bluuebunny/crossref_metadata_2025 huggingface dataset:
Towns in Kalidāsa’s Kāvyas and the Thesis of Urban Decay
Authors: Veluthat Kesavan
Published: March 2024

This essay tries to look at the way in which Kālidāsa approaches towns in his three kāvyas: Meghadūta, Kumārasaṁbhava and Raghuvaṁśa. Most of the descriptions are stereotypical, using stock phrases and formulaic expressions, some of them straight from texts like the Arthaśāstra. However, there is one city that is described somewhat realistically—Ayodhya, which was deserted following Rāma’s departure. Both these—the stereotypes of prosperous towns and the realism of a decayed town—fit into the pattern of ‘urban decay’ presented by historians on the basis of archaeological evidence, a landmark in Indian historiography.
Posterior Ankle Impingement: It’s Not Only About the Os Trigonum
Authors: Mansur Nacime Salomao Barbachan , Femino John E. , Chinnakkannu Karthikeyan , Fayed Aly , Glass Natalie , Phisitkul Phinit , Amendola Annunziato
Published: March 2024

Background:

Os trigonum and Stieda process are common etiologies for posterior ankle impingement syndrome (PAIS), and diagnosis is typically made by radiographs, computed tomographic, or magnetic resonance imaging. However, these static tests may not detect associated soft tissue and bony pathologies. Posterior ankle and hindfoot arthroscopy (PAHA) is dynamic, providing at least ×8 magnification with full anatomical visualization. The primary aim of this study was to report the prevalence of associated conditions seen with trigonal impingement treated with PAHA.

Methods:

In this retrospective comparative study, patients who underwent PAHA for PAIS due to trigonal impingement, from January 2011 to September 2016, were reviewed. Concomitant open posterior procedures and other indications for PAHA were excluded. Demographic data were collected with pre- and postoperative diagnosis, arthroscopic findings, type of impingement, location, associated procedures, and anatomical etiologies. Trigonal impingements were divided in os trigonal or Stieda and subgrouped as isolated, with flexor hallucis longus (FHL) disorders, with FHL plus other impingement, and with other impingement lesions.

Results:

A total of 111 ankles were studied—74 os trigonum and 37 Stieda. Isolated trigonal disorders accounted for 15.3% of PAIS (n = 17). Cases having associated conditions had a mode of 3 additional pathologies. FHL disorders were found in 69.4%, subtalar impingement in 32.4%, posteromedial ankle synovitis in 25.2%, posterolateral ankle synovitis in 22.5%, and posterior inferior tibiofibular ligament impingement in 19.8% of cases. Associated pathologies were observed in 58.6% of cases when FHL was not considered. Significant differences were noted comparing os and Stieda (isolated: 20.3% to 5.4%, P = .040; FHL plus others: 35.1% to 59.5%, P = .015).

Conclusion:

Trigonal bone (os trigonum or Stieda) was found to cause impingement in isolation in a small proportion of cases even when the FHL was considered part of the same disease spectrum. This should alert surgeons when considering removing trigonal impingement. Open approaches may limit the visualization and assessment of associated posterior ankle and subtalar pathoanatomy, thus possibly overlooking concomitant causes of PAIS.

Level of Evidence:

Level III, retrospective comparative study.
Semantic classifiers (determinatives) and categorization in the ancient Egyptian writing system: Rules, list of classifiers, and studies byiClassifieron theStory of Sinuhe
Authors: Goldwasser Orly , Soler Susana
Published: March 2024

In the last two decades, we have extensively explored the semantic classifiers in ancient Egyptian scripts, showing how they encode the world from two complementary perspectives: universal cognitive tendencies of classification along with Egyptian society's categorization of the world. Our central hypothesis is that each graphemic classifier in the Egyptian writing system heads a conceptual category. The assemblage of words classified by a particular classifier presents us with a dynamic map of an emic category in the mind of a culture. Classifiers in the Egyptian script allow us to trace central and marginal members of conceptual categories, spot interrelations and overlaps between categories, observe diachronic developments and changes, and discover incompatibility of categories. The number of classifier occurrences in complex script systems amounts to millions (i.e., big data). In the last decade, we developed in the ArchaeoMind Lab the digital tool iClassifier1(© Goldwasser, Harel, and Nikolaev) designed to check our hypothesis on a large scope of texts from different periods and different scripts. We mark classifiers in imported digitalized corpora—in ancient Chinese, ancient Egyptian, and Sumerian cuneiform. This contribution introduces the reader to the rules of the classifier system in the Egyptian script and presents new results from a pilot project on a genuine Egyptian corpus (variants of the Story of Sinuhe).
Introduction: Graphemic classifiers in complex script systems
Authors: Goldwasser Orly , Handel Zev
Published: March 2024

This article explores the role of unpronounced semantic classifiers, also known as graphemic classifiers or determinatives, in three ancient complex scripts: Egyptian, Chinese and Sumerian. These classifiers are silent hieroglyphs, Chinese characters or cuneiform signs that are combined with other signs that carry phonetic information to form a complete written representation of a word. While these classifiers are written and visible, they are not pronounced. They add silent, motivated semantic information related to the meaning of the word. These classifiers can be found in various positions within words, reflecting cultural and referential information. Classifier studies, in general, have gained significant interest at the intersection of linguistic typology, cognitive linguistics, semiotics of scripts and neuroscience. The research field examines classifiers in oral languages, signed languages and complex scripts, emphasizing that regardless of modality they reflect a shared cognitive effort to organize knowledge. It is our hope that the scholarly contributions in this issue will open up a new chapter in classifier studies and in comparative script analysis. Theoretical and analytical work undertaken in the last few decades has been done primarily by individual researchers specializing in one language or script. Our approach combines large-scale corpus data with comparative script analysis carried out by teams of collaborators who can contribute specialized expertise in different ancient writing systems. The research possibilities opened by our newly developed digital tool iClassifier are presented in detail in the other contributions in this issue. This work has laid a strong comparative foundation that we can now build on, to develop new insights into the early history of script development and the commonalities and differences among ancient cultural conceptualizations of the world.
New design of interdental rubber picks - does the archimedean screw design bring an improvement for experimental cleaning efficacy and force?
Authors: Härdter Ann-Kristin , Nordloh Anna , Cyris Miriam , Straßburger Martin , Rinder Thomas , Dörfer Christof E. , Sälzer Sonja , Graetz Christian
Published: March 2024

Background

Up to date, interdental brushes (IDB) are the first choice for interdental cleaning because of their cleaning efficacy. Cylindrical ones must be selected individually according to the size/morphology of the interdental area (IDR), whereas conical ones cover a larger variability of IDR. However, there is a trend on the part of patients towards interdental rubber picks (IRP) which are in general conically shaped, and which seem to be linked with lower cleaning efficacy. A new IRP with an Archimedes´ screw design was developed to overcome this limitation. Therefore, the in vitro study aimed to measure the experimental cleaning efficacy (ECE) and force (ECF) during interdental use of IDBs versus the new IRP type.

Methods

Three IRPs with different tapers (PHB angled: 0.039, PHB straight S: 0.027, Vitis straight M: 0.045; all Flexipicks, Dentaid, Cerdanyola del Vallès, Spain) were compared to one IDB (Interprox micro PHD 0.9, Dentaid, Cerdanyola del Vallès, Spain). IDR were reproduced by a 3D-printer (Form2, Formlabs Sommerville, MA, USA) according to human teeth and matched to equivalent pairs (isosceles triangle, concave, convex) in three different diameters (1.0 mm,1.1 mm,1.3 mm). Covered with simulated biofilm, pre-/ post-brushing situations of IDR (standardized, computer-aided ten cycles) were photographed and quantified by digital image subtraction to calculate ECE [%]. ECF were registered with a load cell [N]. Statistically significant differences were detected using the Mann-Whitney-U-test and the Kruskal-Wallis-test with Bonferroni correction for multiple testing.

Results

Overall, the ECE (mean ± SD) was higher for IDB micro 0.9 (45.95 ± 11.34%, p < 0.001) compared to all IRPs (PHB angled: 25.37 ± 15.29%; PHB straight: 22.28 ± 16.75%; Vitis straight: 25.24 ± 12.21%; p ≤ 0.001), whereat best ECE was achieved in isosceles triangle IDR of 1.0–1.1 mm (IDB micro 0.9: 70.7 ± 7.7%; PHB angled S: 57.30 ± 4.43%; p < 0.001). The highest ECF occurred for Vitis straight M with 2.11 ± 0.46 N, while IDB micro 0.9 showed lowest ECF values (0.64 ± 0.14 N; p < 0.001).

Conclusions

IRP with an Archimedes´ screw design and a higher taper were associated with advanced ECE but also higher ECF, nevertheless, ECE didn’t reach the cleaning efficacy of conventional IDBs.
Outcomes of neoadjuvant chemotherapy and radical hysterectomy for locally advanced cervical cancer at Kigali University Teaching Hospital, Rwanda: a retrospective descriptive study
Authors: Ngabonziza Eugene , Ghebre Rahel , DeBoer Rebecca J. , Ntasumbumuyange Diomede , Magriples Urania , George Jessica , Grover Surbhi , Bazzett-Matabele Lisa
Published: March 2024

Background

Half of countries in Africa lack access to radiation (RT), which is essential for standard treatment of locally advanced cervical cancers. We evaluated outcomes for patients treated with neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in settings where no RT is available.

Methods

We performed a retrospective descriptive study of all patients with FIGO stage IB2-IIA2 and some exceptional stage IIB cases who received NACT and surgery at Kigali University Teaching Hospital in Rwanda. Patients were treated with NACT consisting of carboplatin and paclitaxel once every 3 weeks for 3–4 cycles before radical hysterectomy. We calculated recurrence rates and overall survival (OS) rate was determined by Kaplan-Meier estimates.

Results

Between May 2016 and October 2018, 57 patients underwent NACT and 43 (75.4%) were candidates for radical hysterectomy after clinical response assessment. Among the 43 patients who received NACT and surgery, the median age was 56 years, 14% were HIV positive, and FIGO stage distribution was: IB2 (32.6%), IIA1 (7.0%), IIA2 (51.2%) and IIB (9.3%). Thirty-nine (96%) patients received 3 cycles and 4 (4%) received 4 cycles of NACT. Thirty-eight (88.4%) patients underwent radical hysterectomy as planned and 5 (11.6%) had surgery aborted due to grossly metastatic disease. Two patients were lost to follow up after surgery and excluded from survival analysis. For the remaining 41 patients with median follow-up time of 34.4 months, 32 (78%) were alive with no evidence of recurrence, and 8 (20%) were alive with recurrence. One patient died of an unrelated cancer. The 3-year OS rate for the 41 patients who underwent NACT and surgery was 80.8% with a recurrence rate of 20%.

Conclusions

Neoadjuvant chemotherapy with radical hysterectomy is a feasible treatment option for locally advanced cervical cancer in settings with limited access to RT. With an increase in gynecologic oncologists skilled at radical surgery, this approach may be a more widely available alternative treatment option in countries without radiation facilities.
Longitudinal BMI change and outcomes in Chronic Obstructive Pulmonary Disease: a nationwide population-based cohort study
Authors: Kim Taeyun , Shin Sun Hye , Kim Hyunsoo , Im Yunjoo , Cho Juhee , Kang Danbee , Park Hye Yun
Published: March 2024

Background

The association between longitudinal body mass index (BMI) change and clinical outcomes in patients with chronic obstructive pulmonary disease (COPD) has not fully investigated.

Methods

This retrospective cohort study included 116,463 COPD patients aged ≥ 40, with at least two health examinations, one within 2 years before and another within 3 years after COPD diagnosis (January 1, 2014, to December 31, 2019). Associations between BMI percentage change with all-cause mortality, primary endpoint, and initial severe exacerbation were assessed.

Results

BMI decreased > 5% in 14,728 (12.6%), while maintained in 80,689 (69.2%), and increased > 5% in 21,046 (18.1%) after COPD diagnosis. Compared to maintenance group, adjusted hazard ratio (aHR) for all-cause mortality was 1.70 in BMI decrease group (95% CI:1.61, 1.79) and 1.13 in BMI increase group (95% CI:1.07, 1.20). In subgroup analysis, decrease in BMI showed a stronger effect on mortality as baseline BMI was lower, while an increase in BMI was related to an increase in mortality only in obese COPD patients with aHRs of 1.18 (95% CI: 1.03, 1.36). The aHRs for the risk of severe exacerbation (BMI decrease group and increase group vs. maintenance group) were 1.30 (95% CI:1.24, 1.35) and 1.12 (95% CI:1.07, 1.16), respectively.

Conclusions

A decrease in BMI was associated with an increased risk of all-cause mortality in a dose-dependent manner in patients with COPD. This was most significant in underweight patients. Regular monitoring for weight loss might be an important component for COPD management.
Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study
Authors: Choi JungMin , Lee So‑Ryoung , Choi Eue-Keun , Lee Kyung-Yeon , Ahn Hyo-Jeong , Kwon Soonil , Han Kyung‑Do , Oh Seil , Lip Gregory Y. H.
Published: March 2024

Background

Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF in patients with DM with respect to known DM duration.

Methods

Patients with type 2 DM who underwent the Korean National Health Insurance Service health examination in 2015–2016 were grouped by DM duration: new onset and < 5, 5–9, and ≥ 10 years. Physical activity was classified into four levels: 0, < 500, 500–999, 1,000–1,499, and ≥ 1,500 metabolic equivalent task (MET)-min/week, with the primary outcome being new-onset AF.

Results

The study enrolled 2,392,486 patients (aged 59.3 ± 12.0 years, 39.8% female) with an average follow-up of 3.9 ± 0.8 years and mean DM duration of 5.3 ± 5.1 years. Greater physical activity was associated with a lower AF risk. Lowering of incident AF risk varied with different amounts of physical activity in relation to known DM duration. Among patients with new-onset DM, DM duration < 5 years and 5–9 years and 1,000–1,499 MET-min/week exhibited the lowest AF risk. Physical activity ≥ 1,500 MET-min/week was associated with the lowest incident AF risk in patients with DM duration ≥ 10 years (by 15%), followed DM duration of 5–9 years (12%) and < 5 years (9%) (p-for-interaction = 0.002).

Conclusions

Longer DM duration was associated with a high risk of incident AF, while increased physical activity generally reduced AF risk. Engaging in > 1,500 MET-min/week was associated with the greatest AF risk reduction in patients with longer DM duration, highlighting the potential benefits of higher activity levels for AF prevention.
Evidence that tirzepatide protects against diabetes-related cardiac damages
Authors: Taktaz Fatemeh , Scisciola Lucia , Fontanella Rosaria Anna , Pesapane Ada , Ghosh Puja , Franzese Martina , Tortorella Giovanni , Puocci Armando , Sommella Eduardo , Signoriello Giuseppe , Olivieri Fabiola , Barbieri Michelangela , Paolisso Giuseppe
Published: March 2024

Background

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist.

Methods

A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT.

Results

Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure.

Conclusion

Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

Graphical Abstract
Associations of triglyceride-glucose (TyG) index with chest pain incidence and mortality among the U.S. population
Authors: Zhao Yao , Gu Yu , Zhang Bili
Published: March 2024

Background

The triglyceride and glucose (TyG) index, a simple surrogate marker of insulin resistance, is related to cardiovascular disease. However, there is a lack of evidence for the relationship between the TyG index and chest pain. This study aimed to investigate the association of the TyG index with chest pain and to evaluate the relationship between the TyG index and all-cause mortality in participants with or without chest pain.

Methods

The present study utilized data from the 2001–2012 National Health and Nutrition Examination Survey (NHANES), employing a combination of cross-sectional and cohort study designs. The association between the TyG index and chest pain was investigated using weighted logistic regression models. Weighted Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause mortality. Restricted cubic spline analysis was used to explore linear or nonlinear relationships between the TyG index and chest pain or all-cause mortality.

Results

The findings revealed a positive correlation between the TyG index and chest pain, even after adjusting for potential confounding factors (quartile 4 versus quartile 1, odds ratio [OR] 1.42, 95% confidence interval [CI] 1.14–1.77, P = 0.002). During a mean follow-up time of 139 months, a total of 2286 individuals (27.43%) experienced mortality. Weighted multivariate Cox regression models indicated that for each one-unit increase in the TyG index, the adjusted hazard ratio (HR) for mortality was 1.14 (95% CI = 0.94–1.37) for participants with chest pain and 1.25 (95% CI = 1.09–1.43) for those without chest pain. Furthermore, restricted cubic spline analysis revealed a linear relationship between the TyG index and chest pain (P for nonlinearity = 0.902), whereas a nonlinear relationship was shown between the TyG index and all-cause mortality among populations regardless of chest pain (all P for nonlinearity < 0.01).

Conclusion

The TyG index was positively linked to a higher incidence of chest pain. Moreover, the TyG index was associated with all-cause mortality not only in participants with chest pain but also in those without chest pain.
β-hydroxybutyrate inhibits malignant phenotypes of prostate cancer cells through β-hydroxybutyrylation of indoleacetamide-N-methyltransferase
Authors: Zhang Yifan , Li Yunlong
Published: March 2024

Background

Prostate cancer (PCa) is one of the most prevalent cancers in men and is associated with high mortality and disability rates. β-hydroxybutyrate (BHB), a ketone body, has received increasing attention for its role in cancer. However, its role in PCa remains unclear. This study aimed to explore the mechanism and feasibility of BHB as a treatment alternative for PCa.

Methods

Colony formation assay, flow cytometry, western blot assay, and transwell assays were performed to determine the effect of BHB on the proliferation and metastasis of PCa cells. Tumor sphere formation and aldehyde dehydrogenase assays were used to identify the impact of BHB or indoleacetamide-N-methyltransferase (INMT) on the stemness of PCa cells. N6-methyladenosine (m6A)–meRIP real-time reverse transcription polymerase chain reaction and dual luciferase assays were conducted to confirm INMT upregulation via the METTL3–m6A pathway. Co-IP assay was used to detect the epigenetic modification of INMT by BHB-mediated β-hydroxybutyrylation (kbhb) and screen enzymes that regulate INMT kbhb. Mouse xenograft experiments demonstrated the antitumor effects of BHB in vivo.

Results

BHB can inhibit the proliferation, migration, and invasion of PCa cells by suppressing their stemness. Mechanistically, INMT, whose expression is upregulated by the METTL3–m6A pathway, was demonstrated to be an oncogenic gene that promotes the stem-like characteristics of PCa cells. BHB can suppress the malignant phenotypes of PCa by kbhb of INMT, which in turn inhibits INMT expression.

Conclusions

Our findings indicate a role of BHB in PCa metabolic therapy, thereby suggesting an epigenetic therapeutic strategy to target INMT in aggressive PCa.

Trial registration

Not applicable.
The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up
Authors: Jiang Wen-Mei , Tian Jia-Yuan , Guo Yi-Han , Qiu Li-Hong , Luo Xing-Yu , Huang Yang-Yu , Long Hao , Zhang Lan-Jun , Lin Peng , Xu Xin-Xin , Wu Lei-Lei , Ma Guo-Wei
Published: March 2024

Objective

This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up.

Methods

The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS).

Results

A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients’ prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001).

Conclusions

Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.
Receipt of seasonal malaria chemoprevention by age-ineligible children and associated factors in nine implementation states in Nigeria
Authors: Ibinaiye Taiwo , Rotimi Kunle , Balogun Ayodeji , Aidenagbon Adaeze , Oguoma Chibuzo , Rassi Christian , Baker Kevin , Oresanya Olusola , Nnaji Chuks
Published: March 2024

Background

As part of implementation quality standards, community distributors are expected to ensure that only age-eligible children (aged 3–59 months) receive seasonal malaria chemoprevention (SMC) medicines during monthly campaigns. There is uncertainty about the extent to which SMC medicines are administered to ineligible children. This study aimed to assess the magnitude of this occurrence, while exploring the factors associated with it across nine states where SMC was delivered in Nigeria during the 2022 round.

Methods

This analysis was based on data from representative end-of-round SMC household surveys conducted in nine SMC-implementing states in Nigeria. Data of 3299 age-ineligible children aged > 5 years and their caregivers were extracted from the survey dataset. Prevalence of receipt of SMC medicines by ineligible children was described by child-, caregiver- and SMC-related factors. Mixed-effects multivariable logistic regression models were fitted to explore the factors associated with ineligible receipt of SMC medicines.

Results

30.30% (95% CI 27.80–32.90) of ineligible children sampled received at least one dose of SMC medicines in 2022, the majority (60.60%) of whom were aged 5–6 years while the rest were aged 7–10 years. There were lower odds of an age-ineligible child receiving SMC medicines among caregivers who were knowledgeable of SMC age eligibility (OR: 0.53, 95% CI 0.37–0.77, p < 0.001), compared with those who were not knowledgeable of age eligibility. Higher odds of receipt of SMC were found among age-ineligible children whose caregivers had higher confidence in the protective effect of SMC against malaria (OR: 2.01, 95% CI 1.07–3.72, p = 0.030), compared with those whose caregivers were less confident. Compared with ineligible children of younger caregivers (aged < 20 years), those whose caregivers were older had lower odds of receiving SMC than those whose caregivers were younger; with lower odds among children of caregivers aged 20–39 years (OR: 0.50, 95% CI 0.30–0.82, p = 0.006).

Conclusions

This study contributes important evidence on the magnitude of the receipt of SMC medicines by age-ineligible children, while identifying individual and contextual factors associated with it. The findings provide potentially useful insights that can help inform and guide context-specific SMC implementation quality improvement efforts.
Dual-targeting tigecycline nanoparticles for treating intracranial infections caused by multidrug-resistant Acinetobacter baumannii
Authors: Lan Xing , Qin Shugang , Liu Huan , Guo Mengran , Zhang Yupei , Jin Xinyang , Duan Xing , Sun Min , Liu Zhenjun , Wang Wenyan , Zheng Qian , Liao Xuelian , Chen Jinpeng , Kang Yan , Xie Yongmei , Song Xiangrong
Published: March 2024

Multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) is a formidable pathogen responsible for severe intracranial infections post-craniotomy, exhibiting a mortality rate as high as 71%. Tigecycline (TGC), a broad-spectrum antibiotic, emerged as a potential therapeutic agent for MDR A. baumannii infections. Nonetheless, its clinical application was hindered by a short in vivo half-life and limited permeability through the blood–brain barrier (BBB). In this study, we prepared a novel core–shell nanoparticle encapsulating water-soluble tigecycline using a blend of mPEG-PLGA and PLGA materials. This nanoparticle, modified with a dual-targeting peptide Aβ11 and Tween 80 (Aβ11/T80@CSs), was specifically designed to enhance the delivery of tigecycline to the brain for treating A. baumannii-induced intracranial infections. Our findings demonstrated that Aβ11/T80@CSs nanocarriers successfully traversed the BBB and effectively delivered TGC into the cerebrospinal fluid (CSF), leading to a significant therapeutic response in a model of MDR A. baumannii intracranial infection. This study offers initial evidence and a platform for the application of brain-targeted nanocarrier delivery systems, showcasing their potential in administering water-soluble anti-infection drugs for intracranial infection treatments, and suggesting promising avenues for clinical translation.

Graphical abstract
An integrated framework for prognosis prediction and drug response modeling in colorectal liver metastasis drug discovery
Authors: Zhou Xiuman , Qian Yuzhen , Ling Chen , He Zhuoying , Shi Peishang , Gao Yanfeng , Sui Xinghua
Published: March 2024

Background

Colorectal cancer (CRC) is the third most prevalent cancer globally, and liver metastasis (CRLM) is the primary cause of death. Hence, it is essential to discover novel prognostic biomarkers and therapeutic drugs for CRLM.

Methods

This study developed two liver metastasis-associated prognostic signatures based on differentially expressed genes (DEGs) in CRLM. Additionally, we employed an interpretable deep learning model utilizing drug sensitivity databases to identify potential therapeutic drugs for high-risk CRLM patients. Subsequently, in vitro and in vivo experiments were performed to verify the efficacy of these compounds.

Results

These two prognostic models exhibited superior performance compared to previously reported ones. Obatoclax, a BCL-2 inhibitor, showed significant differential responses between high and low risk groups classified by prognostic models, and demonstrated remarkable effectiveness in both Transwell assay and CT26 colorectal liver metastasis mouse model.

Conclusions

This study highlights the significance of developing specialized prognostication approaches and investigating effective therapeutic drugs for patients with CRLM. The application of a deep learning drug response model provides a new drug discovery strategy for translational medicine in precision oncology.
Hypoxia inducible factor-1α regulates microglial innate immune memory and the pathology of Parkinson’s disease
Authors: Dong Hongtian , Zhang Xiaoshuang , Duan Yufei , He Yongtao , Zhao Jiayin , Wang Zishan , Wang Jinghui , Li Qing , Fan Guangchun , Liu Zhaolin , Shen Chenye , Zhang Yunhe , Yu Mei , Fei Jian , Huang Fang
Published: March 2024

Neuroinflammation is one of the core pathological features of Parkinson’s disease (PD). Innate immune cells play a crucial role in the progression of PD. Microglia, the major innate immune cells in the brain, exhibit innate immune memory effects and are recognized as key regulators of neuroinflammatory responses. Persistent modifications of microglia provoked by the first stimuli are pivotal for innate immune memory, resulting in an enhanced or suppressed immune response to second stimuli, which is known as innate immune training and innate immune tolerance, respectively. In this study, LPS was used to establish in vitro and in vivo models of innate immune memory. Microglia-specific Hif-1α knockout mice were further employed to elucidate the regulatory role of HIF-1α in innate immune memory and MPTP-induced PD pathology. Our results showed that different paradigms of LPS could induce innate immune training or tolerance in the nigrostriatal pathway of mice. We found that innate immune tolerance lasting for one month protected the dopaminergic system in PD mice, whereas the effect of innate immune training was limited. Deficiency of HIF-1α in microglia impeded the formation of innate immune memory and exerted protective effects in MPTP-intoxicated mice by suppressing neuroinflammation. Therefore, HIF-1α is essential for microglial innate immune memory and can promote neuroinflammation associated with PD.
Prediction of dysphagia aspiration through machine learning-based analysis of patients’ postprandial voices
Authors: Kim Jung-Min , Kim Min-Seop , Choi Sun-Young , Ryu Ju Seok
Published: March 2024

Background

Conventional diagnostic methods for dysphagia have limitations such as long wait times, radiation risks, and restricted evaluation. Therefore, voice-based diagnostic and monitoring technologies are required to overcome these limitations. Based on our hypothesis regarding the impact of weakened muscle strength and the presence of aspiration on vocal characteristics, this single-center, prospective study aimed to develop a machine-learning algorithm for predicting dysphagia status (normal, and aspiration) by analyzing postprandial voice limiting intake to 3 cc.

Methods

Conducted from September 2021 to February 2023 at Seoul National University Bundang Hospital, this single center, prospective cohort study included 198 participants aged 40 or older, with 128 without suspected dysphagia and 70 with dysphagia-aspiration. Voice data from participants were collected and used to develop dysphagia prediction models using the Multi-Layer Perceptron (MLP) with MobileNet V3. Male-only, female-only, and combined models were constructed using 10-fold cross-validation. Through the inference process, we established a model capable of probabilistically categorizing a new patient's voice as either normal or indicating the possibility of aspiration.

Results

The pre-trained models (mn40_as and mn30_as) exhibited superior performance compared to the non-pre-trained models (mn4.0 and mn3.0). Overall, the best-performing model, mn30_as, which is a pre-trained model, demonstrated an average AUC across 10 folds as follows: combined model 0.8361 (95% CI 0.7667–0.9056; max 0.9541), male model 0.8010 (95% CI 0.6589–0.9432; max 1.000), and female model 0.7572 (95% CI 0.6578–0.8567; max 0.9779). However, for the female model, a slightly higher result was observed with the mn4.0, which scored 0.7679 (95% CI 0.6426–0.8931; max 0.9722). Additionally, the other models (pre-trained; mn40_as, non-pre-trained; mn4.0 and mn3.0) also achieved performance above 0.7 in most cases, and the highest fold-level performance for most models was approximately around 0.9. The ‘mn’ in model names refers to MobileNet and the following number indicates the ‘width_mult’ parameter.

Conclusions

In this study, we used mel-spectrogram analysis and a MobileNetV3 model for predicting dysphagia aspiration. Our research highlights voice analysis potential in dysphagia screening, diagnosis, and monitoring, aiming for non-invasive safer, and more effective interventions.

Trial registration: This study was approved by the IRB (No. B-2109-707-303) and registered on clinicaltrials.gov (ID: NCT05149976).
Peg-IFNα combined with hepatitis B vaccination contributes to HBsAg seroconversion and improved immune function
Authors: Liu Yisi , Ren Shan , Ma Lina , Lin Xiao , Lu Junfeng , Cao Zhenhuan , Zheng Sujun , Hu Zhongjie , Xu Xiaoxue , Chen Xinyue
Published: March 2024

Purpose

The purpose of this study was to investigate immunological variations between a group that received the hepatitis B vaccine and a non-vaccine group. We focused on a cohort that achieved HBsAg seroclearance after Peg-IFNα treatment of CHB.

Methods

We enrolled twenty-eight individuals who achieved HBsAg seroclearance after Peg-IFNα treatment. They were divided into two groups: a vaccine group (n = 14) and a non-vaccine group (n = 14). We assessed lymphocyte subpopulations, B cell- and T cell-surface costimulatory/inhibitory factors, cytokines and immunoglobulin levels were detected at different time points to explore immune-function differences between both groups.

Results

The seroconversion rate in the vaccine group at 24 weeks post-vaccination was 100%, which was significantly higher (p = 0.006) than that of the non-vaccine group (50%). Additionally, more individuals in the vaccine group exhibited anti-HBs levels exceeding 100 IUs/L and 300 IUs/L compared to the non-vaccine group (p < 0.05). The vaccine group demonstrated significantly increase total B cells and class-switched B cells at 24 weeks and plasma cells, CD80+B cells, Tfh cells, and ICOS+Tfh cell at 12 weeks, compared with baseline levels (p < 0.05). Conversely, Bregs (CD24+CD27+ and CD24+CD38high) decreased significantly at 24 weeks (p < 0.05). None of the above changes were statistically significance in the non-vaccine group (p > 0.05). Total IgG increased significantly in the vaccine group, and IL-2, IL-5, and IL-6 concentrations increased significantly at week 24 (p < 0.05). Differences in various types of cytokines and immunoglobulins in the plasma of the non-vaccine group were not significant (p > 0.05). Anti-HBs titers positively correlated with Th1/Th2 cells at 24 weeks (r = 0.448 and 0.458, respectively, p = 0.022 and 0.019, respectively), and negatively with CD24+CD38highBreg cells (r = -0.402, p = 0.042).

Conclusions

After achieving HBsAg seroclearance through Peg-IFNα treatment for CHB, administering the hepatitis B vaccine significantly increased anti-HBs-seroconversion rates and antibody levels. We also observed significant immunological differences between the vaccine and non-vaccine groups. Specifically, the vaccine group exhibited significant increases in B cells, plasma cells, and Tfh cells, while Breg levels was significantly lower. These immunological changes are likely conducive to the production of anti-HBs antibodies. However, in the non-vaccine group, the observed changes were not significantlly significant.
Double lung transplantation is better than single lung transplantation for end-stage chronic obstructive pulmonary disease: a meta-analysis
Authors: Fang Yu-Chi , Cheng Wen-Hsin , Lu Hung-I , Wang Yi-Shi , Chuang Kai-Hao , Lai Hsing-Hua , Chen Yu , Chen Li-Chun , Tsai Meng-Yun , Chang Yu-Ping , Huang Kuo-Tung , Lo Chien-Ming
Published: March 2024

Background

Lung transplantation is one of the most common treatment options for patients with end-stage chronic obstructive pulmonary disease. However, the choice between single and double lung transplantation for these patients remains a matter of debate. Therefore, we performed a systematic search of medical databases for studies on single lung transplantation, double lung transplantation, and chronic obstructive pulmonary disease.

Methods

The rate ratio and hazard ratio of survival were analyzed. The meta-analysis included 15 case–control and retrospective registry studies.

Results

The rate ratios of the 3-year survival (0.937 and P = 0.041) and 5-year survival (0.775 and P = 0.000) were lower for single lung transplantation than for double lung transplantation. However, the hazard ratio did not differ significantly between the two.

Conclusions

Double lung transplantation was found to provide better benefits than single lung transplantation in terms of the long-term survival in patients with chronic obstructive pulmonary disease.
Associations between dietary behaviours and the mental and physical well-being of Swedish adolescents
Authors: Jonsson Kenisha Russell , Bailey Cameron Kymani , Corell Maria , Löfstedt Petra , Adjei Nicholas Kofi
Published: March 2024

Aims

This study aims to investigate the association between dietary behaviours, overweight/obesity, and mental health and well-being among Swedish adolescents.

Methods

Data from the 2017/2018 Health Behaviour in School-aged Children (HBSC) survey of 3692 adolescents aged ≈11, ≈13, and ≈15 years was analysed. We evaluated the prevalence and association of dietary behaviours, characterised by daily intake of fruits and vegetables, consumption of sugar-sweetened beverages (SSBs) and sweets once per week, and daily consumption of family meals and breakfast, with socioeconomic and demographic factors. Multivariate logistic regression models (adjusted and unadjusted) were then used to examine the relationship between dietary behaviours, overweight/obesity, and mental health and well-being including psychosomatic complaints, life satisfaction, and school-related pressure.

Results

Boys were more likely to eat breakfast and have meals together with their family than girls, but their fruit and vegetable intake was lower compared to girls. Adolescents with lower socioeconomic status (low family affluence, families perceived ’not well-off’ and two unemployed parents), single-parent households and twoforeign born parents were more likely to engage in poorer dietary behaviours. Daily breakfast, family meals, fruit and vegetable intake were positively associated with mental health and well-being. Specifically, daily family meals were linked to higher life satisfaction, fewer psychosomatic complaints, and reduced school-related pressure. Breakfast emerged as a beneficial dietary habit, associated with higher life satisfaction, and a lower likelihood of psychosomatic complaints, school-related pressure, and overweight/obesity. Fruit and vegetable consumption was consistently associated with better mental health and well-being while associations between SSBs and sweets were mixed.

Conclusions

Improving mental health and well-being, along with tackling the rising rates of mental illness and challenges related to overweight/obesity in adolescents constitute key public health priorities. Implementing policies that promote the intake of fruits and vegetables, reducing the consumption of SSBs and sweets, and emphasizing the value of having breakfast and sharing family meals could offer a cost-effective public health intervention.
Application of a magnetically separable Zr-MOF for fast extraction of palladium before its spectrophotometric detection
Authors: Piri Amin , Kaykhaii Massoud , Khajeh Mostafa , Oveisi Ali Reza
Published: March 2024

In this research, a novel magnetic zirconium-based metal-organic framework (Fe3O4@SiO2@MIP-202, MMOF), was fabricated, fully characterized, and applied for the batch-mode solid phase extraction of trace amounts of Pd2+ ions from water and wastewater samples before its spectrophotometric detection. Pd2+ ions were desorbed from MMOF by nitric acid and were complexed by treating with KI solution to have a maximum absorbance at 410 nm. The synthesized MMOF composite showed a very large surface area (65 m2.g− 1), good magnetization (1.7 emu.g− 1) and a large pore volume (0.059 cm3.g− 1) with adsorption capacity of 194.5 mg of Pd2+ ions/g of the adsorbent. This nanosorbent boasts chemo-mechanical stability, high adsorption capacity due to its vast active sites, and facile recovery facilitated by its magnetic properties. Parameters affecting the extraction efficiency of the method were optimized as pH of the sample 7.4, volume of the sample 25 mL, 15 mg adsorbent, 1 mL of 0.1 M HNO3 eluent, with 10 and 15 min as the extraction and desorption times, respectively. The calibration curve was found to be linear across the 10.0–1500.0 µg.L− 1 range with a limit of detection of 1.05 µg.L− 1. The obtained extraction efficiency and enrichment were 98% and 245, respectively. The total analysis time was less than 30 min. This MMOF has never been used for the extraction of Pd2+ ions before.
Development of a hybrid bio-purification process of lactic acid solutions employing an engineered E. coli strain in a membrane bioreactor
Authors: Nastouli Alexandra , Sweeney Joseph , Harasek Michael , Karabelas Anastasios J. , Patsios Sotiris I.
Published: March 2024

Background

A potential alternative to lactic acid production through sugar fermentation is its recovery from grass silage leachate. The separation and purification of lactic acid from fermentation broths remain a key issue, as it amounts to up to 80% of its industrial production cost. In this study, a genetically engineered E. coli strain (A1:ldhA), that cannot catabolize lactic acid, has been used to selectively remove impurities from a synthetic medium comprising typical components (i.e., glucose and acetic acid) of green grass silage leachate. A systematic approach has been followed to provide a proof-of-concept for a bio-purification process of lactic acid solutions in a membrane bioreactor operating in semi-continuous mode.

Results

The synthetic medium composition was initially optimized in shake-flasks experiments, followed by scale-up in bench-scale bioreactor. Complete (i.e., 100%) and 60.4% removal for glucose and acetic acid, respectively, has been achieved in batch bioreactor experiments with a synthetic medium comprising 0.5 g/L glucose and 0.5 g/L acetic acid as carbon sources, and 10 g/L lactic acid; no lactic acid catabolism was observed in all batch fermentation tests. Afterwards, a hybrid biotechnological process combining semi-continuous bioreactor fermentation and ultrafiltration membrane separation (membrane bioreactor) was applied to in-situ separate purified medium from the active cells. The process was assessed under different semi-continuous operating conditions, resulting in a bacteria-free effluent and 100% glucose and acetic acid depletion, with no lactic acid catabolism, thus increasing the purity of the synthetic lactic acid solution.

Conclusions

The study clearly demonstrated that a bio-purification process for lactic acid employing the engineered E. coli strain cultivated in a membrane bioreactor is a technically feasible concept, paving the way for further technological advancement.
Plasmapheresis in thyrotoxicosis: a single-center case series
Authors: Rami I. , Zerrouki D. , Assarrar I. , Rouf S. , Latrech H.
Published: March 2024

Background

Plasmapheresis represent an alternative therapeutic option for hyperthyroidism with thyroid storm or refractory cases. It provides a rapid decrease in plasma thyroid hormones and anti-thyroid antibodies. The aim of this paper was to report our single center’s experience in managing particular situations of hyperthyroidism using apheresis.

Cases presentation

The following case series describes three young African patients (two females, one male) aged 29, 37, and 25 years old, respectively, with Graves’ disease who presented with drug ineffectiveness, drug-induced agranulocytosis, and thyroid storm with multi-organ failure. The three patients underwent plasmapheresis sessions leading to effective decline of thyroid hormone levels and offering a window for processing total thyroidectomy.

Discussion/conclusion

The standard management of thyrotoxicosis and thyroid storm was usually codified by the concomitant use of antithyroid medication, iodine, beta-blockers, and corticosteroids. This medical preparation can be effective in most cases. However, drug toxicity or ineffectiveness can limit the use of such therapeutics. Our paper supports the efficiency and safety of therapeutic plasma exchange in the preoperative management of thyrotoxicosis.