bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer
Authors: Jia Lejiao , Yang Huatian , Liu Yue , Zhou Ying , Li Guosheng , Zhou Qian , Xu Yan , Huang Zhiping , Ye Feng , Ye Jingjing , Liu Anchang , Ji Chunyan
Published: April 2024

Heat shock protein 90 (HSP90) is overexpressed in numerous cancers, promotes the maturation of numerous oncoproteins and facilitates cancer cell growth. Certain HSP90 inhibitors have entered clinical trials. Although less than satisfactory clinical effects or insurmountable toxicity have compelled these trials to be terminated or postponed, these results of preclinical and clinical studies demonstrated that the prospects of targeting therapeutic strategies involving HSP90 inhibitors deserve enough attention. Nanoparticulate-based drug delivery systems have been generally supposed as one of the most promising formulations especially for targeting strategies. However, so far, no active targeting nano-formulations have succeeded in clinical translation, mainly due to complicated preparation, complex formulations leading to difficult industrialization, incomplete biocompatibility or nontoxicity. In this study, HSP90 and CD44-targeted A6 peptide functionalized biomimetic nanoparticles (A6-NP) was designed and various degrees of A6-modification on nanoparticles were fabricated to evaluate targeting ability and anticancer efficiency. With no excipients, the hydrophobic HSP90 inhibitor G2111 and A6-conjugated human serum albumin could self-assemble into nanoparticles with a uniform particle size of approximately 200 nm, easy fabrication, well biocompatibility and avoidance of hepatotoxicity. Besides, G2111 encapsulated in A6-NP was only released less than 5% in 12 h, which may avoid off-target cell toxicity before entering into cancer cells. A6 peptide modification could significantly enhance uptake within a short time. Moreover, A6-NP continues to exert the broad anticancer spectrum of Hsp90 inhibitors and displays remarkable targeting ability and anticancer efficacy both in hematological malignancies and solid tumors (with colon tumors as the model cancer) both in vitro and in vivo. Overall, A6-NP, as a simple, biomimetic and active dual-targeting (CD44 and HSP90) nanomedicine, displays high potential for clinical translation.
Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine
Authors: Wang Suyang , Chen Chao-Cheng , Hu Ming-Hung , Cheng Michelle , Tu Hsin-Fang , Tsai Ya-Chea , Yang Jr-Ming , Wu T. C. , Huang Chuan-Hsiang , Hung Chien-Fu
Published: April 2024

Background

Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier.

Method

Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7.

Results

Due to OMV’s intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells.

Conclusion

The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.
Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis
Authors: Ono Sawako , Hirose Katsutoshi , Sukegawa Shintaro , Obata Kyoichi , Masui Masanori , Hasegawa Kazuaki , Fujimura Ai , Shimada Katsumitsu , Nakamura Satoko , Teramoto Akari , Hori Yumiko , Morii Eiichi , Motooka Daisuke , Igawa Takuro , Tanaka Takehiro , Nagatsuka Hitoshi , Toyosawa Satoru , Yamamoto Hidetaka
Published: April 2024

Background

Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology.

Methods

Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes.

Results

We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1–4) were one woman and three men with a mean age of 53.75 years (range: 15–74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1–3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases.

Conclusions

We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated.
Revival of the mother-baby friendly initiative (MBFI) in South Africa: towards a quality improvement project
Authors: Lubbe Welma , Kubeka Zandile , Behr Ann , Tshitaudzi Gilbert , Dlamini-Nqeketo Sithembile , Botha Jessica
Published: April 2024

Background

The discontinuation of “Mother-Baby Friendly” accreditation, coupled with the impact of the COVID-19 pandemic, has contributed to reduced breastfeeding rates observed in parts of South Africa. Consequently, the Child, Youth and School Health cluster of the National Department of Health, with support from the World Health Organization and United Nations Children’s Fund, organised a Mother-Baby Friendly initiative revitalisation workshop.

Methods

Held in Johannesburg, South Africa, on June 29–30, 2022, the workshop brought together local and international breastfeeding promotion experts to engage on issues related to the revitalisation of the Mother-Baby Friendly Initiative. The workshop included presentations and group sessions aimed at setting expectations, evaluating the Ten Steps to Successful Breastfeeding, and developing actionable revitalisation strategies.

Results

Inadequate monitoring of the Mother-Baby Friendly Initiative implementation and adherence to the Ten Steps was identified as a major implementation bottleneck. Participants identified steps ten (coordinating discharge so that parents and their infants have timely access to ongoing support and care), five (supporting mothers to initiate and maintain breastfeeding and manage common difficulties), and two (ensuring that staff have sufficient knowledge, competence, and skills to support breastfeeding) of the Baby-Friendly Hospital Initiative as the most difficult to implement. Step seven (enabling mothers and their infants to remain together and to practise rooming-in 24 h a day) was the least difficult to implement. Workshop participants identified the following proposed solutions to revitalise breastfeeding promotion: strengthening capacity building and mentorship, improving monitoring and accountability measures, and certification of facilities meeting the initiative’s standards.

Conclusion

Current breastfeeding policies and practices must be evaluated by the National Department of Health in collaboration with provincial and private representatives of the initiative to effectively revitalise the Mother-Baby Friendly Initiative. Moreover, an integrative monitoring framework must be developed through stakeholder engagement, role clarification, and ownership. While collaboration between the private and public sectors is required to promote training and communication within healthcare facilities and communities.
Cross-cultural adaptation, reliability, validity and responsiveness of the Michigan Hand Outcomes Questionnaire (MHQ-Sp) in Spain
Authors: Martínez-Fernández María Visitación , Sarabia-Cobo Carmen María , Sánchez-Labraca Nuria
Published: April 2024

Background

The Michigan Hand Outcomes Questionnaire (MHQ) is a self-report tool widely recognized for measuring the health status of patients with hand and wrist problems from a multidimensional perspective. The aim of this study is to translate and culturally adapt the MHQ and validate its psychometric properties of validity, reliability, and responsiveness for different hand problems in Spain.

Methods

The MHQ was translated and culturally adapted following the recommendations of the American Association of Orthopaedic Surgeons. The validation process adhered to the current Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) group and was conducted on 262 hand patients. Reliability was assessed through internal consistency using Cronbach's alpha. The study evaluated the test–retest reliability of the measurements using the intraclass correlation coefficient (ICC). Additionally, the measurement error was calculated using the standard error of measurement (SEM) and smallest detectable change (SDC). To assess the structural validity, confirmatory factor analysis (CFA) was employed, while construct validity was evaluated using Pearson's correlation coefficient. Finally, responsiveness was assessed using effect size (ES), standardized response mean (SRM), and minimum clinically important difference (MCID).

Results

The reliability of the test was confirmed through internal consistency analysis, with a good Crombach's Alpha (0.82–0.85), and test–retest analysis, with good values of ICC (0.74–0.91). The measurement error was also assessed, with low values of SEM (1.70–4.67) and SDC (4.71–12.94)). The CFA confirmed the unidimensionality of each scale with goodness of fit indices, while the MHQ showed a high and negative correlation with DASH (r = − 0.75, P < 0.001) and DASH-work (r = − 0.63, P < 0.001) and was irrelevant with EQ-5D (r = − 0.01, P > 0.005) and grip strength (r = 0.05, P > 0.005). At week 5, all 222 patients across the three diagnosed hand subgroups showed moderate to high values above 0.92 for ES and SRM, with one MCID above 6.85.

Conclusions

The MHQ-Sp was culturally adapted, and the results of this version showed good reliability and validity as well as high responsiveness for a wide range of hand conditions after surgical or conservative treatment in Spain.
CircPRKD3/miR-6783-3p responds to mechanical force to facilitate the osteogenesis of stretched periodontal ligament stem cells
Authors: Liu Jiani , Liu Rui , Wang Hong , Zhang Zijie , Wang Jixiao , Wei Fulan
Published: April 2024

Background

The mechanotransduction mechanisms by which cells regulate tissue remodeling are not fully deciphered. Circular RNAs (circRNAs) are crucial to various physiological processes, including cell cycle, differentiation, and polarization. However, the effects of mechanical force on circRNAs and the role of circRNAs in the mechanobiology of differentiation and remodeling in stretched periodontal ligament stem cells (PDLSCs) remain unclear. This article aims to explore the osteogenic function of mechanically sensitive circular RNA protein kinase D3 (circPRKD3) and elucidate its underlying mechanotransduction mechanism.

Materials and methods

PDLSCs were elongated with 8% stretch at 0.5 Hz for 24 h using the Flexcell® FX-6000™ Tension System. CircPRKD3 was knockdown or overexpressed with lentiviral constructs or plasmids. The downstream molecules of circPRKD3 were predicted by bioinformatics analysis. The osteogenic effect of related molecules was evaluated by quantitative real-time PCR (qRT‐PCR) and western blot.

Results

Mechanical force enhanced the osteogenesis of PDLSCs and increased the expression of circPRKD3. Knockdown of circPRKD3 hindered PDLSCs from osteogenesis under mechanical force, while overexpression of circPRKD3 promoted the early osteogenesis process of PDLSCs. With bioinformatics analysis and multiple software predictions, we identified hsa-miR-6783-3p could act as the sponge of circPRKD3 to indirectly regulate osteogenic differentiation of mechanically stimulated PDLSCs.

Conclusions

Our results first suggested that both circPRKD3 and hsa-miR-6783-3p could enhance osteogenesis of stretched PDLSCs. Furthermore, hsa-miR-6783-3p could sponge circPRKD3 to indirectly regulate RUNX2 during the periodontal tissue remodeling process in orthodontic treatment.
Robotic-assisted plate fixation of the anterior acetabulum - clinical description of a new technique
Authors: Kabir Koroush , von Rundstedt Friedrich-Carl , Roos Jonas , Gathen Martin
Published: April 2024

Introduction

We present a detailed procedure for the robotic-assisted plate osteosynthesis of an anterior acetabular fracture. The purpose of this work was to describe a robotic-assisted minimally invasive technique as a possible method for reducing complications, pain, and hospitalization. Another goal was to present technical recommendations and to assess potential pitfalls and problems of the new surgical approach.

Methods

Surgery was performed in an interdisciplinary setting by an experienced orthopedic surgeon and a urologist. The DaVinci System with standard instruments was used. Reduction was achieved through indirect traction of a pin that was introduced into the femoral neck and direct manipulation via the plate. The plate position and fixation were achieved through 7 additional minimally invasive incisions.

Results

The technique has multiple advantages, such as no detachment of the rectus abdominal muscle, a small skin incision, and minimal blood loss. Furthermore, this approach might lower the incidence of hernia formation, infection, and postoperative pain.

Discussion

We see the presented technique as a demanding yet progressive and innovative surgical method for treating acetabular fractures with indications for anterior plate fixation.

Trial registration

The study was approved by the local institutional review board (Nr. 248/18).
Promoting osteogenesis and bone regeneration employing icariin-loaded nanoplatforms
Authors: Mohammadzadeh Mahsa , Zarei Masoud , Abbasi Hossein , Webster Thomas J. , Beheshtizadeh Nima
Published: April 2024

There is an increasing demand for innovative strategies that effectively promote osteogenesis and enhance bone regeneration. The critical process of bone regeneration involves the transformation of mesenchymal stromal cells into osteoblasts and the subsequent mineralization of the extracellular matrix, making up the complex mechanism of osteogenesis. Icariin’s diverse pharmacological properties, such as anti-inflammatory, anti-oxidant, and osteogenic effects, have attracted considerable attention in biomedical research. Icariin, known for its ability to stimulate bone formation, has been found to encourage the transformation of mesenchymal stromal cells into osteoblasts and improve the subsequent process of mineralization. Several studies have demonstrated the osteogenic effects of icariin, which can be attributed to its hormone-like function. It has been found to induce the expression of BMP-2 and BMP-4 mRNAs in osteoblasts and significantly upregulate Osx at low doses. Additionally, icariin promotes bone formation by stimulating the expression of pre-osteoblastic genes like Osx, RUNX2, and collagen type I. However, icariin needs to be effectively delivered to bone to perform such promising functions.

Encapsulating icariin within nanoplatforms holds significant promise for promoting osteogenesis and bone regeneration through a range of intricate biological effects. When encapsulated in nanofibers or nanoparticles, icariin exerts its effects directly at the cellular level. Recalling that inflammation is a critical factor influencing bone regeneration, icariin's anti-inflammatory effects can be harnessed and amplified when encapsulated in nanoplatforms. Also, while cell adhesion and cell migration are pivotal stages of tissue regeneration, icariin-loaded nanoplatforms contribute to these processes by providing a supportive matrix for cellular attachment and movement. This review comprehensively discusses icariin-loaded nanoplatforms used for bone regeneration and osteogenesis, further presenting where the field needs to go before icariin can be used clinically.
Rapidly improving ARDS differs clinically and biologically from persistent ARDS
Authors: Valda Toro Patricia L. , Willmore Andrew , Wu Nelson E. , Delucchi Kevin L. , Jauregui Alejandra , Sinha Pratik , Liu Kathleen D. , Hendrickson Carolyn M. , Sarma Aartik , Neyton Lucile P. A. , Leligdowicz Aleksandra , Langelier Charles R. , Zhuo Hanjing , Jones Chayse , Kangelaris Kirsten N. , Gomez Antonio D. , Matthay Michael A. , Calfee Carolyn S.
Published: April 2024

Background

Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes.

Methods

We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described.

Results

RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001).

Conclusions

This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.
Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection
Authors: Kwon Mi-ri , Chang Yoosoo , Ham Soo-Youn , Cho Yoosun , Kim Eun Young , Kang Jeonggyu , Park Eun Kyung , Kim Ki Hwan , Kim Minjeong , Kim Tae Soo , Lee Hyeonsoo , Kwon Ria , Lim Ga-Young , Choi Hye Rin , Choi JunHyeok , Kook Shin Ho , Ryu Seungho
Published: April 2024

Background

Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women.

Methods

We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI’s performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A–D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories.

Results

Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7–77.3] vs. 67.1% [95% CI, 58.8–74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9–93.2] vs. 77.6% [95% CI, 61.7–77.9]), PPV (1.5% [95% CI, 1.2–1.9] vs. 0.5% [95% CI, 0.4–0.6]), recall rate (7.1% [95% CI, 6.9–7.2] vs. 22.5% [95% CI, 22.2–22.7]), and AUC values (0.8 [95% CI, 0.76–0.84] vs. 0.74 [95% CI, 0.7–0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category.

Conclusions

AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.
The clinical value of mNGS of bronchoalveolar lavage fluid versus traditional microbiological tests for pathogen identification and prognosis of severe pneumonia (NT-BALF):study protocol for a prospective multi-center randomized clinical trial
Authors: Song Xiao , Jiang Hui , Zong Liang , Shi Di , Zhu Huadong
Published: April 2024

Background

Early, rapid, and accurate pathogen diagnosis can help clinicians select targeted treatment options, thus improving prognosis and reducing mortality rates of severe pneumonia. Metagenomic next-generation sequencing (mNGS) has a higher sensitivity and broader pathogen spectrum than traditional microbiological tests. However, the effects of mNGS-based antimicrobial treatment procedures on clinical outcomes and cost-effectiveness in patients with severe pneumonia have not been evaluated.

Methods

This is a regional, multi-center, open, prospective, randomized controlled trial to evaluate that whether the combination of mNGS and traditional testing methods could decrease 28-day call-cause mortality with moderate cost-effectiveness. A total of 192 patients with severe pneumonia will be recruited from four large tertiary hospitals in China. Bronchoalveolar lavage fluid will be obtained in all patients and randomly assigned to the study group (mNGS combined with traditional microbiological tests) or the control group (traditional microbiological tests only) in a 1:1 ratio. Individualized antimicrobial treatment and strategy will be selected according to the analysis results. The primary outcome is 28-day all-cause mortality. The secondary outcomes are ICU and hospital length of stay (LOS), ventilator-free days and ICU-free days, consistency between mNGS and traditional microbiological tests, detective rate of mNGS and traditional microbiological tests, turn-out time, time from group allocation to start of treatment, duration of vasopressor support, types and duration of anti-infective regimens, source of drug-resistant bacteria or fungi, and ICU cost.

Discussion

The clinical benefits of mNGS are potentially significant, but its limitations should also be considered.

Trial registration

ChineseClinicalTrialRegistry.org, ChiCTR2300076853. Registered on 22 October 2023.
Sex differences of post-Covid patients undergoing outpatient pulmonary rehabilitation
Authors: Kautzky Alexander , Nopp Stephan , Gattinger Dietlinde , Petrovic Milos , Antlinger Martin , Schomacker Dustin , Kautzky-Willer Alexandra , Zwick Ralf Harun
Published: April 2024

Background

Following years of pandemic severe acute respiratory syndrome coronavirus 2 infections labelled Covid-19, long lasting impairment summarized as post-Covid syndrome (PCS) challenges worldwide healthcare. Patients benefit from rehabilitation programs, but sex specific aspects of improvement remain little understood. The aim of the study was to assess whether women and men differ in response to outpatient pulmonary rehabilitation for PCS.

Methods

263 (54.4% female) patients partaking in outpatient pulmonary rehabilitation (OPR) due to PCS between March 2020 and July 2022 were included in a prospective observational cohort study. Outcomes were assessed at baseline and before discharge from OPR and included six-minute walking distance (6MWD), 1-second forced expiratory volume (FEV1), diffusion capacity for carbon monoxide, maximal inspiratory pressure (MIP), dyspnea (medical research council scale), and post-Covid functional status scale (PCFS). Sexspecific changes in outcomes following OPR were assessed by linear mixed model and presented as mean differences (MD) with 95% confidence intervals. Linear regression was applied to test whether 6MWD correlates with PCFS and the minimal clinically important difference (MCID) in 6MWD regarding an improvement of at least one point in PCFS was computed with logistic regression.

Results

Significant improvement throughout OPR was observed for all outcomes (all p < 0.0001). Despite less severe Covid-19 infections, PCFS scores remained higher in females after OPR (p = 0.004) and only 19.4% of women compared to 38.5% of men achieved remission of functional impairment. At baseline as well as after OPR, females showed higher symptom load compared to men in dyspnea (p = 0.0027) and scored lower in FEV1 (p = 0.009) and MIP (p = 0.0006) assessment. Performance in 6MWD was comparable between men and women. An increase of 35 m in 6MWD was computed as minimal clinically important difference to improve functional impairment.

Conclusion

Both subjective symptoms such as fatigue and dyspnea and objective impairment in performance in pulmonary function were more frequently observed among women. Despite improvement throughout OPR in both women and men, the sex-gap in symptom load could not be closed as women less often achieved remission from functional impairment due to PCS. Intensified treatment of these symptoms should be considered in women undergoing rehabilitation for PCS.
Meeting the challenges of the 21st century: the fundamental importance of trust for transformation
Authors: McKee Martin , van Schalkwyk May CI , Greenley Rachel
Published: April 2024

Background

This paper is one of a collection on challenges facing health systems in the future. One obvious challenge is how to transform to meet changing health needs and take advantage of emerging treatment opportunities. However, we argue that effective transformations are only possible if there is trust in the health system.

Main body

We focus on three of the many relationships that require trust in health systems, trust by patients and the public, by health workers, and by politicians. Unfortunately, we are seeing a concerning loss of trust in these relationships and, for too long, the importance of trust to health policymaking and health system functioning has been overlooked and under-valued. We contend that trust must be given the attention, time, and resources it warrants as an indispensable element of any health system and, in this paper, we review why trust is so important in health systems, how trust has been thought about by scholars from different disciplines, what we know about its place in health systems, and how we can give it greater prominence in research and policy.

Conclusion

Trust is essential if health systems are to meet the challenges of the 21st century but it is too often overlooked or, in some cases, undermined.
Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences
Authors: Camara Mahamadou D. , Zhou Yitian , De Sousa Taís Nóbrega , Gil José P. , Djimde Abdoulaye A. , Lauschke Volker M.
Published: April 2024

Background

CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates.

Results

We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16–36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9–19.8% for *3 and 2.3–7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20–60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3–12.8% of South and West Asian individuals.

Conclusions

Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.
Falling and rising in the vortex of cancer: children’s adaptation with cancer: a qualitative study
Authors: Sepahvand Fatemeh , Valizadeh Fatemeh , Karami Kimia , Abdolkarimi Babak , Ghasemi Fatemeh
Published: April 2024

Background

Cancer is a considerable health problem worldwide and the second leading cause of death in children. It has many physical, psychological, and social consequences for children and their families. The ability to adapt to cancer plays a vital role in the recovery and quality of life of affected children. This study aimed to explain the adaptation of children with cancer to their disease.

Methods

This qualitative study adopted the directed content analysis approach based on the Roy nursing model. The participants were nine children with cancer aged 6–18 years old, five family members, four nurses, one doctor, one teacher, and two charity association members, recruited by purposive sampling method. The information was collected via individual semi-structured interviews, a focus group discussion, and field notes. The data were analyzed simultaneously with data collection using the Elo and Kyngäs method. The study rigor was ensured based on the Guba and Lincoln criteria.

Findings

Of the four categories of physical challenges, fragile self-concept, the difficulty of role transition, and disruption of the path to independence, the theme of Falling and rising in the cancer vortex was abstracted.

Conclusion

Based on the Roy model, the children in the present study were at the compensatory level of adaptation. This research demonstrates that the adaptation of children being treated for cancer is fragile and not constant. With each hospitalization and exacerbation of the disease, they made efforts to adapt to their disease using regulatory and cognitive subsystems. Paying attention to different stimulants and the effects of support systems on physical challenges, fragile self-concept, difficult role transition, and disruption of the path to independence for each child, as well as providing individualized care for these children, can help their adaptation to and healthy transition from the vortex of cancer. The Roy adaptation model was helpful and efficient for elucidating the adaptation of children with cancer. Providing care for children by healthcare specialists, especially nurses, should be theory-based and individualized.
Initiatives for promoting educator wellbeing: a Delphi study
Authors: P Patrick , A Reupert , E Berger , Z Morris , Z Diamond , M Hammer , R Hine , C Fathers
Published: April 2024

Background

Growing demands on educators have resulted in increased levels of burnout and stress and decreasing wellbeing. This study aimed to establish expert consensus on the key characteristics required in prospective educator wellbeing initiatives.

Methods

The Delphi approach is a process of forecasting that is based on the aggregated opinion of panel members (or experts) within a field of study. Using a Delphi approach, academic and practitioner expertise were sought over a two-rounds, with 17 and 14 participants in each round respectively. The study aimed to identify how systemic factors (e.g., leadership) could be utilised to promote educator wellbeing. The study also sought expert consensus on enablers and barriers for engagement in educator wellbeing initiatives.

Results

Findings highlighted the importance of fostering positive relationships with colleagues, communities and families, and the active role of wellbeing teams to promote wellbeing initiatives. The need for leaders to address their own wellbeing and build trust within teams was also identified. Panel members identified the need for prospective funding to prioritise wellbeing initiatives. There was also a preference for ongoing initiatives rather than stand-alone wellbeing events that conveyed the ongoing importance of managing one’s wellbeing.

Conclusions

This paper presents practical recommendations that can be used to inform the development and evaluation of future initiatives and policy. Applying the consensus derived from this study is likely to make wellbeing initiatives more viable and facilitate uptake amongst educators.
Investigating learning burnout and academic performance among management students: a longitudinal study in English courses
Authors: Pham Thi Thuy Dung , Duong Nam Tien
Published: April 2024

This study aims to move away from the cross-sectional approach related to burnout and conduct a longitudinal study to explore the factors influencing learning burnout among management students. The study primarily adopts a questionnaire survey, with students majoring in business management. Descriptive statistics and structural equation modeling (SEM) are used to analyze the data and validate the hypotheses. The findings are: (1) There is a significant negative relationship between English anxiety and self-efficacy and a significant positive relationship between past English learning performance and self-efficacy. (2) The changes in self-efficacy are negatively related to the changes in burnout, while the changes in workload are positively related to the changes in burnout. Additionally, there is a positive relationship between English anxiety and learning burnout. (3) There is a significant negative relationship between English learning performance and burnout. The direct impact of self-efficacy on English learning performance is not supported, but it has an indirect effect through the mediating role of burnout. The study proposes strategies to improve student outcomes and well-being: (1) making English courses more engaging to boost performance and confidence, reducing learning burnout; (2) encouraging and supporting students to enhance self-efficacy and motivation; (3) assigning tasks seen as useful and interesting to lessen perceived workload and emotional exhaustion; (4) and considering English anxiety in admissions to decrease learning burnout, especially as schools gain more autonomy in their policies.
Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy
Authors: Shan Yukai , Xie Tianao , Sun Yuchao , Lu Ziyi , Topatana Win , Juengpanich Sarun , Chen Tianen , Han Yina , Cao Jiasheng , Hu Jiahao , Li Shijie , Cai Xiujun , Chen Mingyu
Published: April 2024

Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.
Spatial transcriptomics reveals segregation of tumor cell states in glioblastoma and marked immunosuppression within the perinecrotic niche
Authors: Liu Mengyi , Ji Zhicheng , Jain Vaibhav , Smith Vanessa L. , Hocke Emily , Patel Anoop P. , McLendon Roger E. , Ashley David M. , Gregory Simon G. , López Giselle Y.
Published: April 2024

Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM.
Extracellular vesicle encapsulated nicotinamide delivered via a trans-scleral route provides retinal ganglion cell neuroprotection
Authors: Kim Myungjin , Kim Jun Yong , Rhim Won-Kyu , Cimaglia Gloria , Want Andrew , Morgan James E. , Williams Pete A. , Park Chun Gwon , Han Dong Keun , Rho Seungsoo
Published: April 2024

The progressive and irreversible degeneration of retinal ganglion cells (RGCs) and their axons is the major characteristic of glaucoma, a leading cause of irreversible blindness worldwide. Nicotinamide adenine dinucleotide (NAD) is a cofactor and metabolite of redox reaction critical for neuronal survival. Supplementation with nicotinamide (NAM), a precursor of NAD, can confer neuroprotective effects against glaucomatous damage caused by an age-related decline of NAD or mitochondrial dysfunction, reflecting the high metabolic activity of RGCs. However, oral supplementation of drug is relatively less efficient in terms of transmissibility to RGCs compared to direct delivery methods such as intraocular injection or delivery using subconjunctival depots. Neither method is ideal, given the risks of infection and subconjunctival scarring without novel techniques. By contrast, extracellular vesicles (EVs) have advantages as a drug delivery system with low immunogeneity and tissue interactions. We have evaluated the EV delivery of NAM as an RGC protective agent using a quantitative assessment of dendritic integrity using DiOlistics, which is confirmed to be a more sensitive measure of neuronal health in our mouse glaucoma model than the evaluation of somatic loss via the immunostaining method. NAM or NAM-loaded EVs showed a significant neuroprotective effect in the mouse retinal explant model. Furthermore, NAM-loaded EVs can penetrate the sclera once deployed in the subconjunctival space. These results confirm the feasibility of using subconjunctival injection of EVs to deliver NAM to intraocular targets.
Green and sustainable AI research: an integrated thematic and topic modeling analysis
Authors: Raman Raghu , Pattnaik Debidutta , Lathabai Hiran H. , Kumar Chandan , Govindan Kannan , Nedungadi Prema
Published: April 2024

This investigation delves into Green AI and Sustainable AI literature through a dual-analytical approach, combining thematic analysis with BERTopic modeling to reveal both broad thematic clusters and nuanced emerging topics. It identifies three major thematic clusters: (1) Responsible AI for Sustainable Development, focusing on integrating sustainability and ethics within AI technologies; (2) Advancements in Green AI for Energy Optimization, centering on energy efficiency; and (3) Big Data-Driven Computational Advances, emphasizing AI’s influence on socio-economic and environmental aspects. Concurrently, BERTopic modeling uncovers five emerging topics: Ethical Eco-Intelligence, Sustainable Neural Computing, Ethical Healthcare Intelligence, AI Learning Quest, and Cognitive AI Innovation, indicating a trend toward embedding ethical and sustainability considerations into AI research. The study reveals novel intersections between Sustainable and Ethical AI and Green Computing, indicating significant research trends and identifying Ethical Healthcare Intelligence and AI Learning Quest as evolving areas within AI’s socio-economic and societal impacts. The study advocates for a unified approach to innovation in AI, promoting environmental sustainability and ethical integrity to foster responsible AI development. This aligns with the Sustainable Development Goals, emphasizing the need for ecological balance, societal welfare, and responsible innovation. This refined focus underscores the critical need for integrating ethical and environmental considerations into the AI development lifecycle, offering insights for future research directions and policy interventions.
Exogenous melatonin strengthens saline-alkali stress tolerance in apple rootstock M9-T337 seedlings by initiating a variety of physiological and biochemical pathways
Authors: Xian Xulin , Zhang Zhongxing , Wang Shuangcheng , Cheng Jiao , Gao Yanlong , Ma Naiying , Li Cailong , Wang Yanxiu
Published: April 2024

Melatonin (MT) is an important plant growth regulator that significantly regulates the growth and development of plants. Previous studies confirmed the effectiveness of MT in improving plant stress tolerance. In this study, annual M9-T337 seedlings were selected as subjects, and five treatments were applied: control (CK), in which only half the concentration of Hoagland was applied; Saline-alkaline stress treatment (SA, 100 mmol·L−1 saline-alkaline solution); melatonin treatment (MT, CK + 200 μmol L−1 exogenous MT); Saline-alkaline + melatonin treatment (MS, SA + 200 μmol L−1 exogenous MT); and saline-alkaline stress + melatonin + inhibitor treatment (HS, additional 100 μmol L−1 p-CPA treatment to MS). The results showed that saline-alkaline stress negatively affected the growth of M9-T337 seedlings by reducing photosynthetic capacity, increasing Na+, promoting reactive oxygen species such as H2O2, and changing the osmotic content and antioxidant system. However, the application of exogenous MT effectively alleviated saline-alkaline damage and significantly promoted the growth of M9-T337 seedlings. It significantly increased plant height, diameter, root length, root surface area, volume and activity. Furthermore, MT alleviated osmotic stress by accumulating proline, soluble sugars, soluble proteins and starch. MT improved photosynthetic capacity by delaying chlorophyll degradation and regulating gas exchange parameters as well as fluorescence parameters in leaves. Additionally, MT reduced the Na+/K+ ratio to reduce ion toxicity by upregulating the expression of Na+ transporter genes (MhCAX5, MhCHX15, MhSOS1, and MhALT1) and downregulating the expression of K+ transporter genes (MhSKOR and MhNHX4). In addition, MT can increase antioxidant enzyme activity (superoxide dismutase (SOD), peroxidase(POD), catalase (CAT), ascorbic acid oxidase (AAO), ascorbate peroxidase (APX) and monodehydroascorbate reductase (MDHAR)) in the ASA-GSH cycle and increase ascorbic acid (AsA), reduced glutathione (GSH) and oxidized glutathione (GSSG) levels to counteract the accumulation of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and Superoxide anion free radicals (O2−), reducing oxidative damage. Exogenous MT promotes M9-T337 seedlings growth under saline-alkaline stress by responding synergistically with auxin (IAA), gibberellin (GA3) and zeatin (ZT) to saline-alkaline stress. Our results confirm that MT has the potential to alleviate Saline-alkaline stress by promoting root growth, increasing biomass accumulation and photosynthetic capacity, strengthening the antioxidant defense system, maintaining ionic balance, the ascorbate–glutathione cycle and the Osmoregulation facilitates and regulates endogenous hormone levels in M9-T337 seedlings.

Graphical Abstract