bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancing screening tool for hospice needs and end-of-life decision-making process in the emergency department
Authors: Wang Yu-Jing , Hsu Chen-Yang , Yen Amy Ming-Fang , Chen Hsiu-Hsi , Lai Chao-Chih
Published: February 2024

Background

Predicting mortality in the emergency department (ED) is imperative to guide palliative care and end-of-life decisions. However, the clinical usefulness of utilizing the existing screening tools still leaves something to be desired.

Methods

We advanced the screening tool with the A-qCPR (Age, qSOFA (quick sepsis-related organ failure assessment), cancer, Performance Status Scale, and DNR (Do-Not-Resuscitate) risk score model for predicting one-year mortality in the emergency department of Taipei City Hospital of Taiwan with the potential of hospice need and evaluated its performance compared with the existing screening model. We adopted a large retrospective cohort in conjunction with in-time (the trained and the holdout validation cohort) for the development of the A-qCPR model and out-of-time validation sample for external validation and model robustness to variation with the calendar year.

Results

A total of 10,474 patients were enrolled in the training cohort and 33,182 patients for external validation. Significant risk scores included age (0.05 per year), qSOFA ≥ 2 (4), Cancer (5), Eastern Cooperative Oncology Group (ECOG) Performance Status score ≥ 2 (2), and DNR status (2). One-year mortality rates were 13.6% for low (score ≦ 3 points), 29.9% for medium (3 < Score ≦ 9 points), and 47.1% for high categories (Score > 9 points). The AUROC curve for the in-time validation sample was 0.76 (0.74–0.78). However, the corresponding figure was slightly shrunk to 0.69 (0.69–0.70) based on out-of-time validation. The accuracy with our newly developed A-qCPR model was better than those existing tools including 0.57 (0.56–0.57) by using SQ (surprise question), 0.54 (0.54–0.54) by using qSOFA, and 0.59 (0.59–0.59) by using ECOG performance status score. Applying the A-qCPR model to emergency departments since 2017 has led to a year-on-year increase in the proportion of patients or their families signing DNR documents, which had not been affected by the COVID-19 pandemic.

Conclusions

The A-qCPR model is not only effective in predicting one-year mortality but also in identifying hospice needs. Advancing the screening tool that has been widely used for hospice in various scenarios is particularly helpful for facilitating the end-of-life decision-making process in the ED.
Strategies used by midwives to enhance knowledge and skill development in midwifery students: an appreciative inquiry study
Authors: Arundell Fiona , Sheehan Athena , Peters Kath
Published: February 2024

Background

Midwifery practice experience for midwifery students is an important component of education to enhance knowledge and skill development. Practicing midwives provide student support in the clinical setting, there is minimal literature relating to strategies midwives use to support students.

Objective

To explore midwifery student experiences of the strategies used by midwives to facilitate knowledge and skill development in the clinical practice setting.

Methods

Qualitative approach based on Appreciative Inquiry. The setting is one University in Australia. Participants, thirteen Graduate Diploma in Midwifery students. Individual interviews followed by thematic analysis.

Results

Data analysis identified six themes, Willingness to share knowledge and develop skills; The positive use of questioning; Moderating support; Teaching through the woman; Learning through problematisation and Providing constructive affirmation.

Conclusions

Midwives incorporated varied strategies to support student development in the clinical setting. For an equitable clinical experience, all midwives need support to develop skills and confidence in facilitating student learning.
Exploring recent trends (2014–21) in preferencing and accepting Queensland medical internships in rural hospitals
Authors: McGrail Matthew , Woolley Torres , Pinidiyapathirage Janani , Paton Kath , Smith Deborah , Brumpton Kay , Teague Peta-Ann
Published: February 2024

Background

Medical internship is a key transition point in medical training from student to independent (junior) doctor. The national Regional Training Hubs (RTH) policy began across Australia in late 2017, which aims to build medical training pathways for junior doctors within a rural region and guide students, interns and trainees towards these. This study aims to explore preferencing and acceptance trends for rural medical internship positions in Queensland. Moreover, it focuses on internship preference and acceptance outcomes prior to and following the establishment of RTHs, and their association with key covariates such as rural training immersions offered by medical schools.

Methods

Data from all applicants to Queensland Health intern positions between 2014–2021 were available, notably their preference order and location of accepted internship position, classified as rural or metropolitan. Matched data from Queensland’s medical schools were added for rural training time and other key demographics. Analyses explored the statistical associations between these factors and preferencing or accepting rural internships, comparing pre-RTH and post-RTH cohorts.

Results

Domestic Queensland-trained graduates first preferencing rural intern positions increased significantly (pre-RTH 21.1% vs post-RTH 24.0%, p = 0.017), reinforced by a non-significant increase in rural acceptances (27.3% vs 29.7%, p = 0.070). Rural interns were more likely to have previously spent ≥ 11-weeks training in rural locations within medical school, be rurally based in the year applying for internship, or enrolled in the rural generalist pathway.

Conclusions

The introduction of the RTH was associated with a moderate increase of graduates both preferencing and accepting a rural internship, though a richer understanding of the dominant reasons for and against this remain less clear. An expansion of graduates who undertook longer periods of undergraduate rural training in the same period did not diminish the proportion choosing a rural internship, suggesting there remains an appetite for these opportunities. Overall, domestic graduates are identified as a reliable source of intern recruitment and retention to rural hospitals across Queensland, with entry to the rural generalist pathway and extended rural placement experiences enhancing uptake of rural practice.
Experiences of an interprofessional follow-up program in primary care practice
Authors: Kolltveit Beate-Christin Hope , Oftedal Bjørg Frøysland , Thorne Sally , Lomborg Kirsten , Graue Marit
Published: February 2024

Background

An integrative cooperation of different healthcare professional is a key component for high quality health services. With an aging population and many with long-term conditions, more health tasks and follow-up care are being transferred to primary care and locally where people live. Interprofessional collaboration among providers of different professional designations will be of increasing importance to optimizing primary care capacity in years to come. There is a call for further exploration of models of interprofessional collaboration that might be applicable in Norwegian primary care. The aim of this study was to explore experiences of interprofessional collaboration between primary care physicians and nurses working in primary care by applying an intervention for people with type 2 diabetes. Specifically, this study was designed to strengthen and gain deeper insight into interprofessional collaboration between primary care physicians and nurses in primary care settings.

Methods

We applied Interpretive Description as a research strategy. The participants within this study were primary care physicians and nurses from four different primary care practices in the western and eastern parts of Norway. We used semi-structured telephone interviews for collecting the data between January and September 2021.

Results

The analysis revealed two key features of the primary care physicians and the nurses experience with interprofessional collaboration in primary care practices. The first involved managing the influence of discrepancies in their expectations of IPC and the second involved becoming aware of the competence they developed that allowed for better complementarity consultation.

Conclusions

This study indicates that interprofessional collaboration in primary care practice requires that primary care physicians and nurses clarify their expectations and, in turn, determine how flexible they can become in changing their usual primary care practices. Moreover, findings reveal that nurses and primary care physicians had discrepancies in expectations of how interprofessional collaboration should be carried out in primary care practice. However, both the nurses and primary care physicians appreciated the blending of complementary competencies and skills that facilitated a more collaborative care practice. They experienced that this interprofessional collaboration represented an essential quality improvement in the primary care services.

Trial registration

The trial is registered 03/09/2019 in ClinicalTrials.gov (ID: NCT04076384).
Comparative analysis of tuberculin and defined antigen skin tests for detection of bovine tuberculosis in buffaloes (Bubalus bubalis) in Haryana state, India
Authors: Kumar Mohit , Kumar Tarun , Jangir Babu Lal , Singh Mahavir , Arora Devan , Bangar Yogesh , Conlan Andrew , Vordermeier Martin , Bakker Douwe , Byregowda S. M. , Srinivasan Sreenidhi , Kapur Vivek , Jindal Naresh
Published: February 2024

Background

Bovine tuberculosis (bTB) is a chronic disease that results from infection with any member of theMycobacterium tuberculosiscomplex. Infected animals are typically diagnosed with tuberculin-based intradermal skin tests according to World Organization of Animal Health which are presently in use. However, tuberculin is not suitable for use in BCG-vaccinated animals due to a high rate of false-positive reactions. Peptide-based defined skin test (DST) antigens have been identified using antigens (ESAT-6, CFP-10 and Rv3615c) which are absent from BCG, but their performance in buffaloes remains unknown. To assess the comparative performance of DST with the tuberculin-based single intradermal test (SIT) and the single intradermal comparative cervical test (SICCT), we screened 543 female buffaloes from 49 organized dairy farms in two districts of Haryana state in India.

Results

We found that 37 (7%), 4 (1%) and 18 (3%) buffaloes were reactors with the SIT, SICCT and DST tests, respectively. Of the 37 SIT reactors, four were positive with SICCT and 12 were positive with the DST. The results show that none of the animals tested positive with all three tests, and 6 DST positive animals were SIT negative. Together, a total of 43 animals were reactors with SIT, DST, or both, and the two assays showed moderate agreement (Cohen’s Kappa 0.41; 95% Confidence Interval (CI): 0.23, 0.59). In contrast, only slight agreement (Cohen’s Kappa 0.18; 95% CI: 0.02, 0.34) was observed between SIT and SICCT. Using a Bayesian latent class model, we estimated test specificities of 96.5% (95% CI, 92–99%), 99.7% (95% CI: 98–100%) and 99.0% (95% CI: 97–100%) for SIT, SICCT and DST, respectively, but considerably lower sensitivities of 58% (95% CI: 35–87%), 9% (95% CI: 3–21%), and 34% (95% CI: 18–55%) albeit with broad and overlapping credible intervals.

Conclusion

Taken together, our investigation suggests that DST has a test specificity comparable with SICCT, and sensitivity intermediate between SIT and SICCT for the identification of buffaloes suspected of tuberculosis. Our study highlights an urgent need for future well-powered trials with detailed necropsy, with immunological and microbiological profiling of reactor and non-reactor animals to better define the underlying factors for the large observed discrepancies in assay performance, particularly between SIT and SICCT.
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

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

Background

Tele-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.

Methods

During 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.

Results

Of 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.

Conclusion

PWID 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

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

Acute 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

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

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

A 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

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

Extraintestinal 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

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

In 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

This 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.
Radiosynthesis, structural identification and in vitro tissue binding study of [18F]FNA-S-ACooP, a novel radiopeptide for targeted PET imaging of fatty acid binding protein 3
Authors: Dillemuth Pyry , Karskela Tuomas , Ayo Abiodun , Ponkamo Jesse , Kunnas Jonne , Rajander Johan , Tynninen Olli , Roivainen Anne , Laakkonen Pirjo , Airaksinen Anu J. , Li Xiang-Guo
Published: February 2024

Background

Fatty acid binding protein 3 (FABP3) is a target with clinical relevance and the peptide ligand ACooP has been identified for FABP3 targeting. ACooP is a linear decapeptide containing a free amino and thiol group, which provides opportunities for conjugation. This work is to develop methods for radiolabeling of ACooP with fluorine-18 (18F) for positron emission tomography (PET) applications, and evaluate the binding of the radiolabeled ACooP in human tumor tissue sections with high FABP3 expression.

Results

The prosthetic compound 6-[18F]fluoronicotinic acid 4-nitrophenyl ester was conveniently prepared with an on-resin 18F-fluorination in 29.9% radiochemical yield and 96.6% radiochemical purity. Interestingly, 6-[18F]fluoronicotinic acid 4-nitrophenyl ester conjugated to ACooP exclusively by S-acylation instead of the expected N-acylation, and the chemical identity of the product [18F]FNA-S-ACooP was confirmed. In the in vitro binding experiments, [18F]FNA-S-ACooP exhibited heterogeneous and high focal binding in malignant tissue sections, where we also observed abundant FABP3 positivity by immunofluorescence staining. Blocking study further confirmed the [18F]FNA-S-ACooP binding specificity.

Conclusions

FABP3 targeted ACooP peptide was successfully radiolabeled by S-acylation using 6-[18F]fluoronicotinic acid 4-nitrophenyl ester as the prosthetic compound. The tissue binding and blocking studies together with anti-FABP3 immunostaining confirmed [18F]FNA-S-ACooP binding specificity. Further preclinical studies of [18F]FNA-S-ACooP are warranted.
Reflections on the importance of built heritage inventory as a tool for preservation in Karachi–a case study of Wadhumal Odharam (Jail) Quarter in Karachi, Sindh, Pakistan
Authors: Soomro Tania Ali
Published: February 2024

The cultural heritage inventory is an alternate tool to document historic buildings to establish a protected enlistment process. Recognising the importance of inventories for developing knowledge of historical and cultural patterns, multiple attempts are being made to record Karachi’s historic buildings in the form of inventory documents. This research investigates the various approaches used for inventorying Karachi’s cultural heritage and their potential impact on the survival of the city’s historical ensemble. As literature, this research provides a brief overview of Karachi’s architectural development before and after its annexation to the British Raj (Term used by scholars to represent the British Crown in India. The term ‘The Raj’ is also sometimes used.) (1843–1947), which is now considered the historic core of the city of Karachi, together with the systems of inventorying the built heritage over time. Wadhumal Odharam (Jail) Quarter is shortlisted as a case study for this research, which will be examined from the perspective of inventory making in relation to its specific physical and sociocultural context as documented through the inventorying process. The Quarter is also referred to as ‘Jail Quarter’ because of the presence of the Jail building within the Quarter precinct, which was demolished during the British era; it is discussed in further detail later in this article. The research approach follows a survey of the quarter conducted between August and September 2022, followed by a mapping of the historic properties. The inventory mapping of the Quarter is performed by using an available database (Database of various historic Quarters of Karachi by Heritage Cell-DAPNED). The data for inventory also helps provide an understanding of the history and development of the area. The other aspects of the research methodology include intreating questions and collecting data about various aspects of the Quarter, such as the building information, photographic documentation of the properties, and analysis of the present conservation status based on inventory mapping. Moreover, this study also suggests that inventorying aided the enlistment process for the Quarter under the Sindh Cultural Heritage Preservation Act 1994 (SCHPA), which was first implemented in 1997 and again in 2011 until 2021. The protected status helped stop the illicit demolitions; however, vandalism continued in many forms, for instance, the need-based alterations relying on the ever-increasing population, upgradation of the building bylaws, inadequate heritage legislation and its enforcement.
Target-oriented least-squares reverse time migration with Marchenko redatuming and double focusing: Field data application
Authors: Shoja Aydin , van der Neut Joost , Wapenaar Kees
Published: February 2024

Recently, the focus of reflection seismologists has shifted to applications for which a high-resolution image of the subsurface is required. Least-squares reverse time migration (LSRTM) is a common tool used to compute such images. Even so, its high computational costs have led seismologists to use target-oriented LSRTM for imaging only a small target of interest within a larger subsurface block. Redatuming the data to the upper boundary of the target of interest is one approach to target-oriented LSRTM, but many redatuming methods cannot account for multiple scattering within the overburden. We apply a target-oriented LSRTM algorithm that integrates Marchenko redatuming and double focusing to a field data set. This redatuming method accounts for all orders of multiple scattering in the overburden, thus improving the accuracy of target-oriented LSRTM. Moreover, we determine the effectiveness of a double-focusing algorithm in reducing the data size by decreasing spatial and temporal dimensions of the model and the data. The algorithm’s performance is evaluated using field data acquired in the Norwegian Sea. The numerical results indicate that the target-oriented LSRTM algorithm with Marchenko double-focusing can reduce the internal multiple effects and increase the resolution of the resulting image.
Shortening the Alzheimer’s disease assessment scale cognitive subscale
Authors: Levine Stephen Z. , Goldberg Yair , Rotstein Anat , Samara Myrto , Yoshida Kazufumi , Cipriani Andrea , Iwatsubo Takeshi , Leucht Stefan , Furukawa Toshiaki A.
Published: February 2024

Background

A short yet reliable cognitive measure is needed that separates treatment and placebo for treatment trials for Alzheimer’s disease. Hence, we aimed to shorten the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and test its use as an efficacy measure.

Methods

Secondary data analysis of participant-level data from five pivotal clinical trials of donepezil compared with placebo for Alzheimer’s disease (N = 2,198). Across all five trials, cognition was appraised using the original 11-item ADAS-Cog. Statistical analysis consisted of sample characterization, item response theory (IRT) to identify an ADAS-Cog short version, and mixed models for repeated-measures analysis to examine the effect sizes of ADAS-Cog change on the original and short versions in the placebo versus donepezil groups.

Results

Based on IRT, a short ADAS-Cog was developed with seven items and two response options. The original and short ADAS-Cog correlated at baseline and at weeks 12 and 24 at 0.7. Effect sizes based on mixed modeling showed that the short and original ADAS-Cog separated placebo and donepezil comparably (ADAS-Cog original ES = 0.33, 95% CI = 0.29, 0.40, ADAS-Cog short ES = 0.25, 95% CI =0.23, 0.34).

Conclusions

IRT identified a short ADAS-cog version that separated donepezil and placebo, suggesting its clinical potential for assessment and treatment monitoring.
Therapeutic Strategies for Gliomas Associated With Cancer Predisposition Syndromes
Authors: Lam Keng , Kamiya-Matsuoka Carlos , Slopis John M. , McCutcheon Ian E. , Majd Nazanin K.
Published: February 2024

PURPOSE

The purpose of this article was to provide an overview of syndromic gliomas.

DESIGN

The authors conducted a nonsystematic literature review.

RESULTS

Cancer predisposition syndromes (CPSs) are genetic conditions that increase one's risk for certain types of cancer compared with the general population. Syndromes that can predispose one to developing gliomas include neurofibromatosis, Li-Fraumeni syndrome, Lynch syndrome, and tuberous sclerosis complex. The standard treatment for sporadic glioma may involve resection, radiation therapy, and/or alkylating chemotherapy. However, DNA-damaging approaches, such as radiation and alkylating agents, may increase the risk of secondary malignancies and other complications in patients with CPSs. In some cases, depending on genetic aberrations, targeted therapies or immunotherapeutic approaches may be considered. Data on clinical characteristics, therapeutic strategies, and prognosis of syndromic gliomas remain limited.

CONCLUSION

In this review, we provide an overview of syndromic gliomas with a focus on management for patients with CPSs and the role of novel treatments that can be considered.
Computational study of stability, photovoltaic, and thermoelectric properties of new inorganic lead-free halide perovskites
Authors: Agouri M. , Ouhenou H. , Waqdim A. , Zaghrane A. , Darkaoui E. , Abbassi A. , Manaut B. , Taj S. , Driouich M.
Published: February 2024

Due to their rich and extraordinary properties, halide perovskites have gained attention over time for their applications in thermoelectric and solar cells. Here, several physical properties (stability, photovoltaic, and thermoelectric) of inorganic halide perovskites XZnI3 (X = Na, K, Rb, Cs) are predicted using the density functional theory (DFT) within the Wien2k code. The optimization of structural parameters has been calculated using PBE-GGA approach. The tolerance factor, Born criteria, phonon dispersion, and negative formation energy show the formation and stability of these studied materials in the ideal cubic structure. Additionally, the modified Becke-Johnson method is applied for optoelectronic and transport properties. All compounds exhibit the nature of indirect band gap semiconductors with better absorption in the visible and ultraviolet regions

. The transport properties present high electrical conductivity, large Seebeck coefficient, and good (PF, ZT) factors for all these materials. Finally, all these properties of inorganic halide perovskites open up new possibilities for efficient applications in thermoelectric and solar cells.
Retrosigmoid Transmiddle Cerebellar Peduncle Approach for Resection of a Giant Pontine Cavernous Malformation: 2-Dimensional Operative Video
Authors: Kalani M. Yashar S.
Published: February 2024

Pioneering work in defining brainstem safe entry zones and development of surgical techniques has made microsurgical removal of brainstem cavernous malformation possible.
1,2
The middle cerebellar peduncle (MCP) is a robust route for access to deep-seated lesions within the pons. The peduncle can be accessed by splitting the petrosal fissure of the cerebellum to obtain a more direct view to the MCP through a retrosigmoid approach. The author presents a case of a female with a history of 3 bleeds attributable to a giant pontine cavernous malformation. The patient consented to the procedure. Given the aggressive natural history of deep cavernous malformations, especially in the year following a bleed, surgical removal was recommended. Step-by-step description of access to the MCP through splitting the petrosal fissure, and key steps for removal of a pontine cavernous malformation are described.