the emotional and behavioral problems that characterize PWS.
Improving management of ARDS: uniting acute management and long-term recovery
Authors: Latronico Nicola , Eikermann M. , Ely E. W. , Needham D. M. 
Published: February 2024

AbstractAcute Respiratory Distress Syndrome (ARDS) is an important global health issue with high in-hospital mortality. Importantly, the impact of ARDS extends beyond the acute phase, with increased mortality and disability for months to years after hospitalization. These findings underscore the importance of extended follow-up to assess and address the Post-Intensive Care Syndrome (PICS), characterized by persistent impairments in physical, cognitive, and/or mental health status that impair quality of life over the long-term. Persistent muscle weakness is a common physical problem for ARDS survivors, affecting mobility and activities of daily living. Critical illness and related interventions, including prolonged bed rest and overuse of sedatives and neuromuscular blocking agents during mechanical ventilation, are important risk factors for ICU-acquired weakness. Deep sedation also increases the risk of delirium in the ICU, and long-term cognitive impairment. Corticosteroids also may be used during management of ARDS, particularly in the setting of COVID-19. Corticosteroids can be associated with myopathy and muscle weakness, as well as prolonged delirium that increases the risk of long-term cognitive impairment. The optimal duration and dosage of corticosteroids remain uncertain, and there's limited long-term data on their effects on muscle weakness and cognition in ARDS survivors. In addition to physical and cognitive issues, mental health challenges, such as depression, anxiety, and post-traumatic stress disorder, are common in ARDS survivors. Strategies to address these complications emphasize the need for consistent implementation of the evidence-based ABCDEF bundle, which includes daily management of analgesia in concert with early cessation of sedatives, avoidance of benzodiazepines, daily delirium monitoring and management, early mobilization, and incorporation of family at the bedside. In conclusion, ARDS is a complex global health challenge with consequences extending beyond the acute phase. Understanding the links between critical care management and long-term consequences is vital for developing effective therapeutic strategies and improving the quality of life for ARDS survivors.
Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases
Authors: Jung Minsun , Song Seung Geun , Cho Soo Ick , Shin Sangwon , Lee Taebum , Jung Wonkyung , Lee Hajin , Park Jiyoung , Song Sanghoon , Park Gahee , Song Heon , Park Seonwook , Lee Jinhee , Kang Mingu , Park Jongchan , Pereira Sergio , Yoo Donggeun , Chung Keunhyung , Ali Siraj M. , Kim So-Woon 
Published: February 2024

Abstract
Background
Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations.

Methods
AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment.

Results
Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance.

Conclusions
This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.
RARRES1 inhibits hepatocellular carcinoma progression and increases its sensitivity to lenvatinib through interaction with SPINK2
Authors: Guo Yarong , Chai Bao , Zhang Hezhao , Chai Xinhao , Chen Yan , Xu Jun , Qin Liwei , Chai Yuting 
Published: February 2024

Abstract
Background
Lenvatinib is an oral small molecule inhibitor approved for treating patients with unresectable hepatocellular carcinoma (HCC) worldwide. Increasing cell sensitivity to lenvatinib would be an effective method of improving therapeutic efficacy.

Methods
High throughput methods was used to scan the differentially expressed genes (DEGs) related to lenvatinib sensitivity in HCC cells. Gain- and loss-function experiments were used to explore the functions of these DEGs in HCC and lenvatinib sensitivity. CO-IP assay and rescue experiments were utilized to investigate the mechanism.

Results
We identified that RAR responder protein 1 (RARRES1), a podocyte-specific growth arrest gene, was among significantly upregulated DEGs in HCC cells following lenvatinib treatment. Functional analysis showed that ectopic RARRES1 expression decreased HCC progression in vitro and in vivo, as well as improving tumor sensitivity to lenvatinib, while RARRES1 silencing increased HCC cell proliferation and migration. Mechanistically, co-immunoprecipitation assays demonstrated that RARRES1 interacted with serine protease inhibitor Kazal-type 2 (SPINK2) in HCC cells. Further, SPINK2 overexpression suppressed HCC cell proliferation and migration, as well as increasing sensitivity to lenvatinib whereas SPINK2 knockdown promoted cell progression and decreased lenvatinib sensitivity. The mRNA and protein levels of RARRES1 and SPINK2 were low in HCC tissue samples, relative to those in normal liver tissue.

Conclusions
Our findings highlighted that RARRES1 can inhibit HCC progression and regulate HCC sensitivity to lenvatinib by interacting SPINK2, representing a new tumor suppressor RARRES1/SPINK2 axis in HCC that modulates sensitivity to lenvatinib.
Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors
Authors: Abdel-Mohsen Heba T. , Ibrahim Marwa A. , Nageeb Amira M. , El Kerdawy Ahmed M. 
Published: February 2024

AbstractA receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew’s correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.
Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome
Authors: Zhang Jingyuan , Luo Yi , Wu Bingxuan , Huang Xin , Zhao Mengzhu , Wu Na , Miao Junke , Li Ji , Zhu Lei , Wu Di , Shen Min 
Published: February 2024

Abstract
Background and objectives
The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants.

Methods
RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines.

Results
Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement.

Conclusion
Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.
TRS-PCR profiles correlate with polymorphisms of the genomic o454-nlpD region, virulence factors repertoire, and phylogenetic groups among uropathogenic Escherichia coli strains isolated from patients from Lodz region, Poland
Authors: Kubiak-Szeligowska Anna B. , Majchrzak Marta , Parniewski Pawel 
Published: February 2024

AbstractExtraintestinal urinary tract infections are mainly caused by uropathogenic strains of E. coli. UPECs are a heterogeneous group of strains possessing various genes associated with virulence traits. It was demonstrated that changes in the composition of the o454-nlpD region and genetic variation in the mutS-rpoS chromosomal region in ExPEC strains are correlated with their virulence, particularly in those with the pattern III o454-nlpD region and belonging to phylogenetic group B2. In this study, we investigated the presence and distribution of the o454-nlpD genomic polymorphism in our collection of 124 uropathogenic E. coli strains, examining the correlation of o454-nlpD region types with the virulence factors studied. Our findings revealed a positive association between certain virulence factors in UPEC strains and the presence of pattern III in the o454-nlpD region. Additionally, all these strains were classified under phylogenetic group B2. We also showed that the highly pathogenic group of E. coli identified by examining the polymorphism of the o454-nlpD region coincides with the highly pathogenic group of uropathogens we identified in the averaged TRS-PCR analysis.
Two-stage association study of mitochondrial DNA variants in allergic rhinitis
Authors: Yuan Huajie , Wang Lingling , Wang Song , Li Linge , Liu Qingping , Wang Yan , Yang Yuping , Zhang Hua 
Published: February 2024

Abstract
Background
Correlations between mitochondrial DNA (mtDNA) and allergic rhinitis (AR) have not been reported before. This study aimed to better understand the mitochondrial genome profile with AR and to investigate the associations between AR in China and the mitochondrial genome at a single variant and gene level.

Methods
Mitochondrial sequencing was conducted on a total of 134 unrelated individual subjects (68 patients with AR, 66 healthy controls) at discovery stage. Heteroplasmy was analyzed using the Mann-Whitney U test. Sequence kernel association tests (SKAT) were conducted to study the association between mitochondrial genes and AR. Single-variant analysis was performed using logistic regression analysis and further validated in 120 subjects (69 patients with AR, 51 healthy controls). Candidate genes were further explored based on differences in mRNA and protein abundance in nasal mucosal tissue.

Results
In the discovery stage, 886 variants, including 836 SNV and 50 indels, were identified with mitochondrial sequencing. No statistically significant differences were identified for the mitochondrial heteroplasmy or SKAT analysis between these two groups after applying a Boferroni correction. One nonsynonymous variants, rs3135028 (MT8584.G/A) in ATP6, was related to a reduced risk of AR in both the discovery and validation cohorts. Furthermore, mRNA levels of MT-ATP6 in nasal mucosal tissue were significantly lower in AR individuals than in controls (P < 0.05).

Conclusions
In a two-stage analysis of associations between AR and mtDNA variations, mitochondrial gene maps of Chinese patients with AR indicated that the ATP6 gene was probably associated with AR at the single-variant level.
Quasilinear Schrödinger equations with superlinear terms describing the Heisenberg ferromagnetic spin chain
Authors: Cheng Yongkuan , Shen Yaotian 
Published: February 2024

AbstractIn this paper, we consider a model problem arising from a classical planar Heisenberg ferromagnetic spin chain: $$ -\Delta u+V(x)u-\frac{u}{\sqrt{1-u^{2}}}\Delta \sqrt{1-u^{2}}=c \vert u \vert ^{p-2}u,\quad x\in \mathbb{R}^{N}, $$
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Upper and lower solutions method for a class of second-order coupled systems
Authors: Yu Zelong , Bai Zhanbing , Shang Suiming 
Published: February 2024

AbstractThis paper provides a class of upper and lower solution definitions for second-order coupled systems by transforming the fourth-order differential equation into a second-order differential system. Then, by constructing a homotopy parameter and utilizing the maximum principle, we propose an upper and lower solutions method for studying a class of second-order coupled systems with Dirichlet boundary conditions and obtain an existence result.