bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of different drying processes on the quality changes in Arapgir purple basil (Ocimum basilicum L.) leaves and drying‐induced changes in bioactive and volatile compounds and essential oils
Authors: Altay Kadriye , Dirim Safiye Nur , Hayaloglu Ali Adnan
Published: November 2024

The aim of this research is to examine the effects of drying purple basil leaves (Ocimum basilicum L.) under different drying conditions (freeze drying, sun‐drying, and convective drying [CD] at 45, 50, and 55°C and microwave drying at 350, 460, and 600 W) on color properties, total phenolic and anthocyanin content, antioxidant activities, and changes in the composition of volatile compounds and essential oils (EOs). Increasing the drying temperature and microwave power led to an improvement in the preservation of the total phenolic content of the samples by an average of 16.28% and 27.98%, respectively. Increasing the drying temperature resulted in lower anthocyanin content and antioxidant activity (AA); in contrast, increasing the microwave power resulted in higher anthocyanin content and AA when drying purple basil. The drying methods significantly changed the composition of volatiles and EOs, and microwave drying resulted in a different profile of volatiles and EO composition. The key volatile compounds in purple basil leaves were linalol (81.19–1176.09 µg/g dw), 1,8‐cineole (45.15–816.16 µg/g dw), and methyl cinnamate (13.20–637.65 µg/g dw). On the other hand, methyl cinnamate (11.68%–57.66%) and linalool (0.02%–20.39%) were the main volatile compounds of EOs in basil leaves. In conclusion, the following drying methods are suitable for the protection of phenolic and anthocyanin compounds and high performance of AA: freeze drying, sun‐drying, and CD at 45°C and microwave drying at 600 W.
A green replacement route to produce phosphatidylserine in environmentally friendly edible oil–water systems and investigations on the enzymatic mechanism
Authors: Zhang Tiantian , Lan Haizhi , Wang Huan , Li Binglin , Gand Martin , Wang Jiao
Published: November 2024

Phosphatidylserine (PS) has many applications in functional food and pharmaceutical industries because of its critical role in activating important signal transduction pathways and modulating neurotransmitter release and receptor function. Several edible oils have been used to construct oil–water systems for the efficient production of PS under mild conditions by phospholipase D (PLD)‐mediated transphosphatidylation. Toxic organic solvents were completely avoided throughout the process, from manufacturing to encapsulation. Results showed that higher enzyme selectivity and activity were found in the coconut oil–water and olive oil–water systems than in the traditional diethyl ether–water system. The maximum yields of PS in the two oil–water systems were more than 93%, whereas that in the diethyl ether–water system was only 78%. Hence, the coconut oil–water and olive oil–water systems should be the promising medium to produce PS and its microcapsules. Moreover, the enzymatic mechanism of PLD was simulated using molecular dynamics (MD) to understand diffusion channels, competitive bindings, solvent effects, structural changes, system stabilities, and product dissociation from the enzyme. MD results showed that more PLD‐substrate complexes were detected in the oil–water systems than in the diethyl ether–water system. The conformational transition states of the protein between open and closed conformations were directly affected by the solvents used, and structural changes were observed in loop I (Asp309‐Thr336). PLD in oil–water systems can not only maintain the native structure but also broaden the diffusion channels for substrates, which contributes to a higher enzymatic activity.
Spectroscopy‐based analysis of the effect of Maillard reaction products on oxidative stability of carp myoglobin
Authors: Cao Jiarong , Yan Haixia , Ye Bo , Shen Yixiao , Liu Ling
Published: November 2024

As a pro‐oxidant, myoglobin (Mb) can induce lipid oxidation in meat. In this study, Fourier‐transform infrared spectroscopy (FTIR), circular dichroism (CD), fluorescence spectroscopy, UV–vis spectrophotometry, and fluorescence microscopy were used to evaluate the impact of Maillard reaction products (MRPs) formed from glucose and lysine on the oxidative stability of carp Mb. MRPs were found to inhibit the auto‐oxidation of Mb, reducing MetMb production by 8.45%. The static quenching of fluorescence indicated that MRPs interacted with Mb through hydrogen bonding and van der Waals forces, thereby enhancing the α‐helical content by 11.57% and reducing the random coil content by 2.72%. The enhanced stability of this advanced structure helps to minimize the exposure of amino acid in the side chain and prevent the formation of MetMb. Fluorescence microscopy showed that MRPs reduce porphyrin ring degradation, consequently decreasing heme iron release. It is evident that MRPs play a crucial role in maintaining Mb structure stability and inhibiting its oxidation.
When is competition price‐increasing? The impact of expected competition on prices
Authors: Mangin Sephorah
Published: November 2024

We examine the effect of expected competition on markups in a random utility model where the number of competing firms may differ across consumers. Firms observe consumers' utility shocks and set prices using personalized pricing. We derive a precise condition under which the expected markup across consumers can be represented by a simple expression involving consumers' expected utility and the expected demand. This delivers a general condition under which greater expected competition is price‐increasing. Whether this condition holds depends on the distribution of utility shocks, consumers' outside option, the expected number of competing firms, and the distribution of the number of firms competing for each consumer.
Comparative genome‐wide association study of single‐ and multi‐locus models with ontology analysis for enhancing Hanwoo cow reproductive traits
Authors: Kim Ji Yeong , Kim Eun Ho , Kang Ho Chan , Myung Cheol Hyun , Lim Hyun Tae
Published: November 2024

The reproductive characteristics of Hanwoo play a significant role in farm profitability by decreasing the generation interval. This study analyzed 1015 primiparous and 916 multiparous cows using a genome‐wide association study with both single‐locus (GEMMA, GCTA) and multi‐locus models (FarmCPU, BLINK). A significant marker for age at first service was identified across all methods. For age at first conception, GEMMA identified two markers, while FarmCPU and BLINK identified 14 and two markers, respectively. Regarding age at first calving, GEMMA identified two markers, and FarmCPU and BLINK found 15 and two markers, respectively. In multiparous cows, except for days open, one marker for gestation length and two markers for calving interval were identified in the multi‐locus models (FarmCPU and BLINK). Additionally, one marker for the number of services per conception was identified using GEMMA. Key candidate genes included PLCB1 (maintaining pregnancy), MUC1 (fetal development), and ADCY5 (associated with fetal birth), while TXNL1 regulates embryo implantation timing. Gene ontology functions associated with embryo implantation and placental regulation were also confirmed (GO:0046875). Although the multi‐locus models identified a greater number of markers and candidate genes, there was no overlap with the results from the single‐locus models. The multi‐locus models showed enhanced detection power, but slight inflation in test statistics (λ values) necessitates cautious interpretation to avoid false positives. Thus, a combination of both models is recommended to improve reproductive efficiency in cows, providing valuable insights into the genetic aspects of reproductive traits.
Identification of a de novo missense variant in the BRI3BP gene in a Holstein calf with congenital cardiac malformation and carpus valgus
Authors: He Chang , Grau‐Roma Llorenç , Schmid Robin , Häfliger Irene M. , Meylan Mireille , Drögemüller Cord , Jacinto Joana G. P.
Published: November 2024

Congenital malformations in cattle pose a diagnostic challenge with limited treatment options and are often associated with a guarded prognosis. The aim of this study was to characterize the clinicopathological phenotype of a viable calf with complex congenital heart defects and carpus valgus, and to identify a possible genetic cause using a whole genome sequencing trio approach. A 3‐month‐old female Holstein calf was referred for respiratory distress and congenital carpal deviation. Clinicopathologic findings included ventricular septal defect, ventricular dilatation, atrioventricular valve dysplasia, an overriding aorta, and unilateral carpus valgus. Genetic analysis revealed a private heterozygous missense variant in BRI3BP affecting an evolutionarily conserved residue (c.478G>A; p.Val160Ile). The variant was predicted to be deleterious and was present only in the affected calf and was absent in more than 5100 sequenced bovine genomes, including both parents, indicating a de novo origin. This study implicates an important role for the uncharacterized BRI3 binding protein in cardiac and possibly also bone development. By presenting the first BRI3BP‐related disease model, this study demonstrates the potential to gain new insights into the function of individual genes by using phenotypically well‐studied spontaneous mutants in large animals, and it provides a novel candidate gene for similar conditions in humans.
Influence of the type of anaesthesia on acute kidney injury after nephrectomy: a randomised controlled trial
Authors: Yoon Soo‐Hyuk , Kim Yoon Jung , Seo Jeong‐Hwa , Lim Hanbyeol , Lee Ho‐Jin , Kwak Cheol , Kim Won Ho , Yoon Hyun‐Kyu
Published: November 2024

Introduction

Acute kidney injury develops frequently after nephrectomy, causing increased hospital duration of stay and mortality. Both propofol and volatile anaesthetic agents are thought to have renoprotective effects. We investigated whether the type of maintenance anaesthetic (propofol or desflurane) affected the incidence of acute kidney injury after nephrectomy.

Methods

This single‐centre, randomised controlled trial enrolled adult patients with renal cell carcinoma undergoing nephrectomy. In patients allocated to the propofol group, anaesthesia was induced and maintained using a target‐controlled infusion of propofol. In patients allocated to the desflurane group, anaesthesia was induced with a bolus of thiopental and maintained with desflurane. Both groups received a target‐controlled infusion of remifentanil during surgery. The primary outcome was the incidence of acute kidney injury within 7 postoperative days based on the serum creatinine component of the Kidney Disease: Improving Global Outcomes criteria.

Results

We analysed 317 patients (median (IQR [range]) age 62 (52–70 [26–85] y); 221 (70%) men). Postoperative AKI developed in 79 (25%) patients: 43 (27%) in the propofol group and 36 (23%) in the desflurane group (absolute risk difference (95%CI) 4.6 (‐4.9–14.0%), p = 0.347). The severity of kidney injury was stage 1 in 76 patients, stage 2 in two patients and stage 3 in one patient.

Discussion

The type of anaesthetic maintenance drug (propofol vs. desflurane) did not affect the incidence of acute kidney injury after nephrectomy. Future research might be better directed towards investigating other potentially modifiable risk factors for postoperative acute kidney injury in this patient population.
Is routine axillary staging still required in clinically node negative early breast cancer in women over 74 years?
Authors: Grant Katherine , Po Xiang Yuen , Tiong Leong
Published: November 2024

Background

Investigate incidence and identify predictors of axillary lymph node metastases in early breast cancer in women >74 years Australia and New Zealand to inform decision making about sentinel lymph node (SLN) biopsy in this population.

Methods

Retrospective review of invasive breast cancer in women in Australia and New Zealand between 2010 and 2022 using BreastSurgANZ Quality Audit Database. Data included patient demographics, tumour characteristics, surgery type, axillary nodal status and adjuvant therapy. Descriptive analysis of incidence of axillary nodal metastases and use of adjuvant therapy in various patient and tumour groups was performed, followed by statistical analysis using multivariate logistic regression to identify predictors of axillary nodal positivity and correlation between nodal status and prescription of adjuvant therapy.

Results

Review of 127 436 cases of invasive breast cancer, 17 599 cases >74 years. Two thirds of the overall population and in those >74 years were node negative. In patients >74 years with grade 1–2, T1a‐b cancers, ER+/HER2− 94% were node negative. Patient age, tumour size, grade and biomarker profile correlated with axillary nodal status and analysis of adjuvant therapy revealed significant correlation between nodal stage and adjuvant radiotherapy, chemotherapy and endocrine therapy.

Conclusion

A total of 94% of patients >74 years with T1a/b, ER positive HER2 negative breast cancer were node negative. Nodal status significantly influences adjuvant treatment in this patient group and therefore, we recommend clinicians consider tumour factors and patient fitness in their decision making about SLN biopsy in the elderly population with hormone receptor positive early breast cancer.
Evaluating neuronal damage biomarkers at birth for predicting neurodevelopmental risks in foetal growth restriction
Authors: Benítez‐Marín Mª. José , Blasco‐Alonso Marta , de Rodríguez de Fonseca Fernando , Jiménez Jesús S. , Rivera Patricia , González‐Mesa Ernesto
Published: November 2024

Aim

This study was based on the need to predict neurodevelopmental outcomes of children with foetal growth restriction. The aim was to systematically review the correlation between biomarkers of neural injury in children with foetal growth restriction and their neurodevelopment.

Method

Following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, the review included studies on growth‐restricted foetuses that measured biomarkers of postpartum brain injury and assessed neurodevelopment in childhood. Studies published between 1 January 2014 and 31 March 2024 were identified through PubMed and Embase, with the study protocol registered in PROSPERO (CRD42024520254).

Results

Only five met the inclusion criteria. Results showed that urinary S100B levels were significantly elevated in foetal growth restriction, negatively correlating with neurological development at 7 days of life. Neuron‐specific enolase negatively correlated with cognitive, motor and socio‐emotional development. Urinary nerve growth factor levels were significantly lower in neonates with foetal growth restriction, correlating with poor neurodevelopment. No alterations in BDNF levels were observed. Tau protein levels were lower in children with foetal growth restriction and adverse outcomes.

Conclusion

The study emphasised the need for further research on biomarkers and predictive models of neurodevelopment in children with foetal growth restriction.
Laparoscopic Retroperitoneal Lymph Node Dissection After Chemotherapy for Nonseminomatous Testicular Germ‐Cell Tumor at a Single Center
Authors: Shiota Masaki , Tanegashima Tokiyoshi , Tsukahara Shigehiro , Mutaguchi Jun , Goto Shunsuke , Kobayashi Satoshi , Matsumoto Takashi , Eto Masatoshi
Published: November 2024

Objective

This study investigated the perioperative and oncological outcomes of laparoscopic retroperitoneal lymph node dissection (RPLND) procedures for post‐chemotherapy patients with nonseminomatous testicular germ‐cell tumor at a single center.

Methods

This study included patients with nonseminomatous testicular cancer who underwent RPLND after chemotherapy at the Kyushu University Hospital between 2016 and 2024. The preoperative clinicopathological characteristics, perioperative outcomes, and oncological outcomes were investigated.

Results

A total of 13 patients underwent laparoscopic RPLND. Median maximum retroperitoneal tumor size at post‐chemotherapy before RPLND was 11 mm (range, 2–30 mm). RPLND template was one side and both sides in nine and four patients. Median operative time was 272 min (range, 129–490 min), and median estimated blood loss was 27 mL (range, 0–100 mL). Median time from operation to discharge was 8 days (range, 5–15 days). There was no severe perioperative and postoperative complication. Residual cancer and teratoma were detected in one and seven patients. During median follow‐up of 18.6 months (range, 1.0–95.7 months), no case presented recurrence.

Conclusion

Laparoscopic RPLND presented safety in perioperative outcomes and favorable oncological outcomes. Thus, it was confirmed that laparoscopic RPLND is a feasible minimally invasive procedure for selected cases.
Perioperative Outcomes and Feasibility of Single‐Stage Laparoscopic Common Bile Duct Exploration (LCBDE) and Cholecystectomy With Internal Endo‐Biliary Drainage for Management of Concomitant Cholelithiasis With Choledocholithiasis: A Report From a Tertiary Care Hospital
Authors: Bajpai Ankita , Anand Akshay , Kumar Awanish , Agrawal Manish , Pal Ajay Kumar , Kumar Pankaj , Karnik Amit , Rungta Sumit , Pahwa Harvinder Singh , Sonkar Abhinav Arun
Published: November 2024

Introduction

Managing choledocholithiasis alongside cholelithiasis has seen significant evolution, presenting options such as single‐stage cholecystectomy with common bile duct (CBD) exploration, or a two‐stage procedure involving endoscopic retrograde cholangiopancreatography (ERCP) performed before or after cholecystectomy. Evidence from Western settings may not fully capture the unique disease burden and demographic characteristics prevalent in developing countries. Laparoscopic common bile duct exploration (LCBDE) is more commonly performed in the Indian subcontinent compared to Western centers due to limited access to advanced procedures and specialized instrumentation for complex ERCP cases. The high cost and the need for extensive armamentarium in managing failed ERCPs make LCBDE a more feasible option in many Indian centers.

Methods

This prospective study, conducted from August 2019 to July 2020 at King George's Medical University, UP, India, included n = 24 patients diagnosed with choledocholithiasis. The operative procedures performed included laparoscopic CBD exploration and cholecystectomy, along with internal endo‐biliary drainage. Perioperative outcomes were assessed, and follow‐up data were included to monitor any recurrence until 36 months post‐surgery.

Results

The study population had a mean age of 42.2 years, with 83% (n = of the patients being female). Abdominal pain was the predominant symptom, reported by 91.66% of the patients, followed by nausea/vomiting in 79.20% of cases. The mean CBD diameter observed was consistent with existing literature. The mean operating time was 2.02 h, with primary duct closure taking an average of 13.66 min. Mean blood loss during surgery was 136.25 mL. The average hospital stay was 5.54 days, with the majority of drain removals occurring by the third postoperative day. Complications included fever in 25.0% of the patients and bile leakage in n = 3 out of 24 cases (~12.50%). During the follow‐up period, one patient (4.17%) experienced a retained stone.

Conclusion

Laparoscopic CBD exploration with primary duct closure and internal biliary drainage appears to be a feasible approach, yielding satisfactory perioperative outcomes. However, further studies are required to firmly establish its superiority over alternative approaches within the Indian context.
Investigations into disease associations with feline immunodeficiency virus (FIV) infection in lions (Panthera leo) in Australia: a case–control study
Authors: Dabydeen A , Herrin KV , Woolfenden L , Hall E , Westman ME , Norris JM
Published: November 2024

Background

Feline immunodeficiency virus (FIV) is a highly mutable retrovirus with numerous species‐specific strains, such as those infecting domestic cats (Felis catus, FIVFca) and wild populations of nondomestic cats including lions (Panthera leo, FIVPle). When FIVFca infection manifests as disease in domestic cats, common presentations include lymphadenopathy, lymphoid malignancies, oral cavity disease, immunological dysfunctions and neurological abnormalities. In contrast to domestic cats, there has been little published evidence of direct FIVPle disease associations in lions. The objective of the study, therefore, was to conduct a longitudinal case–control comparison of clinical findings and survival analysis of FIVPle‐infected and FIVPle‐uninfected captive lions to investigate possible FIVPle disease associations in nondomestic felids in Australia.

Methods

Between 2005 and 2023, 38 lions were recruited from zoos across Australia. Lions had been FIV tested as part of a routine diagnostic service. The 38 lions included in the study comprised 15 FIV‐infected (9 males, 6 females) and 23 FIV‐uninfected (9 males, 14 females) animals. Lifetime longitudinal clinical histories and clinicopathological data collected by zoos for these lions were interrogated, including survival data.

Results

FIV‐infected lions were more likely to be reported with lower mean corpuscular volume (MCV) (fL) (P = 0.015), monocytes (%) (P = 0.023), chloride (mmol/L) (P = 0.016) and phosphate (mmol/L) (P = 0.029), but with a higher mean corpuscular hemoglobin concentration (MCHC) (g/L) (P = 0.001) and bicarbonate (mmol/L) (P = 0.035), than FIV‐uninfected lions. The disease associations usually seen in domestic cats with FIV infection were not observed in lions, and there was no difference in survival between FIV‐infected and FIV‐uninfected lions. The main limitation of the study was a small sample size dictated by the number of lions able to be recruited from zoos in Australia over an 18‐year period.

Conclusion

Few differences were found between case and control groups, suggesting that FIV‐infected lions did not experience clinicopathological changes that predisposed them to future disease compared with FIV‐uninfected lions. Further research will help to determine whether these results are indicative of a general absence of FIV‐associated disease in captive lions, or the result of nonpathogenic FIVPle subtype(s) present in Australia.
Chronic eosinophilic leukaemia—Not otherwise specified: Clinical features, genomic insight and therapeutic strategies
Authors: Costa Alessandro , Scalzulli Emilia , Breccia Massimo
Published: November 2024

Chronic eosinophilia leukaemia—not otherwise specified (CEL‐NOS) is a rare myeloproliferative neoplasm characterized by persistent clonal hypereosinophilia. Recent advances in genetics have refined diagnostic criteria, leading to the identification of CEL subtypes with specific cytogenetic and molecular abnormalities now classified as myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, which may benefit from targeted therapies. In contrast, CEL‐NOS lacks specific genetic drivers and intervention points to halt leukemogenesis. Molecular techniques have also enabled the definition of clonality in a considerable percentage of cases otherwise classified as idiopathic hypereosinophilic syndrome. CEL‐NOS poses a significant therapeutic challenge due to limited treatment options, poor prognosis and the risk of progression to acute leukaemia. Patients, often elderly and with comorbidities, face restricted access to transplantation, the only potentially curative treatment. Unfortunately, the prognosis remains poor even post‐transplant, with a 5‐year survival rate of only one‐third of patients. Other therapies, including steroids, cytoreductive and immunomodulatory treatments, offer limited and temporary responses with significant side effects. This review aims to consolidate current knowledge on CEL‐NOS, covering diagnostic approaches, genetic advancements and therapeutic challenges. It seeks to provide a comprehensive overview and highlight critical areas for future research.
Exploring the Cognitive and Behavioral Aspects of Shprintzen‐Goldberg Syndrome; a Novel Cohort and Literature Review
Authors: Sjøstrøm Emilie , Bruel Ange‐Line , Philippe Christophe , Delanne Julian , Faivre Laurence , Menke Leonie A. , Au P. Y. Billie , Cormick Jessica Jane , Moosa Shahida , Bayat Allan
Published: November 2024

Shprintzen‐Goldberg‐syndrome (SGS) is caused by pathogenic exon 1 variants of SKI. Symptoms include dysmorphic features, skeletal and cardiovascular comorbidities, and cognitive and developmental impairments. We delineated the neurodevelopmental and behavioral features of SGS, as they are not well‐documented. We collected physician‐reported data of people with molecularly confirmed SGS through an international collaboration. We identified and deep‐phenotyped the neurodevelopmental and behavioral features in four patients. Within our cohort, all exhibited developmental delays in motor skills and/or speech, with the average age of first words at 2 years and 6 months and independent walking at 3 years and 5 months. All four had learning disabilities and difficulties regulating emotions and behavior. Intellectual disability, ranging from borderline to moderate, was present in all four participants. Moreover, we reviewed the literature and identified 52 additional people with SGS, and summarized the features across both datasets. Mean age was 23 years (9–48 years). When combining our cohort and reported cases, we found that 80% (45/56) had developmental and/or cognitive impairment, with the remainder having normal intelligence. Our study elucidates the developmental, cognitive, and behavioral features in participants with SGS and contributes to a better understanding of this rare condition.
Behavioural Activation and Inhibition Systems of Fathers, Child Abuse and Childhood Psychopathology: The Mediating Role of Demographics
Authors: Rahimian Bougar Mojtaba , Mirahmadi Babaheydari Sayede Hajar , Khodarahimi Siamak , Mazraeh Nasrollah , Sadeghi Marzieh
Published: November 2024

26 November 2024: This article was published in error. The final version of record will be made fully available at a later date.
Allergic contact dermatitis caused by glucose sensors and insulin pumps: A full review
Authors: de Groot Anton , van Oers Emma M. , Ipenburg Norbertus A. , Rustemeyer Thomas
Published: November 2024

During the past 8 years, a large number of reports have appeared on allergic contact dermatitis to glucose sensors and insulin pumps in paediatric and adult patients with type 1 diabetes mellitus. Isobornyl acrylate in one particular sensor sensitised many hundreds of (published) individuals, and many other allergens were discovered in a large number of sensors and pumps. Diagnostic procedures with patch tests proved very complicated, as manufacturers showed a serious lack of cooperation with dermatologists in providing information on the ingredients of their products and samples for patch testing. This two‐part article provides a full and detailed review of all aspects of the subject of allergic contact dermatitis to glucose sensors and insulin pumps. Part 1 begins with a general introduction to sensors and pumps, followed by the cutaneous adverse reactions that they have caused and a full account of the allergens in the diabetes devices. In addition, an overview of the glucose sensors and insulin pumps that have caused allergic contact dermatitis is presented. Part 2 presents all published case reports and case series, clinical features of allergic contact dermatitis to sensors and pumps, patch test procedures, differentiation from irritant dermatitis, management of allergic patients and (proposed) legislation.
Trends of in vitro pharmacological potency and in vivo pharmacokinetics parameters of modern drugs: Can the therapeutic/subtherapeutic dose be estimated from in vitro Ki and pharmacokinetic parameters?
Authors: Tsuchitani Toshiaki , Kato Motohiro , Tomaru Atsuko , Aoki Yasunori , Sugiyama Yuichi
Published: November 2024

In drug discovery and development, estimating therapeutic and subtherapeutic doses is crucial for designing early‐phase clinical trials, particularly first‐in‐human (FIH) studies. While increasing the in vitro pharmacological potency (lowering Ki) of a compound to its target is expected to decrease the therapeutic dose, its benefit is not necessarily clarified. We analyzed in vitro Ki, human in vivo pharmacokinetics (PK) parameters, and therapeutics doses of 144 oral small‐molecule drugs approved in Japan (2010–2021). The data on classic drugs were obtained from Goodman and Gilman's textbook, 9th ed. (published in 1996). Modern drugs had lower Ki (2.5 nM) and daily doses (88 μmol/day) than classic drugs (33 nM and 313 μmol/day), but 3.6‐fold higher intrinsic clearance (CLint; 171 vs. 47 L/h), suggest that increasing potency over the years has not resulted in a reduction in dosage as expected. Estimating therapeutic doses using target receptor occupancy (tRO)‐optimized approach improved estimation accuracy (63% within 10‐fold of observed values) compared with tRO‐fixed approaches. Subtherapeutic dose estimations revealed a risk of overdosing in FIH trials, indicating that these estimates are not necessarily as conservative as is generally understood. Notably, the unbound average concentration‐to‐Ki ratio (Cave,u/Ki) varied among drugs and correlated negatively with Ki, suggesting the possible necessity of incorporating it into dose estimation methods. This study provides insights into the relationship between in vitro Ki, in vivo PK parameters, and therapeutic dose of modern drugs, proposing strategies and revealing the risk for dose estimation and drug development in the era of highly potent small molecules.
Differential effects of imeglimin and metformin on insulin and incretin secretion—An exploratory randomized controlled trial
Authors: Usui Ryota , Hamamoto Yoshiyuki , Imura Masahiro , Omori Yasuhiro , Yamazaki Yuji , Kuwata Hitoshi , Tatsuoka Hisato , Shimomura Kazuhiro , Murotani Kenta , Yamada Yuichiro , Seino Yutaka
Published: November 2024

Aims

Imeglimin is a new oral anti‐diabetic drug with a similar structure to that of metformin; however, unlike metformin, clinical trials indicate that imeglimin elicits its glucose‐lowering effect mainly by enhancement of insulin secretion. The comparative effects of the two drugs on incretin secretion remains to be elucidated.

Materials and Methods

A single‐center, open‐label, randomized controlled trial was conducted in patients with type 2 diabetes who were drug‐naïve or were on a single oral hypoglycaemic agent (OHA). For patients taking a single OHA, an 8‐week washout period was employed before randomization. Participants were randomized to the imeglimin group (IME, 2000 mg/day) or the metformin group (MET, 1000 mg/day), and OGTT was performed before treatment and after 12 and 24 weeks of treatment.

Results

The reduction in HbA1c at 24 weeks was similar in IME and MET. OGTT revealed a comparable decrease in post‐challenge blood glucose excursion in both groups, but insulin levels were increased only in IME. Total and active glucagon‐like peptide‐1 (GLP‐1) levels were increased in both IME and MET; however, total and active glucose‐dependent insulinotropic peptide (GIP) levels were increased only in IME. Interestingly, while an increase in insulin levels in IME was positively correlated with an increase in GLP‐1 at 12 weeks, it was correlated only with an increase in GIP at 24 weeks.

Conclusions

Unlike metformin, imeglimin enhances GIP secretion as well as GLP‐1 secretion, in addition to its direct insulinotropic mechanism of glucose control, emphasizing its potential as a therapeutic option in the treatment of patients with diabetes.
Network Mendelian randomisation analysis deciphers protein pathways linking type 2 diabetes and gastrointestinal disease
Authors: Geng Jiawei , Ruan Xixian , Wu Xing , Chen Xuejie , Fu Tian , Gill Dipender , Burgess Stephen , Chen Jie , Ludvigsson Jonas F. , Larsson Susanna C. , Li Xue , Du Zhongyan , Yuan Shuai
Published: November 2024

Aims

The molecular mechanisms underlying the association between type 2 diabetes (T2D) and gastrointestinal (GI) disease are unclear. To identify protein pathways, we conducted a two‐stage network Mendelian randomisation (MR) study.

Materials and Methods

Genetic instruments for T2D were obtained from a large‐scale summary‐level genome‐wide meta‐analysis. Genetic associations with blood protein levels were obtained from three genome‐wide association studies on plasma proteins (i.e. the deCODE study as the discovery and the UKB‐PPP and Fenland studies as the replication). Summary‐level data on 10 GI diseases were derived from genome‐wide meta‐analysis of the UK Biobank and FinnGen. MR and colocalisation analyses were performed. Pathways were constructed according to the directionality of total and indirect effects, and corresponding proportional mediation was estimated. Druggability assessments were conducted across four databases to prioritise protein mediators.

Results

Genetic liability to T2D was associated with 69 proteins in the discovery protein dataset after multiple testing corrections. All associations were replicated at the nominal significance level. Among T2D‐associated proteins, genetically predicted levels of nine proteins were associated with at least one of the GI diseases. Genetically predicted levels of SULT2A1 (odds ratio = 1.98, 95% CI 1.80–2.18), and ADH1B (odds ratio = 2.05, 95% CI 1.43–2.94) were associated with cholelithiasis and cirrhosis respectively. SULT2A1 and cholelithiasis (PH4 = 0.996) and ADH1B and cirrhosis (PH4 = 0.931) have strong colocalisation support, accounting for the mediation proportion of 72.8% (95% CI 45.7–99.9) and 42.9% (95% CI 15.5–70.4) respectively.

Conclusions

The study identified some proteins mediating T2D‐GI disease associations, which provided biological insights into the underlying pathways.
Effect of exercise on plasma insulin levels in individuals with type 1 diabetes: A systematic review and meta‐analysis
Authors: Kastrati Lum , Alvarez‐Martinez Mario , Thomas Andreas , Thevis Mario , Muka Taulant , Stettler Christoph , Herzig David , Glisic Marija , Bally Lia
Published: November 2024

Aims

Current evidence of the impact of acute exercise on insulin levels in individuals with type 1 diabetes remains controversial. Therefore, we conducted a systematic review and meta‐analysis to explore exercise‐induced changes in insulin levels.

Materials and Methods

We conducted a systematic review (until 05 November 2023) and meta‐analysis exploring the effect of exercise on insulin concentration in individuals with type 1 diabetes. We included randomised cross‐over studies for rapid‐acting insulin and pre‐ and post‐studies for long‐acting insulin in individuals with type 1 diabetes performing any type of acute exercise and had a control condition. The exercise‐induced change in insulin levels was the outcome of interest. When possible, the mean differences (MDs) in insulin levels were pooled using the DerSimonian and Laird random effect method. Risk of bias was assessed for each included study.

Results

Seventeen trials, encompassing 186 participants with type 1 diabetes, were included in the systematic review. Twelve out of 17 studies included participants on rapid‐acting insulin regimens and used a cross‐over design, whereas five out of 17 single‐arm studies included participants on (ultra)long‐acting insulin. Seven out of 12 studies on rapid‐acting insulins and all the single‐arm studies were at high risk of bias. Results suggest a statistically significant, small‐to‐moderate increase of rapid‐acting insulin after 30 min of exercise (MD of 18.44 [95% CI 0.02; 36.86; I2 0%] pmol/L); meanwhile, findings on (ultra)long‐acting insulin were inconclusive.

Conclusions

A small‐to‐moderate increase of insulin levels in studies including rapid‐acting insulin was found after a bout of physical exercise in individuals with type 1 diabetes. However, current gaps in high‐quality evidence challenge our understanding of insulin kinetics around exercise.
Study of Degenerative Mitral Regurgitation Using Three‐Dimensional Echocardiography and EchoPAC GE Health Care Software 4D Auto MVQ: Comparison Between Transthoracic and Transesophageal Examination
Authors: Fioretti Ginevra , Tolomei Alice , Ciaramella Piera , Lio Antonio , Cristiano Ernesto , Cacioli Giulio , Tempestini Federica , Ranocchi Federico , Maestrini Viviana , Pergolini Amedeo
Published: November 2024

Background

Preoperative echocardiographic assessment is critical for patients with severe degenerative mitral regurgitation to ensure personalized surgical mitral valve repair. This study aimed to compare the diagnostic accuracy of three‐dimensional transthoracic echocardiography (3D TTE) and three‐dimensional transesophageal echocardiography (3D TEE) in identifying valvular lesions, using surgical findings as the reference. Additionally, we evaluated whether annular dimensional parameters derived from TTE and TEE, using dedicated 3D software, could confirm whether 3D TTE alone offers a comprehensive preoperative evaluation.

Methods

We enrolled 60 patients with severe organic mitral regurgitation scheduled for surgical valve repair. Each patient underwent preoperative 3D TTE, intraoperative 3D TEE prior to surgery, followed by annuloplasty. Mitral valve reconstructions from both TTE and TEE were compared, and dedicated 3D software (EchoPAC GE‐Health‐Care Software 3D‐auto‐MVQ) was employed to reconstruct annular geometries from both methods.

Results

Both 3D TTE and 3D TEE demonstrated comparable accuracy in identifying diseased scallops (overall accuracy: 3D TTE 91.8%, 3D TEE 98.1%, p > 0.05). However, 3D TTE was inferior to 3D TEE in identifying multiple chordal ruptures (accuracy: 3D TTE 80%, 3D TEE 100%). Quantitative analysis of the mitral annulus revealed that 3D TTE and 3D TEE yielded overlapping results for static parameters (p > 0.05), whereas dynamic parameters differed significantly (p < 0.05).

Conclusions

In the selected population, 3D TTE demonstrated diagnostic accuracy comparable to transesophageal echocardiography in identifying mitral valve lesions. Furthermore, with the use of dedicated 3D software, TTE alone may provide a comprehensive and noninvasive preoperative evaluation, particularly for static annular parameters. Further studies are warranted to corroborate these findings.
Combining past and contemporary species occurrences with ordinal species distribution modeling to investigate responses to climate change
Authors: Beever Erik A. , Westover Marie L. , Smith Adam B. , Gerraty Francis D. , Billman Peter D. , Smith Felisa A.
Published: November 2024

Many organisms leave evidence of their former occurrence, such as scat, abandoned burrows, middens, ancient eDNA or fossils, which indicate areas from which a species has since disappeared. However, combining this evidence with contemporary occurrences within a single modeling framework remains challenging. Traditional binary species‐distribution modeling reduces occurrence to two temporally coarse states (present/absent), so thus cannot leverage the information inherent in temporal sequences of evidence of past occurrence. In contrast, ordinal modeling can use the natural time‐varying order of states (e.g. never occupied versus previously occupied versus currently occupied) to provide greater insights into range shifts. We demonstrate the power of ordinal modeling for identifying the major influences of biogeographic and climatic variables on current and past occupancy of the American pika Ochotona princeps, a climate‐sensitive mammal. Sampling over five years across the species' southernmost, warm‐edge range limit, we tested the effects of these variables at 570 habitat patches where occurrence was classified either as binary or ordinal. The two analyses produced different top models and predictors – ordinal modeling highlighted chronic cold as the most‐important predictor of occurrence, whereas binary modeling indicated primacy of average summer‐long temperatures. Colder wintertime temperatures were associated in ordinal models with higher likelihood of occurrence, which we hypothesize reflect longer retention of insulative and meltwater‐provisioning snowpacks. Our binary results mirrored those of other past pika investigations employing binary analysis, wherein warmer temperatures decrease likelihood of occurrence. Because both ordinal‐ and binary‐analysis top models included climatic and biogeographic factors, results constitute important considerations for climate‐adaptation planning. Cross‐time evidences of species occurrences remain underutilized for assessing responses to climate change. Compared to multi‐state occupancy modeling, which presumes all states occur in the same time period, ordinal models enable use of historical evidence of species' occurrence to identify factors driving species' distributions more finely across time.
Interdisciplinary Approach to Managing Complex Traumatic Dental Injuries in the Young Permanent Dentition
Authors: Gorp Gertrude Van , EzEldeen Mostafa
Published: November 2024

Traumatic dental injuries (TDIs) are a frequent challenge in pediatric dentistry, requiring a coordinated interdisciplinary approach for successful management. These injuries can affect various dental tissues and pose significant diagnostic and therapeutic challenges, particularly in young patients with developing dentition. This review aims to explore the complexities of managing TDIs in young permanent dentition, focusing on the role of orthodontics, endodontics, and other specialties in providing comprehensive care. We highlight the importance of interdisciplinary collaboration in achieving optimal functional and aesthetic outcomes, emphasizing the need for updated diagnostic tools and treatment protocols tailored to the growing child. Specific recommendations are provided for clinicians on integrating orthodontic and endodontic management in trauma cases, focusing on minimizing complications and ensuring long‐term prognosis.
Behaviour of the Apex Predator European Catfish (Silurus glanis) on a Recently Invaded Reservoir
Authors: Santos G. S. , Ribeiro F. , Pereira E. , Silva A. F. , Almeida P. R. , Ribeiro D. , Quintella B. R.
Published: November 2024

The European catfish (Silurus glanis L.) is a large, non‐native, invasive freshwater species known for its high fecundity, long lifespan and significant predatory potential, possibly threatening native fish communities. While some studies exist on its spatial use, most focus on its native range and lack detailed circadian and annual activity patterns. This study uses acoustic biotelemetry to track 10 adult fish in the Tagus River's Belver reservoir, employing transmitters with 3D accelerometer and pressure sensors to record activity and depth over a year. Generalised additive models identify environmental variables influencing activity and depth patterns. The European catfish is active year‐round, with peak activity in summer and minimal in autumn. It occupies shallower depths in spring and summer (median depths of 2.6 and 4.8 m, respectively) and deeper waters in autumn and winter (median depths of 9.8 and 10.8 m, respectively). Circadian vertical movement patterns exhibit high seasonal and individual variability. Significant environmental predictors of the European catfish activity include river flow, water temperature and the photoperiod, while the predictors of depth use are river flow and the photoperiod. These insights can aid in developing effective control measures, such as optimising fishing efforts spatially and temporally to enhance the efficiency of removing this invasive fish.
Distribution and Diversity of Coastal Fish in Fresh and Oligohaline Waters: An Example of the Largest Baltic Sea Estuary of the Neva River
Authors: Uspenskiy Anton A.
Published: November 2024

Understanding how low salinity gradients (0‰–5‰) influence fish life cycles is critical for clarifying principles of fish assemblage formation in estuarine ecosystems. This study is intended to provide a foundation for predicting changes in fish populations amidst ongoing surface salinity decreases in the Baltic Sea. In the Neva River Estuary, differences in fish diversity and distribution between fish assemblages in freshwater and oligohaline areas were assessed using beach seine and multi‐mesh gillnet surveys. The use of multiple sampling gears greatly enhanced understanding of fish distribution across salinity gradients. Fish assemblages were analysed depending on the different areas of the estuary, seasons of sampling, salinity and confounding environmental variables such as water temperature and depth. Salinity was the major influencing factor for the surf zone fish assemblages and a season of sampling was the main factor for coastal assemblages of larger fish studied with the gillnets. Fish assemblages in the surf zone exhibited significant but gradual changes in freshwater and marine‐estuarine fish occurrence and abundance along the critical oligohaline barrier ‘δ‐horohalinicum’ (0.5‰–1.9‰). Although freshwater species showed high occurrence and abundance throughout the estuary, their juveniles were less abundant in the oligohaline surf zone with salinity ≥ 2‰, where small‐size marine‐estuarine and euryhaline species predominated. Coastal multi‐mesh gillnet catches showed remarkable similarity between assemblages of larger fish in freshwater and oligohaline areas. Differences in species richness and diversity indices were not pronounced throughout the salinity gradient; the decline in freshwater species was offset by an increase in marine‐estuarine and euryhaline species.
The Role of Underwater Soundscapes in Shaping the Distribution of Cobitidae Fish: Insights From Multiple Environmental Factors
Authors: Yang Ji , Xu Jiawei , Shi Xiaotao , Wu Yujiao , Ke Senfan , Li Dongqing , Gao Shenghui , Li Xinyu , Li Jiaxin , Jiang Zewen , Cheng Bixin
Published: November 2024

Sound is critical in fish behaviours, including reproduction, feeding, predator avoidance and habitat selection. To investigate the impact of underwater soundscape on the distribution of Cobitidae fishes, we surveyed the status of Cobitidae fish resources and the underwater soundscape along with related environmental factors at 12 sampling sites downstream of the Songxin Hydropower Station in the Heishui River, a major tributary of the Jinsha River in China. Generalised additive models (GAMs) were employed to identify the primary environmental factors influencing the distribution of Cobitidae fishes and we analysed the correlation between the abundance of Cobitidae fish and primary environmental factors. The study revealed that the water depth, flow velocity, water temperature and sound pressure level (SPL) all had highly significant effects on the distribution of Cobitidae fishes (p < 0.001), with SPL showing the lowest relative importance among these factors. Water depth positively correlated with Cobitidae fish abundance, whereas water temperature, SPL and flow velocity showed negative correlations. This study preliminarily explored the response relationship between the distribution of Cobitidae fish and four main environmental factors, offering a technical foundation for predicting the distribution of Cobitidae fishes in rivers and for implementing conservation measures of fish such as suitable habitat creation.