bluuebunny/crossref_metadata_2025 huggingface dataset:
A proof of concept for microcirculation monitoring using machine learning based hyperspectral imaging in critically ill patients: a monocentric observational study
Authors: Kohnke Judith , Pattberg Kevin , Nensa Felix , Kuhlmann Henning , Brenner Thorsten , Schmidt Karsten , Hosch René , Espeter Florian
Published: July 2024

Background

Impaired microcirculation is a cornerstone of sepsis development and leads to reduced tissue oxygenation, influenced by fluid and catecholamine administration during treatment. Hyperspectral imaging (HSI) is a non-invasive bedside technology for visualizing physicochemical tissue characteristics. Machine learning (ML) for skin HSI might offer an automated approach for bedside microcirculation assessment, providing an individualized tissue fingerprint of critically ill patients in intensive care. The study aimed to determine if machine learning could be utilized to automatically identify regions of interest (ROIs) in the hand, thereby distinguishing between healthy individuals and critically ill patients with sepsis using HSI.

Methods

HSI raw data from 75 critically ill sepsis patients and from 30 healthy controls were recorded using TIVITA® Tissue System and analyzed using an automated ML approach. Additionally, patients were divided into two groups based on their SOFA scores for further subanalysis: less severely ill (SOFA ≤ 5) and severely ill (SOFA > 5). The analysis of the HSI raw data was fully-automated using MediaPipe for ROI detection (palm and fingertips) and feature extraction. HSI Features were statistically analyzed to highlight relevant wavelength combinations using Mann–Whitney-U test and Benjamini, Krieger, and Yekutieli (BKY) correction. In addition, Random Forest models were trained using bootstrapping, and feature importances were determined to gain insights regarding the wavelength importance for a model decision.

Results

An automated pipeline for generating ROIs and HSI feature extraction was successfully established. HSI raw data analysis accurately distinguished healthy controls from sepsis patients. Wavelengths at the fingertips differed in the ranges of 575–695 nm and 840–1000 nm. For the palm, significant differences were observed in the range of 925–1000 nm. Feature importance plots indicated relevant information in the same wavelength ranges. Combining palm and fingertip analysis provided the highest reliability, with an AUC of 0.92 to distinguish between sepsis patients and healthy controls.

Conclusion

Based on this proof of concept, the integration of automated and standardized ROIs along with automated skin HSI analyzes, was able to differentiate between healthy individuals and patients with sepsis. This approach offers a reliable and objective assessment of skin microcirculation, facilitating the rapid identification of critically ill patients.
sciMET-cap: high-throughput single-cell methylation analysis with a reduced sequencing burden
Authors: Acharya Sonia N. , Nichols Ruth V. , Rylaarsdam Lauren E. , O’Connell Brendan L. , Braun Theodore P. , Adey Andrew C.
Published: July 2024

DNA methylation is a key component of the mammalian epigenome, playing a regulatory role in development, disease, and other processes. Robust, high-throughput single-cell DNA methylation assays are now possible (sciMET); however, the genome-wide nature of DNA methylation results in a high sequencing burden per cell. Here, we leverage target enrichment with sciMET to capture sufficient information per cell for cell type assignment using substantially fewer sequence reads (sciMET-cap). Accumulated off-target coverage enables genome-wide differentially methylated region (DMR) calling for clusters with as few as 115 cells. We characterize sciMET-cap on human PBMCs and brain (middle frontal gyrus).
The SHOW RESPECT adaptable framework of considerations for planning how to share trial results with participants, based on qualitative findings from trial participants and site staff
Authors: South Annabelle , Snowdon Claire , Burnett Eva , Bierer Barbara E. , Gillies Katie , Isaacs Talia , Sydes Matthew R.
Published: July 2024

Background

Sharing trial results with participants is a moral imperative, but too often does not happen in appropriate ways.

Methods

We carried out semi-structured interviews with patients (n = 13) and site staff (n = 11), and surveyed 180 patients and 68 site staff who were part of the Show RESPECT study, which tested approaches to sharing results with participants in the context of the ICON8 ovarian cancer trial (ISRCTN10356387). Qualitative and free-text data were analysed thematically, and findings used to develop the SHOW RESPECT adaptable framework of considerations for planning how to share trial results with participants. This paper presents the framework, with illustrations drawn from the Show RESPECT study.

Results

Our adaptable ‘SHOW RESPECT’ framework covers (1) Supporting and preparing trial participants to receive results, (2) HOw will the results reach participants?, (3) Who are the trial participants?, (4) REsults—what do they show?, (5) Special considerations, (6) Provider—who will share results with participants?, (7) Expertise and resources, (8) Communication tools and (9) Timing of sharing results. While the data upon which the framework is based come from a single trial, many of our findings are corroborated by findings from other studies in this area, supporting the transferability of our framework to trials beyond the UK ovarian cancer setting in which our work took place.

Conclusions

This adaptable ‘SHOW RESPECT’ framework can guide researchers as they plan how to share aggregate trial results with participants. While our data are drawn from a single trial context, the findings from Show RESPECT illustrate how approaches to communication in a specific trial can influence patient and staff experiences of feedback of trial results. The framework generated from these findings can be adapted to fit different trial contexts and used by other researchers to plan the sharing of results with their own participants.

Trial registration

ISRCTN96189403. Registered on February 26, 2019. Show RESPECT was supported by the Medical Research Council (MC_UU_12023/24 and MC_UU_00004/08) and the NIHR CRN.
Propionate production by Bacteroidia gut bacteria and its dependence on substrate concentrations differs among species
Authors: Döring Carolin , Basen Mirko
Published: July 2024

Background

Propionate is a food preservative and platform chemical, but no biological process competes with current petrochemical production routes yet. Although propionate production has been described for gut bacteria of the class Bacteroidia, which also carry great capacity for the degradation of plant polymers, knowledge on propionate yields and productivities across species is scarce. This study aims to compare propionate production from glucose within Bacteroidia and characterize good propionate producers among this group.

Results

We collected published information on propionate producing Bacteroidia, and selected ten species to be further examined. These species were grown under defined conditions to compare their product formation. While propionate, acetate, succinate, lactate and formate were produced, the product ratios varied greatly among the species. The two species with highest propionate yield, B. propionicifaciens (0.39 gpro/ggluc) and B. graminisolvens (0.25 gpro/ggluc), were further examined. Product formation and growth behavior differed significantly during CO2-limited growth and in resting cells experiments, as only B. graminisolvens depended on external-added NaHCO3, while their genome sequences only revealed few differences in the major catabolic pathways. Carbon mass and electron balances in experiments with resting cells were closed under the assumption that the oxidative pentose pathway was utilized for glucose oxidation next to glycolysis in B. graminisolvens. Finally, during pH-controlled fed-batch cultivation B. propionicifaciens and B. graminisolvens grew up to cell densities (OD600) of 8.1 and 9.8, and produced 119 mM and 33 mM of propionate from 130 and 105 mM glucose, respectively. A significant production of other acids, particularly lactate (25 mM), was observed in B. graminisolvens only.

Conclusions

We obtained the first broad overview and comparison of propionate production in Bacteroidia strains. A closer look at two species with comparably high propionate yields, showed significant differences in their physiology. Further studies may reveal the molecular basis for high propionate yields in Bacteroidia, paving the road towards their biotechnological application for conversion of biomass-derived sugars to propionate.
Differentiating between benign and malignant breast lesions using dual-energy CT-based model: development and validation
Authors: Xia Han , Chen Yueyue , Cao Ayong , Wang Yu , Huang Xiaoyan , Zhang Shengjian , Gu Yajia
Published: July 2024

Objectives

To develop and validate a dual-energy CT (DECT)-based model for noninvasively differentiating between benign and malignant breast lesions detected on DECT.

Materials and methods

This study prospectively enrolled patients with suspected breast cancer who underwent dual-phase contrast-enhanced DECT from July 2022 to July 2023. Breast lesions were randomly divided into the training and test cohorts at a ratio of 7:3. Clinical characteristics, DECT-based morphological features, and DECT quantitative parameters were collected. Univariate analyses and multivariate logistic regression were performed to determine independent predictors of benign and malignant breast lesions. An individualized model was constructed. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic ability of the model, whose calibration and clinical usefulness were assessed by calibration curve and decision curve analysis.

Results

This study included 200 patients (mean age, 49.9 ± 11.9 years; age range, 22–83 years) with 222 breast lesions. Age, lesion shape, and the effective atomic number (Zeff) in the venous phase were significant independent predictors of breast lesions (all p < 0.05). The discriminative power of the model incorporating these three factors was high, with AUCs of 0.844 (95%CI 0.764–0.925) and 0.791 (95% CI 0.647–0.935) in the training and test cohorts, respectively. The constructed model showed a preferable fitting (all p > 0.05 by the Hosmer-Lemeshow test) and provided enhanced net benefits than simple default strategies within a wide range of threshold probabilities in both cohorts.

Conclusion

The DECT-based model showed a favorable diagnostic performance for noninvasive differentiation between benign and malignant breast lesions detected on DECT.

Critical relevance statement

The combination of clinical and morphological characteristics and DECT-derived parameter have the potential to identify benign and malignant breast lesions and it may be useful for incidental breast lesions on DECT to decide if further work-up is needed.

Key Points

It is important to characterize incidental breast lesions on DECT for patient management.

DECT-based model can differentiate benign and malignant breast lesions with good performance.

DECT-based model is a potential tool for distinguishing breast lesions detected on DECT.

Graphical Abstract
MicroRNA-21 modulates brown adipose tissue adipogenesis and thermogenesis in a mouse model of polycystic ovary syndrome
Authors: Rezq Samar , Huffman Alexandra M. , Basnet Jelina , Alsemeh Amira E. , do Carmo Jussara M. , Yanes Cardozo Licy L. , Romero Damian G.
Published: July 2024

Background

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure.

Methods

Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot.

Results

MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpβ) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression.

Conclusions

Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.
“It’s just politics”: an exploration of people’s frames of the politics of mobility in Germany and their consequences
Authors: Sonnberger Marco , Leger Matthias , Radtke Jörg
Published: July 2024

Background

The decarbonization of the mobility sector is one of the main challenges in the context of climate mitigation. In Germany, as in many other countries, policy measures aiming to make the mobility system greener frequently fail to produce substantial results, not least due to a lack of support by large sections of the general public. Policy measures directed at reducing car traffic in particular are often met with indifference and resistance. The question thus arises: what basis do citizens use to form their (often negative) opinions about sustainable mobility policies? As a conceptual starting point for our empirical analysis, we draw on the frame concept and focus on people’s frames of the politics of mobility. With “politics of mobility” we refer to everything people could consider as political with regard to mobility. We understand frames as culturally mediated patterns of interpretation that ultimately motivate and guide actions.

Results

Based on interviews and focus group data gathered in the region of the city of Stuttgart (Germany), we identify two dominant frames as well as combinations of these frames by which people make sense of the activities of political actors in the field of mobility. In one frame, which we labeled “politics-as-actor”, mobility politics are interpreted with reference to politics as some kind of monolithic abstract actor. In the other, which we labeled as “politics-as-staged-process”, mobility politics are portrayed as an interest-driven, opaque process that only purport to being democratic.

Conclusions

In terms of policy recommendations, we use our findings to derive suggestions for how to increase support for green mobility policies: transparent implementation of policy measures, pragmatic policy styles and the involvement of intermediaries.
Revised cardiac risk index in predicting cardiovascular complications in patients receiving chronic kidney replacement therapy undergoing elective general surgery
Authors: Palamuthusingam Dharmenaan , Pascoe Elaine M. , Hawley Carmel M. , Johnson David Wayne , Fahim Magid
Published: July 2024

Introduction

The Revised Cardiac Risk Index (RCRI) is a six-parameter model that is commonly used in assessing individual 30-day perioperative cardiovascular risk before general surgery, but its use in patients on chronic kidney replacement therapy (KRT) is unvalidated. This study aimed to externally validate RCRI in this patient group over a 15-year period.

Methods

Data linkage was used between the the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry and jurisdictional hospital admisisons data across Australia and New Zealand to identify all incident and prevalent patients on chronic KRT between 2000 and 2015 who underwent elective abdominal surgery. Chronic KRT was categorised as haemodialysis (HD), peritoneal dialysis (PD), home haemodialysis (HHD) and kidney transplant. The outcome of interest was major adverse cardiovascular event (MACE) which was defined as nonfatal myocardial infarction, nonfatal stroke, non-fatal cardiac arrest and cardiovascular mortality at 30 days. Logistic regression was used with the RCRI score included as a continuous variable to estimate discrimination by area under the receiver operating curve (AUROC). Calibration was evaluated using a calibration plot. Clinical utility was assessed using a decision curve analysis to determine the net benefit.

Results

A total of 5094 elective surgeries were undertaken, and MACE occurred in 153 individuals (3.0%). Overall, RCRI had poor discrimination in patients on chronic KRT undergoing elective surgery (AUROC 0.67), particularly in patients aged greater than 65 years (AUROC 0.591). A calibration plot showed that RCRI overestimated risk of MACE. The expected-to-observed outcome ratio was 6.0, 5.1 and 2.5 for those with RCRI scores of 1, 2 and ≥ 3, respectively. Discrimination was moderate in patients under 65 years and in kidney transplant recipients, with AUROC values of 0.740 and 0.718, respectively. Overestimation was common but less so for kidney transplant recipients. Decision curve analysis showed that there was no net benefit of using the tool in neither the overall cohort nor patients under 65 years, but a slight benefit associated with threshold probability > 5.5% in kidney transplant recipients.

Conclusions

The RCRI tool performed poorly and overestimated risk in patients on chronic dialysis, potentially misinforming patients and clinicians about the risk of elective surgery. Further research is needed to define a more comprehensive means of estimating risk in this unique population.
Mechanistic insights into the conversion of flavin adenine dinucleotide (FAD) to 8-formyl FAD in formate oxidase: a combined experimental and in-silico study
Authors: Wen Kai , Wang Sirui , Sun Yixin , Wang Mengsong , Zhang Yingjiu , Zhu Jingxuan , Li Quanshun
Published: July 2024

Formate oxidase (FOx), which contains 8-formyl flavin adenine dinucleotide (FAD), exhibits a distinct advantage in utilizing ambient oxygen molecules for the oxidation of formic acid compared to other glucose-methanol-choline (GMC) oxidoreductase enzymes that contain only the standard FAD cofactor. The FOx-mediated conversion of FAD to 8-formyl FAD results in an approximate 10-fold increase in formate oxidase activity. However, the mechanistic details underlying the autocatalytic formation of 8-formyl FAD are still not well understood, which impedes further utilization of FOx. In this study, we employ molecular dynamics simulation, QM/MM umbrella sampling simulation, enzyme activity assay, site-directed mutagenesis, and spectroscopic analysis to elucidate the oxidation mechanism of FAD to 8-formyl FAD. Our results reveal that a catalytic water molecule, rather than any catalytic amino acids, serves as a general base to deprotonate the C8 methyl group on FAD, thus facilitating the formation of a quinone-methide tautomer intermediate. An oxygen molecule subsequently oxidizes this intermediate, resulting in a C8 methyl hydroperoxide anion that is protonated and dissociated to form OHC-RP and OH−. During the oxidation of FAD to 8-formyl FAD, the energy barrier for the rate-limiting step is calculated to be 22.8 kcal/mol, which corresponds to the required 14-hour transformation time observed experimentally. Further, the elucidated oxidation mechanism reveals that the autocatalytic formation of 8-formyl FAD depends on the proximal arginine and serine residues, R87 and S94, respectively. Enzymatic activity assay validates that the mutation of R87 to lysine reduces the kcat value to 75% of the wild-type, while the mutation to histidine results in a complete loss of activity. Similarly, the mutant S94I also leads to the deactivation of enzyme. This dependency arises because the nucleophilic OH− group and the quinone-methide tautomer intermediate are stabilized through the noncovalent interaction provided by R87 and S94. These findings not only explain the mechanistic details of each reaction step but also clarify the functional role of R87 and S94 during the oxidative maturation of 8-formyl FAD, thereby providing crucial theoretical support for the development of novel flavoenzymes with enhanced redox properties.
Improving Likert scale big data analysis in psychometric health economics: reliability of the new compositional data approach
Authors: Lehmann René , Vogt Bodo
Published: July 2024

Bipolar psychometric scales data are widely used in psychologic healthcare. Adequate psychological profiling benefits patients and saves time and costs. Grant funding depends on the quality of psychotherapeutic measures. Bipolar Likert scales yield compositional data because any order of magnitude of agreement towards an item assertion implies a complementary order of magnitude of disagreement. Using an isometric log-ratio (ilr) transformation the bivariate information can be transformed towards the real valued interval scale yielding unbiased statistical results increasing the statistical power of the Pearson correlation significance test if the Central Limit Theorem (CLT) of statistics is satisfied. In practice, however, the applicability of the CLT depends on the number of summands (i.e., the number of items) and the variance of the data generating process (DGP) of the ilr transformed data. Via simulation we provide evidence that the ilr approach also works satisfactory if the CLT is violated. That is, the ilr approach is robust towards extremely large or infinite variances of the underlying DGP increasing the statistical power of the correlation test. The study generalizes former results pointing out the universality and reliability of the ilr approach in psychometric big data analysis affecting psychometric health economics, patient welfare, grant funding, economic decision making and profits.
CONUT score as a predictor for anamorelin efficacy in patients with cancer cachexia receiving chemotherapy
Authors: Fujii Hironori , Makiyama Akitaka , Nishimura Kayoko , Iihara Hirotoshi , Hirose Chiemi , Ohata Koichi , Yamada Yunami , Watanabe Daichi , Yasufuku Itaru , Okumura Naoki , Tanaka Yoshihiro , Takahashi Takao , Kobayashi Ryo , Matsuhashi Nobuhisa , Suzuki Akio
Published: July 2024

Background

Anamorelin is expected to improve cancer cachexia by increasing lean body mass (LBM) due to increased appetite and protein synthesis. However, the effect of anamorelin on cancer cachexia in real-world practice is unclear. The purpose of this study was to evaluate the efficacy and safety of anamorelin and to identify predictors of efficacy on treatment with anamorelin.

Methods

We retrospectively analyzed data from patients with cancer cachexia treated with chemotherapy between May 2021 and August 2022. Efficacy of anamorelin was evaluated using LBM, with “12-week sustained effective response” to anamorelin treatment defined as maintenance or an increase in LBM for 12 weeks. We examined factors associated with “12-week sustained effective response” to anamorelin treatment using a multivariable logistic model that included controlling nutritional status (CONUT) score, an objective assessment of nutritional disorders, and the modified Glasgow prognostic score (mGPS), which scores the cachexia status of cancer patients. To assess patient subjective quality of life (QOL) changes related to eating after starting anamorelin treatment, we used a questionnaire (QOL-ACD appetite-related items: Q8, 9, 11). Adverse events were evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

Results

On analysis of data from 40 patients, 23 patients showed a 12-week sustained effective response to anamorelin (57.5%). At 12 weeks, LBM significantly increased by 1.63 ± 3.73 kg (mean ± SD). Multivariable logistic analysis revealed that a low CONUT score was significantly associated with “12-week sustained effective response” to anamorelin treatment (adjusted odds ratio: 13.5, 95% confidence intervals: 2.2–84.2, P = 0.004). QOL assessment showed a trend toward increased appetite and enjoyment of meals after anamorelin initiation. Five patients (12.5%) had an increase in HbA1c of more than 1.0% during the 12 weeks after the start of anamorelin. No patient had QT interval prolongation or grade 3 or higher hepatic transaminase elevation.

Conclusion

Anamorelin may maintain or increase LBM with tolerable safety in patients with cancer cachexia undergoing chemotherapy. A low CONUT score, despite meeting criteria for cancer cachexia, is suggested as a predictor for the efficacy of anamorelin, indicating that patients with a low CONUT score may benefit from early introduction of anamorelin.
Demonstrating the benefit of a cellulitis-specific patient reported outcome measure (CELLUPROM©) as part of the National Cellulitis Improvement Programme in Wales
Authors: Gabe-Walters Marie , Thomas Melanie , Jenkins Linda
Published: July 2024

Purpose

Despite a known risk of cellulitis recurrence, the management of the wider impact and risk factors has been neglected. The innovative National Cellulitis Improvement Programme (NCIP) addresses this by providing evidence-based and individualised care to improve patient reported outcomes and reduce the risk of recurrence. The aim of this paper is to examine the longer-term impact of cellulitis and to identify a suitable and clinically relevant Patient Reported Outcome Measure (PROM).

Methods

A review of existing cellulitis-specific PROMs was undertaken, alongside literature detailing the patient-focused impact of cellulitis, to identify a suitable PROM for clinical use. A group of expert therapists and patient representatives (n = 14) shared their individual and collective experiences over a series of events to discuss and debate the impact of cellulitis and review available PROMs. CELLUPROM© is introduced with anonymised PROM data and case study information reported to establish the impact of CELLUPROM© within usual NCIP care.

Results

No cellulitis-specific PROMs were identified. Literature focused on the signs and symptoms of an acute episode of cellulitis, with outcome measures primarily used to evidence the impact of an intervention. An enduring physical, social and emotional impact of cellulitis was identified in this study, providing the basis for the new cellulitis-specific PROM (CELLUPROM©), which has been implemented with good effect in clinical care.

Conclusion

This study has highlighted the lasting impact of cellulitis. Using CELLUPROM© within the risk-reduction NCIP has helped develop Value-Based Healthcare and support programme evaluation.
High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades
Authors: Horvat-Menih Ines , Li Hao , Priest Andrew N. , Li Shaohang , Gill Andrew B. , Mendichovszky Iosif A. , Francis Susan T. , Warren Anne Y. , O’Carrigan Brent , Welsh Sarah J. , Jones James O. , Riddick Antony C. P. , Armitage James N. , Mitchell Thomas J. , Stewart Grant D. , Gallagher Ferdia A.
Published: July 2024

Background

Clinical imaging tools to probe aggressiveness of renal masses are lacking, and T2-weighted imaging as an integral part of magnetic resonance imaging protocol only provides qualitative information. We developed high-resolution and accelerated T2 mapping methods based on echo merging and using k-t undersampling and reduced flip angles (TEMPURA) and tested their potential to quantify differences between renal tumour subtypes and grades.

Methods

Twenty-four patients with treatment-naïve renal tumours were imaged: seven renal oncocytomas (RO); one eosinophilic/oncocytic renal cell carcinoma; two chromophobe RCCs (chRCC); three papillary RCCs (pRCC); and twelve clear cell RCCs (ccRCC). Median, kurtosis, and skewness of T2 were quantified in tumours and in the normal-adjacent kidney cortex and were compared across renal tumour subtypes and between ccRCC grades.

Results

High-resolution TEMPURA depicted the tumour structure at improved resolution compared to conventional T2-weighted imaging. The lowest median T2 values were present in pRCC (high-resolution, 51 ms; accelerated, 45 ms), which was significantly lower than RO (high-resolution; accelerated, p = 0.012) and ccRCC (high-resolution, p = 0.019; accelerated, p = 0.008). ROs showed the lowest kurtosis (high-resolution, 3.4; accelerated, 4.0), suggestive of low intratumoural heterogeneity. Lower T2 values were observed in higher compared to lower grade ccRCCs (grades 2, 3 and 4 on high-resolution, 209 ms, 151 ms, and 106 ms; on accelerated, 172 ms, 160 ms, and 102 ms, respectively), with accelerated TEMPURA showing statistical significance in comparison (p = 0.037).

Conclusions

Both high-resolution and accelerated TEMPURA showed marked potential to quantify differences across renal tumour subtypes and between ccRCC grades.

Trial registration

ClinicalTrials.gov, NCT03741426. Registered on 13 November 2018.

Relevance statement

The newly developed T2 mapping methods have improved resolution, shorter acquisition times, and promising quantifiable readouts to characterise incidental renal masses.

Graphical Abstract
The evolving landscape of publishing in human reproduction: an analysis of scientometric data, open-access publishing, and article processing charges
Authors: Uzun Hakki , Akça Görkem , Sönmez Berat , Orman Erdem , Kaçan Yakup , Dil Eyüp
Published: July 2024

Background

This bibliometric study aims to examine the associations of journals in the field of human reproduction with their access types and article processing charges to evaluate the evolving landscape of publishing in human reproduction.

Methods

The primary databases, including Clarivate Analytics Master Journal List, Scopus®, PubMed, and Directory of Open Access Journals, were scrutinized to identify pertinent journals within the realm of human reproduction, utilizing keywords such as reproductive, reproduction, fertility, and infertility. Journals were excluded if they were not actively publishing in English or primarily focused on reproductive health, men’s health, sexual medicine, embryogenesis, developmental biology, or veterinary medicine concerning animal reproduction. A thorough characterization of the journals was conducted, followed by a comparative analysis of citation metrics and article processing charges across various access models.

Results

Forty-one journals were included into the study. A significant increase in the proportion of gold and diamond open-access journals was observed, rising from 42% (13 out of 31) to 53.6% (22 out of 41) by 2023. Hybrid journals demonstrated superior citation metrics compared to diamond open-access journals. For hybrid journals, a statistically significant, moderately positive correlation was found between article processing charges and CiteScore (rs (27) = 0.515, p < .024). Conversely, no correlation was observed between article processing charges and CiteScore for gold open-access journals (rs (27) = 0.445, p = 0.147). The mean article processing charges for all hybrid and gold open-access journals were calculated as US $3032.88 ± 1108.514 (312 to 4430). Specifically, the mean article processing charges for hybrid journals (US $3617.4 ± 610.19) were significantly higher than those for gold open-access journals (US $1916.82 ± 988.32), with a difference of 1700.658 (95% CI: 1124.861–2276.455), t (30) = 6.032, and p < .0005.

Conclusion

Hybrid journals in the field of human reproduction carry fees nearly twice as high as those of gold open-access journals. The charging policies of gold open-access journals, which are not contigent upon citation metrics, emphasize the importance of caution for both authors and funders.
Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence
Authors: Ogieuhi Ikponmwosa Jude , Ugiomoh Oshomoh Mark-Anthony , Muzofa Kudzaishe , Callender Kristen , Ayodeji Johnson David , Nnekachi Nnokam Prayer , Thiyagarajan Barkavi , Uduigwome Emmanuel Obokhai , Kapoor Abhay , Odoeke Moses Chukwuebuka , Mohamed Reem Gamaleldin Hassan , Idahor Courage
Published: July 2024

Background

Amyloidosis is a heterogeneous group of disorders caused by the extracellular deposition of insoluble misfolded proteins, leading to end-organ damage. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a subtype in which a protein known as transthyretin accumulates within the heart tissue, progressively resulting in restrictive cardiomyopathy and heart failure. Due to the progressive nature of ATTR-CM, clinical management requires efficacious regimens to manage the debilitating condition and Tafamidis shows promising results in this regard.

Main body

ATTR-CM poses a significant challenge due to its nature and limited therapeutic options. Tafamidis is a novel therapy designed to stabilize the transthyretin tetramers, inhibiting the formation of amyloid fibrils. It has emerged as a promising treatment and the only FDA-approved drug for ATTR-CM. Tafamidis' role in slowing disease progression and improving outcomes in patients with ATTR-CM has been demonstrated in the major randomized control trial ATTR-ACT with promising open-label extension studies, some still ongoing. Additionally, real-world evidence supports its use in clinical practice, showing its role in reducing morbidity and mortality associated with this condition. Clinical evidence shows its efficacy in improving symptoms and cardiac function in patients. Case studies also reveal significant benefits to patients like reducing myocardial damage, reversal of atrial fibrillation, and resolution of heart failure symptoms. Real-world outcomes and clinical trials show a consistent reduction in amyloid deposition, cardiovascular-related hospitalizations, and all-cause mortality with Tafamidis therapy.

Conclusion

Tafamidis is an essential component of the treatment of ATTR-CM and this narrative review synthesizes the current evidence regarding safety, efficacy, and utilization in real practice. While it shows promising effects, its effectiveness may also vary and high cost precludes real-world large-scale studies. Overall, Tafamidis emerges as a valuable therapeutic option for managing ATTR-CM.
Analytical quality by design (AQbD) based optimization of RP-UPLC method for determination of nivolumab and relatlimab in bulk and pharmaceutical dosage forms
Authors: Nuli Mohana Vamsi , Seemaladinne Ramanjaneyulu , Tallam Anil Kumar
Published: July 2024

Background

The Analytical Quality by Design (AQbD) methodology extends the application of Quality by Design (QbD) principles to the management of the analytical procedure life cycle, encompassing method creation, optimization, validation, and continuous improvement. AQbD assists in creating analytical procedures that are robust, reliable, precise, and cost-efficient. Opdualag™ is a combination of Nivolumab and Relatlimab, which are antibodies that block programmed death receptor-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) receptors, used to treat advanced melanoma. This work aims to develop and validate a reversed-phase ultra-performance liquid chromatography (RP-UPLC) method using AQbD principles to determine NLB and RTB in pharmaceutical products.

Results

A central composite design (CCD) comprising three factors arranged in five distinct levels was implemented via Design-expert® software to optimize the chromatographic conditions. A mathematical model was constructed and the effects of three independent factors namely flow rate (X1), percentage of methanol in the mobile phase (X2), and temperature (X3) on responses including retention time (Y1–2), resolution factor (Y3), theoretical plates (Y4–5), and tailing factor (Y6–7) were investigated. The software determined the optimal chromatographic conditions for the separation of NLB and RTB, which were as follows: 32.80% methanol in the mobile phase, 0.272 mL/min flow rate, 29.42 °C column temperature, and 260 nm UV detection. The retention time for NLB and RTB were 1.46 and 1.88 min, respectively. The method exhibited linearity across the concentration ranges of 4–24 µg/mL for RTB and 12–72 µg/mL for NLB. The limits of detection (LOD) and limit of quantification (LOQ) for NLB and RTB, respectively, were 0.89 µg/mL, 2.69 µg/mL and 0.15 µg/mL and 0.46 µg/mL. The percentage relative standard deviation (%RSD) of intraday and interday precision for NLB and RTB was below 2. The recovery percentages for NLB and RTB were determined to be 99.57–100.43% and 99.59–100.61%, respectively. Both drugs were found to be susceptible to oxidative and photolytic degradation in forced degradation studies.

Conclusions

Employing the AQbD-based methodology, a straightforward, fast, accurate, precise, specific, and stability-indicating RP-UPLC method has been established for the quantitative analysis of NLB and its RTB in pharmaceutical formulations.
Predictive role of platelets to lymphocytes ratio and neutrophil to lymphocytes ratio in COPD exacerbation
Authors: Fayiad Hussien , Amer Ahmed Mohamed
Published: July 2024

Background

The hallmark of COPD is the progressive destruction of the lung parenchyma, which is frequently brought on by the body's inflammatory reaction to external stimuli (such as smoking cigarettes or pollution). According to reports, the peripheral blood's essential immune-related cell populations' absolute counts and ratios can accurately represent chronic inflammatory diseases. Complex interactions between immune-related cells, such as lymphocytes and neutrophils, are involved in inflammation, which can cause irreversible damage and loss of respiratory tissue. The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), two hematological indicators of inflammation, have been studied in a variety of disease states, including solid tumors, systemic lupus erythematosus, coronary artery disease, retinal artery occlusion, chronic kidney disease, and stable COPD.

Aim

Correlation between NLR and PLR and outcome of COPD exacerbation.

Materials and methods

This cross-sectional study included 80 patients with COPD exacerbation who visited the outpatient clinic or were admitted to the Chest Department. CRP and calculation of NLR and PLR within 24 h from admission and 1 month after discharge were obtained to identify the prognostic value of NLR and PLR for the exacerbation, hospitalization, mechanical ventilation, and mortality in patients with COPD.

Results

During COPD exacerbation PLR, NLR showed a statistically significant correlation with the need for hospitalization with a p value < 0.001. As regards correlation with mortality NLR was statistically significant with a p value of 0.006 while PLR showed a non-significant p value of 0.077. PLR and NLR were correlated with CRP as an inflammatory marker and both were statistically significant with p value 0.004 and < 0.001 respectively. During exacerbation, PLR and NLR were correlated with the need for mechanical ventilation and the results were statistically significant with p value < 0.001. PLR and NLR showed a significant increase during exacerbation compared to stable COPD patients 1 month after discharge with p value of < 0.001.

Conclusion

PLR and NLR are simple tests that could be used to predict the severity of COPD exacerbation and the need for hospitalization, MV, and mortality prediction.
Risk of Type 2 Diabetes, MASLD and Cardiovascular Disease in People Living With Polycystic Ovary Syndrome
Authors: Henney Alex E , Gillespiec Conor S , Lai Jonathan Y M , Schofield Pieta , Riley David R , Caleyachetty Rishi , Barber Thomas M , Miras Alexander D , Dobbie Laurence J , Hughes David M , Alam Uazman , Hydes Theresa J , Cuthbertson Daniel J
Published: July 2024

Background

Polycystic ovary syndrome (PCOS) is associated with adverse clinical outcomes that may differ according to PCOS phenotype.

Methods

Using UK Biobank data, we compared the incidence of type 2 diabetes (T2D), metabolic dysfunction associated steatotic liver disease, cardiovascular disease (CVD), hormone-dependent cancers, and dementia between PCOS participants and age- and body mass index-matched controls. We also compared multiorgan (liver, cardiac, and brain) magnetic resonance imaging (MRI) data and examined the impact of PCOS phenotype (hyperandrogenic and normoandrogenic) on these outcomes.

Results

We included 1008 women with PCOS (defined by diagnostic codes, self-reported diagnoses, or clinical/biochemical features of hyperandrogenism and a/oligoCmenorrhoea) and 5017 matched controls (5:1 ratio); median age, 61 years, body mass index, 28.4 kg/m². Adjusted Cox proportional hazard modeling demonstrated PCOS participants had greater incident T2D [hazard ratio (HR) 1.47; 95% confidence interval (CI), 1.11-1.95] and all-cause CVD (1.76; 1.35-2.30). No between-group differences existed for cancers or dementia. Liver MRI confirmed more PCOS participants had hepatic steatosis (proton density fat fraction >5.5%: 35.9 vs 23.9%; P = .02) and higher fibroinflammation (corrected T1 721.4 vs 701.5 ms; P = <.01) vs controls. No between-group difference existed for cardiac (biventricular/atrial structure and function) or brain (grey and white matter volumes) imaging. Normoandrogenic (but not hyperandrogenic) PCOS participants had greater incident all-cause CVD (1.82; 1.29-2.56) while hyperandrogenic (but not normoandrogenic) PCOS participants were more likely to have hepatic steatosis (8.96 vs 6.04 vs 5.23%; P = .03) with greater fibroinflammation (776.3 vs 707.7 vs 701.9 ms; P=<.01).

Conclusion

Cardiometabolic disease may be increased in PCOS patients with a disease phenotype-specific pattern.
Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier
Authors: Banks David B , Lierz Sydney L , Cannon Ronald E , Korach Kenneth S
Published: July 2024

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-binding cassette transporter breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-Estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries via rapid nongenomic signaling through estrogen receptor α. We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS.
Efficacy and Safety of Long-term Ketogenic Diet Therapy in a Patient With Type 1 Diabetes
Authors: Koutnik Andrew P , Klein Samuel , Robinson Austin T , Watso Joseph C
Published: July 2024

Fewer than 1% of patients with type 1 diabetes achieve normal glycemic control (glycated hemoglobin [HbA1c] < 5.7%/ < 39 mmol/mol). Additionally, exogenous insulin administration often causes “iatrogenic hyperinsulinemia,” leading to whole-body insulin resistance and increased risk of cardiovascular complications. We present data on the clinical efficacy and safety of a long-term (10-year) ketogenic diet (≤50 g carbohydrates/day) therapy in a patient with type 1 diabetes. The use of a ketogenic diet resulted in successful glycemic control, assessed by HbA1c (5.5%; 36.6 mmol/mol), continuous glucose monitoring median glucose (98 mg/dL; 5.4 mmol/L), and glucose time-in-range of 70 to 180 mg/dL (90%) without acute glycemic complications. In conjunction, there was a 43% decrease in daily insulin requirements. Low-density lipoprotein cholesterol increased, whereas small-dense low-density lipoprotein was in the normal range (<90 nmol/L). No adverse effects were observed on thyroid function, kidney function, or bone mineral density. This case report demonstrates that a long-term ketogenic diet in a person with type 1 diabetes has considerable therapeutic benefits.
The origins of pretend like: A syntactic-semantic puzzle in American English and beyond
Authors: Brook Marisa
Published: July 2024

Like can be a finite complementizer in present-day varieties of English after a few verbs of perception, apparentness, and/or behavior. Normally, like in this function is an innovation that has replaced the earlier variants as if and as though. Pretend like CP appears to be an exception: it is not clear that a precedent exists in the form of pretend as if or pretend as though. To investigate, this study employs the Corpus of Historical American English (COHA) (Davies 2010–), extracting more than 5,000 examples of pretend with CPs between 1900 and 2019. The results offer tentative support for increase in pretend like in recent decades, despite verification that pretend as if and pretend as though were never well-attested. The puzzle of a like complementizer coming to compete with that and Ø complementizers in the absence of as if and as though – which does not happen across other English verbs – is interpreted as analogy on the basis of semantically overlapping verbs of behavior: behave like CP, act like CP, and make (out) like CP. This case study thus illuminates the conditions under which an incoming variant of a morphosyntactic variable can spread to new lexical or grammatical contexts.
“I Am Kurdish, My Homeland Is Kurdistan”: Excerpts from Selahattin Demirtaş’s Testimony before the Turkish Court
Authors: Demirtaş Selahattin
Published: July 2024

Selahattin Demirtaş, head of the left-wing pro-Kurdish People's Democratic Party (HDP) in Turkey, was arrested in 2016; his detention stemmed from fabricated charges, allegedly originating from his speeches, political statements, and purported involvement in the Kurdish riots of October 2014, known as the Kobani Protests, across northern Kurdistan. The following excerpts are derived from Demirtaş’s extensive testimony before the Turkish court, spanning nine days between December 2023 and January 2024. He and his legal representatives facilitated the compilation of these statements and the subsequent exchange of edited copies.