bluuebunny/crossref_metadata_2025 huggingface dataset:
A High-Resolution 3D Ultrasound Imaging System Oriented towards a Specific Application in Breast Cancer Detection Based on a 1 × 256 Ring Array
Authors: Zhang Junhui , Wu Fei , Meng Fansheng , Zhang Guojun , Wang Renxin , Yang Yuhua , Cui Jiangong , He Changde , Jia Licheng , Zhang Wendong
Published: January 2024

This paper presents the design and development of a high-resolution 3D ultrasound imaging system based on a 1 × 256 piezoelectric ring array, achieving an accuracy of 0.1 mm in both ascending and descending modes. The system achieves an imaging spatial resolution of approximately 0.78 mm. A 256 × 32 cylindrical sensor array and a digital phantom of breast tissue were constructed using the k-Wave toolbox. The signal is acquired layer by layer using 3D acoustic time-domain simulation, resulting in the collection of data from each of the 32 layers. The 1 × 256 ring array moves on a vertical trajectory from the chest wall to the nipple at a constant speed. A data set was collected at intervals of 1.5 mm, resulting in a total of 32 data sets. Surface rendering and volume rendering algorithms were used to reconstruct 3D ultrasound images from the volume data obtained via simulation so that the smallest simulated reconstructed lesion had a diameter of 0.3 mm. The reconstructed three-dimensional image derived from the experimental data exhibits the contour of the breast model along with its internal mass. Reconstructable dimensions can be achieved up to approximately 0.78 mm. The feasibility of applying the system to 3D breast ultrasound imaging has been demonstrated, demonstrating its attributes of resolution, precision, and exceptional efficiency.
Design and Optimization of Thin-Walled Main Support Structure for Space Camera Based on Additive Manufacturing
Authors: Peng Jiahao , Liu Shijie , Wang Dong , Xu Anpeng , Huang Xin , Ma Tianqi , Wang Jing , Li Hang
Published: January 2024

In order to solve the design requirements of high stiffness and lightweight for the primary support structure of a wide-field auroral imager, we propose a solution for designing and optimizing a large-scale complex thin-walled structure using additive manufacturing. Firstly, we devise an integrated thin-walled structure and test material for the main support. Secondly, shape optimization is achieved via the optimization of the lateral slope angle of the primary support based on Timoshenko cantilever beam theory. Additionally, an active fitting optimization algorithm is proposed for the purpose of refining the wall thickness of the thin-walled structure. Then, we determine the structural design of the main support. This primary support is manufactured via selective laser melting (SLM). Following processing, the structure size is 538 mm × 400 mm × 384 mm, and the mass is 7.78 kg. Finally, frequency scanning experiments indicate that, in the horizontal direction, there is a natural frequency of 105.97 Hz with an error rate of approximately 3% compared to finite element analysis results. This research confirms that our large-scale complex, thin-walled main support structure design meets all design requirements.
Candida albicans Infection Disrupts the Metabolism of Vaginal Epithelial Cells and Inhibits Cellular Glycolysis
Authors: Zhao Yanni , Wang Pengjiao , Sun Xiaodong , Zhao Mei , Chen Yixuan , Gao Xiuli
Published: January 2024

Vulvovaginal candidiasis (VVC) is a common gynecologic disorder caused by fungal infections of the vaginal mucosa, with the most common pathogen being Candida albicans (C. albicans). Exploring metabolite changes in the disease process facilitates further discovery of targets for disease treatment. However, studies on the metabolic changes caused by C. albicans are still lacking. In this study, we used C. albicans-infected vaginal epithelial cells to construct an in vitro model of VVC, analyzed the metabolites by UHPLC-Q-Exactive MS, and screened the potential metabolites based on metabolomics. The results showed that C. albicans infection resulted in significant up-regulation of D-arabitol, palmitic acid, adenosine, etc.; significant down-regulation of lactic acid, nicotinamide (NAM), nicotinate (NA), etc.; and disruption of amino acid metabolism, and that these significantly altered metabolites might be potential therapeutic targets of VVC. Further experiments showed that C. albicans infection led to a decrease in glycolytic enzymes in damaged cells, inhibiting glycolysis and leading to significant alterations in glycolytic metabolites. The present study explored the potential metabolites of VVC induced by C. albicans infection based on metabolomics and verified the inhibitory effect of C. albicans on vaginal epithelial cell glycolysis, which is valuable for the diagnosis and treatment of VVC.
Straw Soil Conditioner Modulates Key Soil Microbes and Nutrient Dynamics across Different Maize Developmental Stages
Authors: Zhang Jianfeng , Ye Libo , Chang Jingjing , Wang Enze , Wang Changji , Zhang Hengfei , Pang Yingnan , Tian Chunjie
Published: January 2024

Soil amendments may enhance crop yield and quality by increasing soil nutrient levels and improving nutrient absorption efficiency, potentially through beneficial microbial interactions. In this work, the effects of amending soil with straw-based carbon substrate (SCS), a novel biochar material, on soil nutrients, soil microbial communities, and maize yield were compared with those of soil amendment with conventional straw. The diversity and abundance of soil bacterial and fungal communities were significantly influenced by both the maize growth period and the treatment used. Regression analysis of microbial community variation indicated that Rhizobiales, Saccharimonadales, and Eurotiales were the bacterial and fungal taxa that exhibited a positive response to SCS amendment during the growth stages of maize. Members of these taxa break down organic matter to release nutrients that promote plant growth and yield. In the seedling and vegetative stages of maize growth, the abundance of Rhizobiales is positively correlated with the total nitrogen (TN) content in the soil. During the tasseling and physiological maturity stages of corn, the abundance of Saccharimonadales and Eurotiales is positively correlated with the content of total carbon (TC), total phosphorus (TP), and available phosphorus (AP) in the soil. The results suggest that specific beneficial microorganisms are recruited at different stages of maize growth to supply the nutrients required at each stage. This targeted recruitment strategy optimizes the availability of nutrients to plants and ultimately leads to higher yields. The identification of these key beneficial microorganisms may provide a theoretical basis for the targeted improvement of crop yield and soil quality. This study demonstrates that SCS amendment enhances soil nutrient content and crop yield compared with conventional straw incorporation and sheds light on the response of soil microorganisms to SCS amendment, providing valuable insights for the future implementation of this material.
Biotechnological Production and Characterization of Extracellular Melanin by Streptomyces nashvillensis
Authors: Restaino Odile Francesca , Manini Paola , Kordjazi Talayeh , Alfieri Maria Laura , Rippa Massimo , Mariniello Loredana , Porta Raffaele
Published: January 2024

Melanins are pigments employed in food, cosmetic, and textile industries, manufactured by extraction from cuttlefishes. Their biotechnological production by Streptomycetes, instead, has been poorly investigated so far. In this paper, for the first time, the strain Streptomyces nashvillensis DSM 40314 was tested as an extracellular melanin producer by investigating the influence of diverse temperatures (26, 28, and 30 °C) and pH values (6.0 and 7.0) on bacterial growth, melanin production, and on the activity of the secreted tyrosinase, the first enzyme of the pigment biosynthetic pathway. In physiological 96-h shake flask experiments, the optimal growth parameters resulted to be 28 °C and pH 7.0, at which a maximum biomass of 8.4 ± 0.5 gcdw/L, a melanin concentration of 0.74 ± 0.01 g/L (yield on biomass of 0.09 ± 0.01 g/gcdw and productivity of 0.008 ± 0.001 g/L/h), and a final tyrosinase activity of 10.1 ± 0.1 U/mL were reached. The produced pigment was purified from the broth supernatant with a two-step purification process (75.0 ± 2.0% of purity with 65.0 ± 5.0% of recovery) and tested for its chemical, antioxidant, and photoprotective properties. Finally, characterization by UV-visible and FT-IR spectroscopy, elemental analyses, and mono- and bi-dimensional NMR suggested the eumelanin-like nature of the pigment.
Diversity, Composition, and Specificity of the Philaenus spumarius Bacteriome
Authors: Cameirão Cristina , Costa Daniela , Rufino José , Pereira José Alberto , Lino-Neto Teresa , Baptista Paula
Published: January 2024

Philaenus spumarius (Linnaeus, 1758) (Hemiptera, Aphrophoridae) was recently classified as a pest due to its ability to act as a vector of the phytopathogen Xylella fastidiosa. This insect has been reported to harbour several symbiotic bacteria that play essential roles in P. spumarius health and fitness. However, the factors driving bacterial assemblages remain largely unexplored. Here, the bacteriome associated with different organs (head, abdomen, and genitalia) of males and females of P. spumarius was characterized using culturally dependent and independent methods and compared in terms of diversity and composition. The bacteriome of P. spumarius is enriched in Proteobacteria, Bacteroidota, and Actinobacteria phyla, as well as in Candidatus Sulcia and Cutibacterium genera. The most frequent isolates were Curtobacterium, Pseudomonas, and Rhizobiaceae sp.1. Males display a more diverse bacterial community than females, but no differences in diversity were found in distinct organs. However, the organ shapes the bacteriome structure more than sex, with the Microbacteriaceae family revealing a high level of organ specificity and the Blattabacteriaceae family showing a high level of sex specificity. Several symbiotic bacterial genera were identified in P. spumarius for the first time, including Rhodococcus, Citrobacter, Halomonas, Streptomyces, and Providencia. Differences in the bacterial composition within P. spumarius organs and sexes suggest an adaptation of bacteria to particular insect tissues, potentially shaped by their significance in the life and overall fitness of P. spumarius. Although more research on the bacteria of P. spumarius interactions is needed, such knowledge could help to develop specific bacterial-based insect management strategies.
An In Vitro Study on the Role of Cellulases and Xylanases of Bacillus subtilis in Dairy Cattle Nutrition
Authors: Bontà Valeria , Battelli Marco , Rama Erlinda , Casanova Michela , Pasotti Lorenzo , Galassi Gianluca , Colombini Stefania , Calvio Cinzia
Published: January 2024

The administration of Bacilli to dairy cows exerts beneficial effects on dry matter intake, lactation performance, and milk composition, but the rationale behind their efficacy is still poorly understood. In this work, we sought to establish whether cellulases and xylanases, among the enzymes secreted by B. subtilis, are involved in the positive effect exerted by Bacilli on ruminal performance. We took advantage of two isogenic B. subtilis strains, only differing in the secretion levels of those two enzymes. A multi-factorial study was conducted in which eight feed ingredients were treated in vitro, using ruminal fluid from cannulated cows, with cultures of the two strains conveniently grown in a growth medium based on inexpensive waste. Feed degradability and gas production were assessed. Fiber degradability was 10% higher (p < 0.001) in feeds treated with the enzyme-overexpressing strain than in the untreated control, while the non-overexpressing strain provided a 5% increase. The benefit of the fibrolytic enzymes was maximal for maize silage, the most recalcitrant feed. Gas production also correlated with the amount of enzymes applied (p < 0.05). Our results revealed that B. subtilis cellulases and xylanases effectively contribute to improving forage quality, justifying the use of Bacilli as direct-fed microbials to increase animal productivity.
A Feasible and Efficient Monitoring Method of Synthetic Fibers Released during Textile Washing
Authors: Świątek Oskar , Dąbrowska Agnieszka
Published: January 2024

Microfibers (MFs) are one of the most common and hazardous forms of microplastic found in the aquatic environment. The methods of collecting and analyzing MFs released during washing have to be developed and standardized to understand and model the process of microfibers’ emission better. This study tests a new, innovative method to check if laundry fiber sampling can be approached comprehensively. Pieces of synthetic materials (aged and new polyester, polyester-cotton blend) were placed in chromium-nickel filters envelope-like folded. Then, textile weathering during washing was monitored by the quality and quantity of fibers found directly on the filter surface. Laundry parameters like temperature, detergent presence, and filter size were changed, and results were monitored by Fourier-transform infrared spectroscopy (FTIR), a well-known standard in microplastic identification. In addition, ATR spectra were collected to characterize the materials in detail and evaluate their aging level. Spectroscopy can be used to detect and examine both mechanical and chemical degradation, and the collected microfibers can be assigned to the material they come from. Finally, a quantitative comparison of fibers released during different washing conditions can be used for the process optimization to minimize its environmental impact.
Geochemical Characteristics of Aluminum-Bearing Iron Ores: A Case Study from the Kolijan Karst-Type Bauxite Deposit, Northwestern Iran
Authors: Abedini Ali , Khosravi Maryam
Published: January 2024

The Kolijan bauxite deposit (southeast Mahabad, northwestern Iran) mainly contains aluminum-bearing iron ores and was deposited in karstic depressions and sinkholes of the middle Permian carbonate rocks of the Ruteh Formation. Based on microscopic observations, the aluminum-bearing iron ores were allogenic in origin. According to XRD and SEM-EDS analyses, hematite and goethite are their main constituents, accompanied by lesser amounts of kaolinite, illite, amesite, boehmite, rutile, anatase, calcite, pyrolusite, crandallite, and parisite-(Ce). Chondrite-normalized REE patterns are indicative of fractionation and enrichment of LREE (La–Eu) compared to HREE (Gd–Lu), along with positive Eu and Ce anomalies (Eu/Eu* = 2.29–5.65; Ce/Ce* = 3.63–5.22). Positive Ce anomalies can be attributed to the role of carbonate bedrock as a geochemical barrier and the precipitation of parisite-(Ce). A strong positive correlation between Eu/Eu* and Ce/Ce* (r = 0.84) indicates that Eu anomalies, similar to Ce anomalies, are closely dependent on an alkaline pH. The distribution and fractionation of elements in the iron ores were controlled by a number of factors, including the pH of the environment in which they formed, wet climatic conditions, adsorption, isomorphic substitution, scavenging, co-precipitation, fluctuations of the groundwater table level, and the role of carbonate bedrock as a geochemical barrier. This research indicates that the aluminum-bearing iron ores were probably generated from the weathering of basaltic protolith.
Correction: de Jesus et al. Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-κB Cascade: In Vitro and In Silico Investigations. Molecules 2022, 27, 1078
Authors: de Jesus Ma. Sheila M. , Macabeo Allan Patrick G. , Ramos John Donnie A. , de Leon Von Novi O. , Asamitsu Kaori , Okamoto Takashi
Published: January 2024

There was an error in the original publication [...]
Special Issue Editorial: “Antibacterial Agents from Natural Sources”
Authors: Martins Carlos Henrique G.
Published: January 2024

Antibacterials derived from natural sources represent a fascinating and promising field of research in the quest for effective and sustainable solutions to bacterial infections [...]
Impact of Industrial Noise on Speech Interaction Performance and User Acceptance when Using the MS HoloLens 2
Authors: Rosilius Maximilian , Spiertz Martin , Wirsing Benedikt , Geuen Manuel , Bräutigam Volker , Ludwig Bernd
Published: January 2024

Even though assistance systems offer more potential due to the increasing maturity of the inherent technologies, Automatic Speech Recognition faces distinctive challenges in the industrial context. Speech recognition enables immersive assistance systems to handle inputs and commands hands-free during two-handed operative jobs. The results of the conducted study (with n = 22 participants) based on the counterbalanced within-subject design demonstrated the performance (word error rate and information transfer rate) of the HMD HoloLens 2 as a function of the sound pressure level of industrial noise. The negative influence of industrial noise was higher on the word error rate of dictation than on the information transfer rate of the speech command. Contrary to expectations, no statistically significant difference in performance was found between the stationary and non-stationary noise. Furthermore, this study confirmed the hypothesis that user acceptance was negatively influenced by erroneous speech interactions. Furthermore, the erroneous speech interaction had no statistically significant influence on the workload or physiological parameters (skin conductance level and heart rate). It can be summarized that Automatic Speech Recognition is not yet a capable interaction paradigm in an industrial context.
Intracranial Gene Delivery Mediated by Albumin-Based Nanobubbles and Low-Frequency Ultrasound
Authors: Koga Takayuki , Kida Hiroshi , Yamasaki Yutaro , Feril Loreto B. , Endo Hitomi , Itaka Keiji , Abe Hiroshi , Tachibana Katsuro
Published: January 2024

Research in the field of high-intensity focused ultrasound (HIFU) for intracranial gene therapy has greatly progressed over the years. However, limitations of conventional HIFU still remain. That is, genes are required to cross the blood-brain barrier (BBB) in order to reach the neurological disordered lesion. In this study, we introduce a novel direct intracranial gene delivery method, bypassing the BBB using human serum albumin-based nanobubbles (NBs) injected through a less invasive intrathecal route via lumbar puncture, followed by intracranial irradiation with low-frequency ultrasound (LoFreqUS). Focusing on both plasmid DNA (pDNA) and messenger RNA (mRNA), our approach utilizes LoFreqUS for deeper tissue acoustic penetration and enhancing gene transfer efficiency. This drug delivery method could be dubbed as the “Spinal Back-Door Approach”, an alternative to the “front door” BBB opening method. Experiments showed that NBs effectively responded to LoFreqUS, significantly improving gene transfer in vitro using U-87 MG cell lines. In vivo experiments in mice demonstrated significantly increased gene expression with pDNA; however, we were unable to obtain conclusive results using mRNA. This novel technique, combining albumin-based NBs and LoFreqUS offers a promising, efficient, targeted, and non-invasive solution for central nervous system gene therapy, potentially transforming the treatment landscape for neurological disorders.
Fraxicon for Optical Applications with Aperture ∼1 mm: Characterisation Study
Authors: Mu Haoran , Smith Daniel , Ng Soon Hock , Anand Vijayakumar , Le Nguyen Hoai An , Dharmavarapu Raghu , Khajehsaeidimahabadi Zahra , Richardson Rachael T. , Ruther Patrick , Stoddart Paul R. , Gricius Henrikas , Baravykas Tomas , Gailevičius Darius , Seniutinas Gediminas , Katkus Tomas , Juodkazis Saulius
Published: January 2024

Emerging applications of optical technologies are driving the development of miniaturised light sources, which in turn require the fabrication of matching micro-optical elements with sub-1 mm cross-sections and high optical quality. This is particularly challenging for spatially constrained biomedical applications where reduced dimensionality is required, such as endoscopy, optogenetics, or optical implants. Planarisation of a lens by the Fresnel lens approach was adapted for a conical lens (axicon) and was made by direct femtosecond 780 nm/100 fs laser writing in the SZ2080™ polymer with a photo-initiator. Optical characterisation of the positive and negative fraxicons is presented. Numerical modelling of fraxicon optical performance under illumination by incoherent and spatially extended light sources is compared with the ideal case of plane-wave illumination. Considering the potential for rapid replication in soft polymers and resists, this approach holds great promise for the most demanding technological applications.
A Study of Ethereum’s Transition from Proof-of-Work to Proof-of-Stake in Preventing Smart Contracts Criminal Activities
Authors: Hall Oliver J. , Shiaeles Stavros , Li Fudong
Published: January 2024

With the ever-increasing advancement in blockchain technology, security is a significant concern when substantial investments are involved. This paper explores known smart contract exploits used in previous and current years. The purpose of this research is to provide a point of reference for users interacting with blockchain technology or smart contract developers. The primary research gathered in this paper analyses unique smart contracts deployed on a blockchain by investigating the Solidity code involved and the transactions on the ledger linked to these contracts. A disparity was found in the techniques used in 2021 compared to 2023 after Ethereum moved from a Proof-of-Work blockchain to a Proof-of-Stake one, demonstrating that with the advancement in blockchain technology, there is also a corresponding advancement in the level of effort bad actors exert to steal funds from users. The research concludes that as users become more wary of malicious smart contracts, bad actors continue to develop more sophisticated techniques to defraud users. It is recommended that even though this paper outlines many of the currently used techniques by bad actors, users who continue to interact with smart contracts should consistently stay up to date with emerging exploitations.
The Role of Diet and Nutritional Interventions for the Infant Gut Microbiome
Authors: Catassi Giulia , Aloi Marina , Giorgio Valentina , Gasbarrini Antonio , Cammarota Giovanni , Ianiro Gianluca
Published: January 2024

The infant gut microbiome plays a key role in the healthy development of the human organism and appears to be influenced by dietary practices through multiple pathways. First, maternal diet during pregnancy and infant nutrition significantly influence the infant gut microbiota. Moreover, breastfeeding fosters the proliferation of beneficial bacteria, while formula feeding increases microbial diversity. The timing of introducing solid foods also influences gut microbiota composition. In preterm infants the gut microbiota development is influenced by multiple factors, including the time since birth and the intake of breast milk, and interventions such as probiotics and prebiotics supplementation show promising results in reducing morbidity and mortality in this population. These findings underscore the need for future research to understand the long-term health impacts of these interventions and for further strategies to enrich the gut microbiome of formula-fed and preterm infants.
Development of a Culinary Medicine Curriculum to Support Nutrition Knowledge for Gastroenterology Fellows and Faculty
Authors: Lindsay Karen L. , Kennedy Jennifer , Kim Daniel , Kalra Ankush , Parekh Nimisha K.
Published: January 2024

Gastroenterologists encounter many nutrition-related disorders in their practice, yet the nutritional needs of patients with chronic gastrointestinal (GI) and liver disease are largely unaddressed by treating physicians, due to suboptimal nutrition education. To address this gap, we developed and piloted a culinary medicine course for a GI fellowship training program. The objective of this study is to describe the development, implementation, and acceptability of the course. A registered dietitian, a chef instructor, and a gastroenterology clinical professor trained in culinary medicine developed the four-class tailored curriculum and delivered the classes remotely. Each class had a theme related to commonly encountered GI disorders and included hands-on meal preparation, a nutrition lecture, and a patient case study discussion. Post-course feedback surveys were disseminated. Twenty-three GI physicians enrolled in the course and the attendance rates in classes 1–4 were 83%, 65%, 61%, and 48%, respectively. Among 15 completed feedback surveys, 80% reported that the class contents were either moderately or extremely useful and all endorsed the curriculum for other gastroenterologists. Future studies of culinary medicine programs tailored to medical specialties should identify strategies to maintain engagement and assess the impact on nutrition knowledge, competencies, and translation of these new skills to clinical practice.
The Impact of Combined Nutrition and Exercise Interventions in Patients with Chronic Kidney Disease
Authors: de Geus Manon , Dam Manouk , Visser Wesley J. , Ipema Karin J. R. , de Mik-van Egmond Anneke M. E. , Tieland Michael , Weijs Peter J. M. , Kruizenga Hinke M.
Published: January 2024

Combined nutrition and exercise interventions potentially improve protein-energy wasting/malnutrition-related outcomes in patients with chronic kidney disease (CKD). The aim was to systematically review the effect of combined interventions on nutritional status, muscle strength, physical performance and QoL. MEDLINE, Cochrane, Embase, Web of Science and Google Scholar were searched for studies up to the date of July 2023. Methodological quality was appraised with the Cochrane risk-of-bias tool. Ten randomized controlled trials (nine publications) were included (334 patients). No differences were observed in body mass index, lean body mass or leg strength. An improvement was found in the six-minute walk test (6-MWT) (n = 3, MD 27.2, 95%CI [7 to 48], p = 0.008), but not in the timed up-and-go test. No effect was found on QoL. A positive impact on 6-MWT was observed, but no improvements were detected in nutritional status, muscle strength or QoL. Concerns about reliability and generalizability arise due to limited statistical power and study heterogeneity of the studies included.
Non Breast-Milk-Fed Very Preterm Infants Are at Increased Risk of Iron Deficiency at 4–6-Months Corrected Age: A Retrospective Population-Based Cohort Study
Authors: Power Grace , Morrison Lisa , Kulkarni Ketan , Barr Hudson , Campbell-Yeo Marsha , Singh Balpreet , Stratas Alexandra , Landry Carmen , Higgins Michelle , Ghotra Satvinder
Published: January 2024

Iron supplementation is routinely recommended for breast-milk-fed preterm infants. However, the Canadian Pediatric Society recommends no additional iron supplementation for preterm infants fed primarily with iron-rich formula. Other pediatric societies don’t provide specific guidance on supplemental iron for formula-fed preterm infants. This study investigated how feeding type influences iron status of very preterm infants at 4–6-months corrected age (CA). A retrospective cohort study was conducted using a population-based database on all very preterm infants (<31 weeks gestational age) born in Nova Scotia, Canada from 2005–2018. Information about feeding type, iron intake from formula, supplemental iron therapy and iron status at 4–6-months CA was extracted. Iron deficiency (ID) was defined as serum ferritin <20 and <12 µg/L at 4-and 6-months CA, respectively. Of 392 infants, 107 were “breast-milk-fed” (exclusively or partially) and 285 were “not breast-milk-fed” (exclusively fed with iron-rich formula) at 4–6-months CA. Total daily iron intake was higher in the non-breast-milk-fed group (2.6 mg/kg/day versus 2.0 mg/kg/day). Despite this, 36.8% of non-breast-milk-fed infants developed ID versus 20.6% of breast-milk-fed infants. ID is significantly more prevalent in non-breast-milk-fed infants than breast-milk-fed infants despite higher iron intake. This suggests the need to revisit recommendations for iron supplementation in non-breast-milk-fed preterm infants.
Mandibular Fracture following Dental Implant Protocol: Clinical Report and One-Year Follow-Up
Authors: Andreucci Calber Artur , Martins Murillo , Andreucci Carlos Aurelio
Published: January 2024

Bone fractures following mandibular dental implant protocols associated with diagnosed osteoporosis are rare in the literature. We present a case in which a 55-year-old male patient with no previous medical history presented to the emergency department with pain in the left mandibular parasymphysis and gingival bleeding. Clinical examination revealed crepitus, mandibular mobility, and clinical signs of localized fracture and infection. Further radiographs confirmed a mandibular fracture in the region of the alveolus of tooth 34 and four implants placed in the mandible as part of the patient’s immediate implant protocol. The infection developed into osteomyelitis, which was treated with a combination of antibiotics. After the infectious process had been eradicated, new complementary tests were carried out, which revealed that the patient had osteoporosis. Oral rehabilitation treatment and calcium replacement were carried out under specialist medical supervision. The importance of proper planning and clinical assessment of the patient is discussed, and the proposed long-term management of the case has been carried out.
Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration
Authors: Djuris Jelena , Cvijic Sandra , Djekic Ljiljana
Published: January 2024

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug’s performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure–permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques.
Antipsychotics and Risks of Cardiovascular and Cerebrovascular Diseases and Mortality in Dwelling Community Older Adults
Authors: Perreault Sylvie , Boivin Proulx Laurie-Anne , Brouillette Judith , Jarry Stéphanie , Dorais Marc
Published: January 2024

This study aims to investigate the effect of antipsychotic agents on cardiovascular and cerebrovascular diseases (CVD/CEV) and mortality risks in the older population living in a community. A cohort of 42,650 new users of antipsychotic agents was built using Quebec healthcare databases (1998–2011). The outcomes were CVD/CEV and mortality incidence in 5 years of follow-up in the total cohort, sub-cohort of patients with no schizophrenia/dementia, sub-cohort with schizophrenia, and sub-cohort with dementia. Comparisons were made between the new users who continued the treatment (adherent level ≥ 60%) vs. those ceasing treatment (adherence level < 60%) using inverse probability of treatment weighting and Cox models. Comparing high adherence vs. low levels, CVD/CEV risk was increased by 36% in the sub-cohort with schizophrenia for atypical antipsychotic users and by 25% in the sub-cohort with dementia for typical antipsychotic users. An increasing mortality risk of 2- to 3-fold was linked with the typical antipsychotic use in all cohorts except the sub-cohort with schizophrenia; in addition, mortality risk is linked with the use of high vs. low doses. Antipsychotics were not linked with CVD/CEV risk, except for atypical antipsychotics in patients with schizophrenia and typical antipsychotics in patients with dementia. The mortality risk was linked with the use of typical antipsychotics and the dose used.
Changes in Epidemiology and Antibiotic Prescription of Influenza: Before and after the Emergence of COVID-19
Authors: Rus Mihai Aronel , Ghițoaica Bogdan , Lazăr Andrei Lucian , Man Maria Ancuța , Briciu Violeta Tincuța , Muntean Monica Iuliana , Leucuța Daniel Corneliu , Lupșe Mihaela Sorina
Published: January 2024

Background: The appearance of COVID-19 had a major impact on healthcare and the epidemiology of other diseases. Following the cessation of non-pharmacologic interventions destined to limit the spread of COVID-19, influenza reemerged. The aim of this study was to compare the pre-pandemic influenza seasons with the influenza seasons after the emergence of the COVID-19 pandemic, and to identify differences in terms of clinical characteristics, risk factors, complications, outcomes, and antiviral and antibiotic treatments. Methods: We conducted a retrospective cohort study from the Teaching Hospital of Infectious Diseases database in Cluj-Napoca, Romania. We analyzed four pre-pandemic seasons and the seasons after the onset of COVID-19. We included adult patients hospitalized with confirmed influenza between October 2016 and August 2023. Variables such as age, sex, duration of hospitalization, severity, clinical manifestations, comorbidities, and Charlson comorbidity index were assessed. Results: A total of 941 patients were included in the analysis. The percentage of severe influenza was similar in both groups, but mortality from influenza was significantly lower after 2022. Virtually all patients were prescribed antivirals; antibiotic prescriptions decreased in the post-COVID-19 influenza seasons. Conclusion: The present study suggests that influenza seasons after 2022 had lower mortality and attenuated clinical presentation.
Comparison and Analysis of Antibiotic Consumption in Two Italian Hospital Settings in Relation to the Fight of Antimicrobial Resistance
Authors: Ferrara Francesco , Pasquinucci Roberta , Capuozzo Maurizio , Polito Giacomo , Bagaglini Gabriele , Vaccaro Marcello , Coluccia Adriana , Langella Roberto , Trama Ugo , Nava Eduardo , Zovi Andrea
Published: January 2024

Introduction: The emergence and spread of drug-resistant pathogens due to the improper use of antibiotics have become increasingly apparent in recent years. Objective: This retrospective comparative analysis aimed to assess and compare antibiotic prescription trends in Italy across two different regions based on geographic area and healthcare structure. One region represents a large hospital institution, while the other represents a populous local Italian health agency. The study also examined the impact of documented antibiotic stewardship programs and efforts to promote responsible antibiotic use at all levels, in alignment with international goals. Antibiotic consumption data were collected from the Umberto I Polyclinic Hospital and the ASL Napoli 3 South Local Health Agency. Methods: To compare consumption between regions, a standardized comparison using the Defined Daily Dose (DDD) was employed. The internal management system of each healthcare facility records all prescriptions and drug dispensations, and these data were extrapolated for this retrospective study. Results: A comparative assessment between the first half of 2022 and 2023 (January–June) highlighted a significant increase in beta-lactam antibiotic consumption, showing a twofold rise compared to the previous year’s term. Regarding prescription averages, there was a noticeable increase of +29.00% in hospitalizations and +28.00% in hospital discharges within the ASL Napoli 3 South. Conversely, at Policlinico Umberto I, there was a marginal increase of +1.60% in hospitalizations and a decrease of −7.40% in hospital discharges. Conclusions: The study offers valuable insights into expenditure patterns and antibiotic consumption, underscoring the need for enhanced prescribing practices and awareness campaigns to address the issue of antibiotic resistance. The findings stress the importance of implementing international guidelines to combat the growing threat of antibiotic resistance and ensure the effective management of infectious diseases.
Rescue Therapy for Supratherapeutic Concentrations of Calcineurin Inhibitors Using Potent Cytochrome P450 Inducers
Authors: Duwor Seth , Enthofer Katharina , Ganter Christoph , Poudel Prabin , Svarin Anna , Kullak-Ublick Gerd A.
Published: January 2024

Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity.
“My Addiction Doesn’t Define Me”—Experiences of Stigma among Mothers with Opioid Use Disorder
Authors: Bakos-Block Christine , Yatsco Andrea , Cohen A. Sarah , Vega Francine , Champagne-Langabeer Tiffany
Published: January 2024

Opioid use in women has increased by 300% since 1999, and opioid use disorder among pregnant women has quadrupled. The stigma of substance use disorder is a significant barrier to treatment, especially among women. The purpose of this study was to explore the experiences and perceptions of stigma among mothers and the underlying themes. (1) Background: To understand the stigmatization of women with substance use disorders, we interviewed mothers in recovery from opioid use disorder. (2) Methods: Qualitative methods and descriptive analysis was used to extrapolate themes related to the experienced stigma. (3) Results: A total of 20 mothers in recovery from opioid use disorder were interviewed and three main themes emerged from the data: internal stigma, external stigma, and healing from stigma. (4) Conclusion: The examination of stigma is important in reducing its effect on all individuals with substance use disorders, and it is important to understand gender inequities.
Piperacillin/Tazobactam Co-Delivery by Micellar Ionic Conjugate Systems Carrying Pharmaceutical Anions and Encapsulated Drug
Authors: Niesyto Katarzyna , Mazur Aleksy , Neugebauer Dorota
Published: January 2024

Previously obtained amphiphilic graft copolymers based on [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA) ionic liquid were used as the matrices of three types of nanocarriers, i.e., conjugates with ionic piperacillin (PIP) and micelles with tazobactam (TAZ), which represented single systems, and dual systems bearing PIP anions and encapsulated TAZ for co-delivery. The exchange of Cl anions in TMAMA units with PIP ones resulted in a yield of 45.6–72.7 mol.%. The self-assembling properties were confirmed by the critical micelle concentration (CMC), which, after ion exchange, increased significantly (from 0.011–0.020 mg/mL to 0.041–0.073 mg/mL). The amphiphilic properties were beneficial for TAZ encapsulation to reach drug loading contents (DLCs) in the ranges of 37.2–69.5 mol.% and 50.4–80.4 mol.% and to form particles with sizes of 97–319 nm and 24–192 nm in the single and dual systems, respectively. In vitro studies indicated that the ionically conjugated drug (PIP) was released in quantities of 66–81% (7.8–15.0 μg/mL) from single-drug systems and 21–25% (2.6–3.9 μg/mL) from dual-drug systems. The release of encapsulated TAZ was more efficient, achieving 47–98% (7.5–9.0 μg/mL) release from the single systems and 47–69% (9.6–10.4 μg/mL) release from the dual ones. Basic cytotoxicity studies showed non-toxicity of the polymer matrices, while the introduction of the selected drugs induced cytotoxicity against normal human bronchial epithelial cells (BEAS-2B) with the increase in concentration.
Mechanical Characterization of Dissolving Microneedles: Factors Affecting Physical Strength of Needles
Authors: Ando Daisuke , Miyatsuji Megumi , Sakoda Hideyuki , Yamamoto Eiichi , Miyazaki Tamaki , Koide Tatsuo , Sato Yoji , Izutsu Ken-ichi
Published: January 2024

Dissolving microneedles (MNs) are novel transdermal drug delivery systems that can be painlessly self-administered. This study investigated the effects of experimental conditions on the mechanical characterization of dissolving MNs for quality evaluation. Micromolding was used to fabricate polyvinyl alcohol (PVA)-based dissolving MN patches with eight different cone-shaped geometries. Axial force mechanical characterization test conditions, in terms of compression speed and the number of compression needles per test, significantly affected the needle fracture force of dissolving MNs. Characterization using selected test conditions clearly showed differences in the needle fracture force of dissolving MNs prepared under various conditions. PVA-based MNs were divided into two groups that showed buckling and unbuckling deformation, which occurred at aspect ratios (needle height/base diameter) of 2.8 and 1.8, respectively. The needle fracture force of PVA-based MNs was negatively correlated with an increase in the needle’s aspect ratio. Higher residual water or higher loading of lidocaine hydrochloride significantly decreased the needle fracture force. Therefore, setting appropriate methods and parameters for characterizing the mechanical properties of dissolving MNs should contribute to the development and supply of appropriate products.
Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP
Authors: Kinsale Talisa S. , Cottrell Mackenzie L. , Li Linying , Brand Rhonda , Gatto Greg , Luecke Ellen , Norton Chasity , Krovi Archana , Dumond Julie B. , Rao Gauri , Yeshwante Shekhar , Van Horne Brian , Van Der Straten Ariane , Kashuba Angela D. M. , Johnson Leah M.
Published: January 2024

Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL’s unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r2 = 0.95) and Ritger–Peppas (r2 = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp’s PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.
Levofloxacin and Ciprofloxacin Co-Crystals with Flavonoids: Solid-State Investigation for a Multitarget Strategy against Helicobacter pylori
Authors: Fiore Cecilia , Antoniciello Federico , Roncarati Davide , Scarlato Vincenzo , Grepioni Fabrizia , Braga Dario
Published: January 2024

In this paper, we address the problem of antimicrobial resistance in the case of Helicobacter pylori with a crystal engineering approach. Two antibiotics of the fluoroquinolone class, namely, levofloxacin (LEV) and ciprofloxacin (CIP), have been co-crystallized with the flavonoids quercetin (QUE), myricetin (MYR), and hesperetin (HES), resulting in the formation of four co-crystals, namely, LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE. The co-crystals were obtained from solution, slurry, or mechanochemical mixing of the reactants. LEV∙QUE and LEV∙MYR were initially obtained as the ethanol solvates LEV∙QUE∙xEtOH and LEV∙MYR∙xEtOH, respectively, which upon thermal treatment yielded the unsolvated forms. All co-crystals were characterized by powder X-ray diffraction and thermal gravimetric analysis. The antibacterial performance of the four co-crystals LEV∙QUE, LEV∙MYR, LEV2∙HES, and CIP∙QUE in comparison with that of the physical mixtures of the separate components was tested via evaluation of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). The results obtained indicate that the association with the co-formers, whether co-crystallized or forming a physical mixture with the active pharmaceutical ingredients (API), enhances the antimicrobial activity of the fluoroquinolones, allowing them to significantly reduce the amount of API otherwise required to display the same activity against H. pylori.