bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of stimulation frequency on isometric and concentric isotonic contractile function in human quadriceps
Authors: Zero Alexander M. , Paris Michael T. , Rice Charles L.
Published: June 2024

In whole human muscle, we showed that the electrically stimulated power-frequency relationship was rightward shifted of the stimulated isometric torque-frequency relationship independent of isotonic load, indicating that higher stimulation frequencies are needed to achieve tetanus. Therefore, interpretations of evoked contractile function differ depending on contraction type (isometric vs. dynamic), load, and frequency. And thus, isometric measures may not be appropriate as a surrogate assessment when evaluating dynamic isotonic contractile function.
The metabolic cost of breathing for exercise ventilations: effects of age and sex
Authors: Kipp Shalaya , Arn Sierra R. , Leahy Michael G. , Guenette Jordan A. , Sheel A. William
Published: June 2024

Here we show that at moderate and high-intensity exercise, older individuals incur a higher cost to breathe than their younger counterparts. However, as individuals age, the sex difference in the cost of breathing narrows. Collectively, our findings suggest that the normative age-related changes in respiratory structure and function, and sex differences in airway anatomy, appear to influence the ventilatory responses to exercise and the oxygen cost to breathe.
The Multifaceted Contributions of Community‐Based Breeding Program of Bonga Sheep to Flock Dynamics, Animal Performance, and Socio‐economic Benefits of Beneficiaries in Kafa Zone, Ethiopia
Authors: Mamiru Metsafe , Melesse Aberra , Haile Aynalem , Getachew Tesfaye
Published: June 2024

The community‐based breeding program (CBBP) for Bonga sheep was introduced with the objective of improving the productivity of sheep and income of producers. Technical evaluation of the program reported outstanding outcomes in growth and reproductive traits of the animals. Further participatory evaluation allowing farmers to assess the relevance and impact of such programs has been suggested. This paper thus aims to explore the multifaceted contributions of the CBBP of Bonga sheep, emphasizing its flock dynamics, improvements in animal performance, and socio‐economic benefits as perceived by beneficiaries. Data were generated through interviews of 222 (111 CBBP members and 111 nonmembers) randomly selected sheep producers. The survey focused on flock dynamics, improvement in biological and aesthetic traits, and livelihood change of farmers. Logistic regression, ANOVA, and Pearson’s chi‐square were the analysis methods used. Results revealed that CBBP members had better flock size by 42.6% and they had higher numbers of breeding rams, suckling lambs, and breeding ewes in their flock by 60.5%, 54.3%, and 41.6%, respectively, compared to non‐members. The study further showed that members acquired and lost more (<0.001) animals annually than non‐members. About 94.6%, 82.8%, and 81.1% of respondents witnessed the improvement in body size, twinning rate, and survival of lambs, respectively. Likewise, 97.3% of members reported substantial improvement in reproductive traits such as age at first lambing (92.8%) and lambing interval (93.7%). Improvement in aesthetic traits like tail size (92.8%) and coat color (92%) too was reported by the farmers. The CBBP farmers produced, slaughtered, and sold more animals than their non‐CBBP counterparts. They also acquired more income by 60%, which enabled them to store assets and fulfill routine home needs better than non‐members. In conclusion, CBBP positively influenced sheep assets, performance, and marketability, elevating the income and livelihoods of beneficiaries. This underlines the need for expansion of the program to benefit more farmers.
Spatial Variation in Excess Mortality in Mexico during the First 2 Years of the COVID‐19 Pandemic
Authors: Sánchez-Carrillo Christian , Santana Castañeda Giovanna , Santana Juárez Marcela Virginia , Quentin Emmanuelle
Published: June 2024

Background. Excess mortality from all causes is a reliable indicator of the direct or indirect effect of the COVID‐19 pandemic. This study aimed to estimate excess deaths in Mexico during the first 2 years of the COVID‐19 pandemic and to examine the spatial and temporal variations in relative excess mortality at the subnational level. Materials and Methods. This ecological study was based on publicly available governmental data and compared 2020–2021 total deaths with the average number of deaths in 5 previous years. The relative excess mortality was then analyzed as a function of time (waves) and space (distribution maps). Results. Between January 1, 2020 and December 31, 2021, Mexico recorded 2,136,611 deaths out of 1,385,240 expected deaths, representing 751,371 excess deaths (95% CI: 709,948.267–792,793.732). During this period, we identified three waves of excess deaths, the second being the most severe, with 109,846 more deaths than expected. When examining each wave, spatial variation in relative excess mortality was identified, with all 32 states experiencing more deaths than expected (values > 0%). However, in Mexico City, Tlaxcala and Queretaro recorded values greater than 100% at different times. Conclusions. During the first 2 years of the COVID‐19 pandemic (2020–2021), the number of deaths increased excessively in the 32 states. The spatial variation in relative excess mortality in each observed wave demonstrated that the response to the effects of the pandemic in Mexico differed due to various factors, such as prevention measures against COVID‐19, the beginning of the vaccination campaign, and pandemic fatigue which caused a certain relaxation and therefore a return of tourism, mainly in coastal areas. Therefore, it is necessary to implement equitable policies for the care of particularly affected areas.
Strategies to Enhance Access and Utilization of Health Services by Older Population: A Comprehensive Scoping Review
Authors: Hajizadeh Alireza , Babaei Aghbolagh Maryam , Babaei Golnoosh , Tajvar Maryam , Heydari Mahdiyeh
Published: June 2024

Objective. Improving access to and utilization of healthcare services are necessary factors for improving the overall health of the ageing population. Accordingly, strategies to improve the access to health services should be considered. The aim of this review study was to identify, categorize, and synthesize the interventions suggested to improve access and utilization of health services by the ageing population. Methods. This scoping review was conducted based on the framework established by Arksey and O’Malley. To find relevant studies, searches were conducted in various databases such as Medline (PubMed), Scopus, Science Direct, and ProQuest, using appropriate keywords ranging from 2000 to 2022. The authors independently screened search results, extracted the data, and synthesized the data from the included studies. A framework analysis identified key interventions based on the framework established by the World Health Organization (WHO) in 2000. Results. Of the 8286 initially retrieved studies, only 79 were eligible for the final inclusion as they met the selection criteria. Results showed out of the 22 countries who have utilized some strategies the United States have implemented the most interventions (27 studies) , with service delivery enhancement being the most commonly area of action(23 items), followed by improvement in financing, stewardship, and creating recourse (12, 11, and 11 items, respectively) functions of health services. Conclusion. This scoping review compiled a range of interventions aimed at enhancing older adults’ access to and utilization of health services. While most of these interventions have been implemented in high‐income countries, other nations can adapt their effective approaches to their unique contexts.
Exploring the Impact of a Railway Corridor on Intermodal Service Networks and Industrial Location: A Land‐Use Transport Interaction Modeling Approach
Authors: Wang Zongbao , Zhong Ming , Pan Xiaofeng , Li Linfeng
Published: June 2024

Given the intricate interactions among the economy, land use, and transportation, it is important to assess the multifaceted impacts of the freight corridor on these systems. This study introduces a land‐use transport interaction (LUTI) modeling approach to quantify the scope and magnitude of the impact of a railway corridor on the distribution of freight flows within an intermodal service network and industrial locations. The proposed model operates on two levels to analyze regional interactions between industrial locations and transportation dynamics. The upper‐level model simulates the industrial interactions among regions. Meanwhile, at the lower level, interregional trade connections are converted into freight demand, which is then assigned to a transportation network. Calibration of the trip length distribution is achieved by integrating data from truck GPS, railway waybills, and ship visas to develop a connection between the intermodal service networks and economic systems. The improved model offers a LUTI modeling approach tailored for the context of intermodal transportation, considering economies of scale associated with intermodal transportation services. It can not only analyze the impact of a freight corridor on freight flow redistribution but also identify areas that may be adversely affected by such redistributions. Taking the Yangtze River Economic Belt (YREB) as a case study, study results indicate significant enhancements in the economies of scale of railway services within the middle part of the YREB due to the development of the Haoji Railway Corridor (HRC). These changes significantly influence the location utility of industrial activities, with the coal processing activities demonstrating the most sensitivity to the evolving transportation dynamics. This study offers insights into LUTI modeling approaches specifically tailored for intermodal transportation.
Enhancing Physicochemical Characteristics of Donkey Meat through High‐Voltage Electrostatic Stimulation during Acid Excretion
Authors: Zhang Xinzhuang , Gong Shuqi , Lin Jingkai , Dugarjaviin Manglai
Published: June 2024

To investigate the impact of high‐voltage electrostatic stimulation on the quality of donkey meat, ten 30‐month‐old Dezhou donkeys (each weighing 250 ± 50 kg) were selected. Following slaughter, longissimus dorsi (LD) samples from both left and right carcasses were collected. The control group refrigerated the right muscle in a 0–4°C refrigerator for normal acid excretion. Meanwhile, the high‐voltage electrostatic group subjected the left muscle to high‐voltage electrostatic stimulation (30000 V) for 60 s before refrigerating it in the same conditions for acid excretion. The study showed that at the 1st, 6th, and 24th h of acid excretion, the high‐voltage electrostatic group exhibited significantly lower pH levels than the control group (P<0.05). Furthermore, a∗ values in the high‐voltage electrostatic group showed an increasing trend relative to the control group at the 6th and 24th h of acid excretion (P = 0.0751, P = 0.0860). With increasing acid excretion time, both treatment groups displayed increased PV and TBARS values. At 48 and 72 h, the PV values in the high‐voltage electrostatic group were significantly lower than those in the control group (P < 0.05). As acid excretion time increased, T‐AOC, SOD, and GSH‐Px in both groups decreased. However, the high‐voltage electrostatic group consistently exhibited higher antioxidant enzyme activity than the control group at all time points. SOD and GSH‐Px activity in the high‐voltage electrostatic group showed an increasing trend at 48 h of acid excretion (P = 0.0838, P = 0.0860). At 72nd h of acid excretion, the shear force of donkey meat in the high‐voltage electrostatic group was significantly lower than that in the ordinary treatment group (P < 0.05). With increasing acid excretion time, the MFI of both treatment groups gradually increased. In particular, at the 1st and 48th h of acid excretion, the MFI of the high‐voltage electrostatic group was significantly higher than that of the ordinary treatment group (P < 0.05). Following high‐voltage electrostatic stimulation, ultrastructure images of donkey meat at 6 and 72 h revealed numerous contractions and stretching bands. Therefore, this stimulation significantly improved the tenderness of donkey meat, reduced the oxidation rate of donkey meat, and improved the quality of donkey meat.
The Effects of Temperature and Humidity on Electrostatic Changes in Respirators and Their Filtration Efficiency
Authors: Kim Jimin , Park Jongmin , Tsai Perng-Jy , Yoon Chungsik
Published: June 2024

The filtering mechanism of respirators involves static electricity and physical mechanisms, such as inertial impaction, interception, and diffusion. Static electricity is used to reduce pressure resistance, but electrostatic effects and the environmental variables that affect them are not well studied. Therefore, this study evaluated the contribution of static electricity to the filtration efficiency of respirators and the effects of changes in temperature and humidity on static electricity and the resulting filtration efficiency. Eight respirators from four manufacturers—four for workers (1st class respirators) and four for citizens (KF‐94 respirators)—were selected, all of which met legal standards in Korea. The filtration efficiency and pressure drop were evaluated at baseline and after removing static electricity with isopropanol. To study the effects of humidity and temperature on the efficiency of the respirators, the respirators were exposed to 30, 50, and 98% humidity while the temperature was fixed at 25°C and to temperatures of −30, 25, and 70°C while the humidity was fixed at 50%. Static electricity was measured using a surface‐potential meter, and the filtration efficiency was measured using NaCl and paraffin oil. When static electricity was removed from the 1st class and KF‐94 respirators, the filtration efficiency decreased by 21.7% and 19.5%, respectively. Humidity affected the change in static electricity slightly more than temperature, but since not all static electricity was removed, the filtration efficiency was not affected greatly. The changes in static electricity and filtration efficiency due to humidity were significant, but this was because the standard deviation was small. Even under 98% humidity, the filtration efficiency was only 1–2% lower than that at 30% humidity and still met the 94% filtration efficiency criterion for respirators.
A New Insight into Finding the Efficient and Reliable Number and Arrangement of Tubes inside a Shell and Tube Latent Heat Storage Unit
Authors: Bahrami Hamid-Reza , Allahdadi Omid
Published: June 2024

This study examines the impact of different circular shell and tube heat exchanger configurations on the system charging time. Various configurations will be evaluated, namely A, B, C, and D, with 1, 2, 3, and 4 tubes, respectively. The shell contains a phase change material (N‐eicosane), and the location of tubes changes in each configuration, forming a new case. A total of 38 numerical experiments were conducted using a commercial software to investigate various tube locations and arrangements. While previous studies have primarily focused on total charging time as the fitness measure for different configurations, this study considers the need to achieve high charging levels within limited time windows. Therefore, a configuration that takes longer to charge completely may have a shorter time to reach 90% of charging, making it more reliable. The top configurations were assessed with gold, silver, and bronze rankings based on their agility to reach milestones (at every level of 50%, 80%, and 90% charging). For instance, case C6 achieved a golden ranking for reaching 90% of full charge in about 328 seconds, 12.5% faster (41 seconds) than the efficient configuration (C5) with the minimum total time. However, C6 has a longer total charge time of 516 seconds (about 20% extra time). On the other hand, C5 also has the fastest time for reaching milestones at 50% and 80% of charging, which shows that it responds to the thermal source very rapidly. The results also demonstrate that increasing the tubes significantly decreases total melting time. For instance, the efficient case of type D, D7, takes only about one‐fifth (80% improvement) of the total charging time compared to the base case, A1. Finally, the performance of various cases during the discharge process is also evaluated.
Experimental Bracket Design Performance on Bonding and Polymerization of Orthodontic Composite
Authors: Salgado Alexandre Daher Yunes , Feitosa Victor Pinheiro , Farrapo Manuela Timbó , Rifane Tainah Oliveira , Ribeiro Lara Leal , Oliveira Andressa Silva de , Lomonaco Diego
Published: June 2024

Objective. To evaluate the enamel bonding ability and orthodontic adhesive resin degree of conversion using the experimental bracket design. Material and Methods. Thirteen bovine teeth were used in the study. The experimental bracket was modified with a translucent region in the center of its body. After enamel etching, Orthocem orthodontic adhesive (FGM, Joinville, Brazil) was applied on the bracket base for bonding. The groups were divided as follows (n = 10 per group): (1) control (CB) with standard brackets and (2) spot bracket (SB) with experimental brackets featuring a 0.8 mm translucent region at the center using carbide bur. Shear bond strength (SBS) was evaluated after 24 hours in a universal testing machine and adhesive remnant index (ARI). The degree of conversion (DC) was analyzed using Raman spectroscopy (n = 3 per group). Data were then analyzed using Student’s t‐test and Mann–Whitney statistical methods. Results. The SB group exhibited a higher mean SBS (10.33 MPa) compared to the CB Group (8.77 MPa). However, there was no statistical difference between the groups (p = 0.376). Both SB and CB groups had a mean ARI score of 1. Raman analysis revealed a higher degree of conversion in the SB group (49.3%) compared to the CB group (25.9%). Conclusions. The experimental support showed a higher degree of adhesive conversion, although there was no significant increase in bond strength.
IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer
Authors: Zarei Mehrdad , Hajihassani Omid , Hue Jonathan J. , Loftus Alexander W. , Graor Hallie J. , Nakazzi Faith , Naji Parnian , Boutros Christina S. , Uppin Vinayak , Vaziri-Gohar Ali , Shalaby Akram S. , Asara John M. , Rothermel Luke D. , Brody Jonathan R. , Winter Jordan M.
Published: June 2024

Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).

Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.
Data from Epigenetic Priming by Hypomethylation Enhances the Immunogenic Potential of Tolinapant in T-cell Lymphoma
Authors: Ward George A. , Zhang Zhiqiang , Jueliger Simone , Potapov Ilya S. , Davis Matthew P. , Boxall Adam R. , Taylor Jason , Keer Harold , Biondo Andrea , Lyons John F. , Sims Martin , Smyth Tomoko
Published: June 2024

Abstract
Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from patients with peripheral TCL treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in IFN signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.
Significance:
The IAP antagonist tolinapant can induce necroptosis, a key immune-activating event, in TCL. Combination with DNA hypomethylation enhances tolinapant sensitivity and primes resistant cells by re-expressing necrosome proteins. In addition, this combination leads to increases in genes involved in IFN signaling and neoantigen expression, providing further molecular rationale for this novel therapeutic option.
Advancing Transfusion Medicine through Raman Tweezers Spectroscopy: A Review of Recent Progress and Future Perspectives
Authors: Nelliat Mithun , Mohan Ganesh , Lukose Jijo , Shastry Shamee , Chidangil Santhosh
Published: June 2024

Background: Raman tweezers spectroscopy (RTS) is a powerful tool that combines optical tweezers and Raman spectroscopy to study single living cells. RTS has become increasingly popular in biomedical and clinical research due to its high molecular specificity and sensitivity, which enable the study of cell viability, cell deformation, cell-protein, cell-nanoparticle, cell-cell interaction, etc. In transfusion medicine, RTS can give valuable insights into the storage lesions and effects of various preservatives and intravenous fluids on blood cells. Summary: By analyzing the Raman spectra of individual blood cells, RTS can detect changes in the cellular blood components which can be used to monitor the quality of blood products during storage and transfusion. The present review article highlights the principle and clinical applications of RTS in transfusion medicine. Key Messages: Raman spectroscopy is a versatile analytical method for biomedical research. Combining the Raman spectroscopy method with the optical tweezers technique will allow us to explore the dynamics of live single cells in their physiological medium.
Assessments of the Quality, Understandability, and Actionability of Arabic Web-Based Content on Oral Cancer and Precancerous Disorders
Authors: Alsoghier Abdullah
Published: June 2024

Introduction: Empowering high-risk individuals to oral cancer and potentially cancerous disorders with written health information is needed for early detection of mucosal changes and self-care. This infodemiological study aimed to assess the web-based and Arabic content related to these disorders when quickly searching the internet. Methods: The top 20 websites yielded from each of the 7 searches were initially screened for eligibility (oral cancer, leukoplakia, erythroplakia, oral submucous fibrosis, oral lichen planus, oral lichenoid lesions, and oral graft-versus-host disease). These related to search terms written for healthcare consumers were assessed for website characteristics, quality criteria (4 JAMA benchmarks [authorship, attribution, disclosure, and currency] and Health on the Net seal), and understandability and actionability (Patient Education Materials Assessment Tool). The latter was scored from 0 to 100% based on meeting the criteria. Data representation and analysis were performed using Microsoft Excel and IBM SPSS. Results: Of the screened 140 websites, 70 (50%) were included in the analysis for all search terms, with oral cancer and lichen planus yielding the most relevant websites (19 and 17, respectively). Commercial and not-for-profit organisations created 50% of the analysed websites. The analysed content was mainly presented as medical facts (71%), often without presenting audiovisual aids (61%). The average JAMA benchmarks achieved per website were 2.5 out of 4, of which “disclosure” and “attribution” were often missing in more than 70% of these websites. Content related to oral cancer and leukoplakia considerably obtained higher average quality benchmarks than other disorders. Acceptable levels for understandability and actionability (≥70%) were found in 52% and 15% of all materials. Conclusion: Patients with these oral disorders seeking web-based information before or after healthcare visits are unlikely to find sufficient and reliable content they can understand and act upon accordingly. Thus, healthcare stakeholders may consider creating and integrating reliable information resources within the health services to support the patients’ informed decision-making on their care plans and to maintain value-based healthcare services in line with Saudi Arabia’s healthcare transformation vision for 2030.
LncRNA GABPB1-IT1 is upregulated in ischemia-induced acute kidney injury and downregulates miR-204-5p to promote hypoxia-induced human renal proximal tubular epithelial cell apoptosis
Authors: Feng Fang , Zhang Ru , Long Lihong
Published: June 2024

Introduction: The present study investigated the role of long non-coding RNA (lncRNA) GABPB1-IT1 in ischemia-induced acute kidney injury (AKI).
Methods: The expression of GABPB1-IT1 in plasma of patients with ischemia-induced AKI and healthy controls was detected by RT-qPCR. GABPB1-IT1 and miR-204-5p were overexpressed in human renal proximal tubular epithelial cells (HRPTEpCs), followed by RT-qPCR to assess the overexpression effect and the regulatory relationship between GABPB1-IT1 and miR-204-5p. Methylation-specific PCR (MSP) was performed to assess the promoter methylation status of miR-204-5p. Additionally, cell apoptosis assay was carried out to evaluate the correlation between miR-204-5p and GABPB1-IT1 in the context of hypoxia-induced apoptosis of HRPTEpCs.
Results: GABPB1-IT1 was upregulated in plasma of patients with ischemia-induced AKI. In HRPTEpCs, hypoxia upregulated the expression of GABPB1-IT1. MiR-204-5p was downregulated in ischemia-induced AKI, and the expression of miR-204-5p was inversely correlated with GABPB1-IT1. In HRPTEpCs, overexpression of GABPB1-IT1 decreased the expression levels of miR-204-5p and increased miR-204-5p gene methylation. In addition, overexpression of GABPB1-IT1 reduced the inhibitory effects of miR-204-5p on the apoptosis of HRPTEpC induced by hypoxia. Furthermore, overexpression of GABPB1-IT1 promoted kidney injury, renal tissue injury scores, and the level of serum creatinine. However, miR-204-5p had the opposite effect.
Conclusion: GABPB1-IT1 was upregulated in ischemia-induced AKI and may induce hypoxia-induced apoptosis of HRPTEpC by methylation of miR-204-5p.
Effects and Safety of Growth Hormone Treatment in Six Children with Pycnodysostosis
Authors: Renes Judith S. , Sas Theo C.J. , Clement-de Boers Agnes , Zwaveling-Soonawala Nitash , Hannema Sabine E. , van der Velden Janiëlle A.E.M. , van der Kaay Daniëlle C.M. , Hokken-Koelega Anita C.S.
Published: June 2024

Introduction: Pycnodysostosis is an extremely rare skeletal dysplasia caused by cathepsin K deficiency. It is characterized by extreme short stature with adult height (AH) in males typically less than 150 cm and in females less than 130 cm. Our objective was to evaluate the effect and safety of growth hormone (GH) treatment in 6 patients with pycnodysostosis treated according to the Dutch national pycnodysostosis guideline. Case Presentation: Six subjects (4 boys, 2 girls) presented with pycnodysostosis, treated with GH 1.4 mg/m2/day (∼0.046 mg/kg/day) for ≥1 year. Median (IQR) age at start of GH was 10.4 years (5.7; 12.2) and median height 113.5 cm (93.3; 129.3) (−4.2 SDS [−4.8; −3.6]). All children were prepubertal at start of GH. After 1 year of GH, median height gain was 7.6 cm (6.5; 8.5) (0.3 SDS [−0.3; 0.7]). Three children are still treated with GH, and the other three subjects reached AH: 1 boy reached an AH of 157.0 cm (−3.8 SDS) after 6.3 years of GH, and 2 girls reached an AH of 138.5 cm (−5.2 SDS) after 4.8 years of GH and 148.0 cm (−3.6 SDS) after 6.4 years of GH, respectively. This last girl received additional GnRH analogue treatment. In all subjects, height SDS remained stable or improved during and after GH treatment. No serious adverse advents were found. Serum IGF-I remained below the +2 SDS. Conclusion: Our data suggest that GH may prevent the decline in height which can be observed in children with pycnodysostosis. Further research is needed to confirm this. Also, the effect of other growth-promoting strategies such as treatment with an additional GnRH analogue warrants further investigation.
Dietary Components in the Pathogenesis and Prevention of Type 1 Diabetes in Children
Authors: Neuman Vit , Plachy Lukas , Pruhova Stepanka , Sumnik Zdenek
Published: June 2024

Background: Type 1 diabetes (T1D) is a disease closely linked to nutrition and modifications in various dietary components have been part of the effort to prevent or slow the progression of the disease even before the discovery of insulin. Summary: The scientific focus in the prevention or progression modification of T1D is mostly centered on four dietary compounds and their modifications – gluten and its omission, vitamin D supplementation, omega-3 fatty acids supplementation, and decreasing of the amount of ingested carbohydrates. The aim of this narrative review was to provide an overview of nutritional interventions studied in children either as preventive methods or as modifiers in the early stages of T1D from autoantibody positive individuals to persons with newly diagnosed T1D. Key Messages: Our review shows that dietary modifications in various dietary components might be useful but none of them seems to provide universal effects in T1D prevention or progression modification. More research is therefore needed with focus on promising modes of action of individual dietary components.
Endovascular Treatment for Cerebral Venous Thrombosis: Applying Lessons Learned from Clinical Trials of Endovascular Treatment in Acute Arterial Ischemic Stroke
Authors: Ospel Johanna Maria , Singh Nishita , Nguyen Thanh N. , Yaghi Shadi , Goyal Mayank , Hill Michael D. , Field Thalia S.
Published: June 2024

Background: Cerebral venous thrombosis (CVT) is a rare but severely disabling form of stroke. Acute treatment mainly consists of medical management, since there is no robust evidence suggesting the benefit of endovascular treatment for CVT. Given the relative lack of data to guide acute treatment decision-making, CVT treatment decisions are mostly made on a case-by-case basis. In some ways, the current status quo of endovascular treatment for CVT resembles the state of endovascular treatment for acute ischemic stroke before the wave of major positive large vessel occlusion endovascular treatment trials in 2015. Summary: The current state of evidence with regard to endovascular CVT treatment is summarized, parallels to acute ischemic stroke are drawn, and it is discussed how the lessons learned from the evolution of acute ischemic stroke endovascular treatment (EVT) trials could be applied to designing a trial of endovascular treatment for CVT. The review ends by outlining possible scenarios for the future of endovascular CVT treatment. Key Messages: CVT is a serious disease, affecting young patients and their families, and harbors a considerable social and economic burden. Working toward high-level evidence for the best possible treatment strategy and exploring a possible role for EVT to improve outcomes in CVT needs to remain a high priority in stroke research.
Potensi Daun Kelor sebagai Herbal untuk Penyakit Hati Stadium Lanjut
Authors: Supriono Supriono , Amaliyah Suci
Published: June 2024

Dalam buku "Potensi Daun Kelor sebagai Herbal untuk Penyakit Stadium Lanjut", penulis mengajak pembaca untuk menjelajahi potensi luar biasa tanaman kelor (Moringa oleifera) sebagai herbal yang memiliki potensi terapi bagi penyakit hati stadium lanjut. Penyakit hati merupakan salah satu masalah kesehatan global yang mempengaruhi jutaan orang di seluruh dunia. Penelitian yang mendalam dan temuan ilmiah terkini mulai mengungkap bahwa daun kelor memiliki peran penting dalam tatalaksana penyakit hati yang kompleks. Hati merupakan organ tubuh manusia yang sangat vital. Kondisi patologis yang awalnya asimptomatis dan selanjutnya berkembang menjadi sirosis atau kanker hati menjadi problem kesehatan dunia karena angka morbiditas dan mortalitasnya tinggi. Patogenesisnya sangat komplek, melibatkan banyak sel, sitokin dan faktor pertumbuhan, sehingga dalam pengobatannya diperlukan agen yang bekerja pada beberapa titik tangkap. Kelor sebagai herbal memiliki kandungan banyak senyawa (multi compound) bioaktif yang dapat bekerja memutus patogenesis penyakit hati yang kompleks. Buku ini mengajak pembaca untuk mengenali potensi luar biasa daun kelor sebagai obat herbal untuk penyakit hati stadium lanjut. Penulis menghadirkan pengetahuan yang mendalam tentang daun kelor, kandungan senyawa yang terkandung di dalam ekstraknya, konsep obat dan herbal, perkembangan terkini tatalaksana penyakit hati stadium lanjut dan hasil studi awal penulis dalam mengeksplor kemampuan kelor untuk mencegah penyakit hati stadium lanjut yang dilakukan pada hewan coba. Dalam buku ini, pembaca akan menemukan bukti ilmiah yang meyakinkan mengenai efektivitas daun kelor sebagai obat herbal dalam tatalaksana penyakit hati melalui mekanisme multitarget yang bekerja pada beberapa titik tangkap.
Espaço geográfico e forças produtivas: argumentos em defesa da centralidade do conceito de técnica em Geografia
Authors: Costa Bruno Moreira Riani
Published: June 2024

Neste artigo argumenta-se em defesa da centralidade da técnica no arcabouço metodológico geográfico. Para tanto, é sucintamente exposta parte da construção teórica de Milton Santos – cuja concepção de espaço geográfico norteia a presente exposição – em que o fenômeno técnico é discutido. Esta abordagem é complementada pela recuperação de formulações marxistas que destacam a primazia explicativa das forças produtivas: para tanto, recorre-se ao trabalho de G. A. Cohen em sua explicação tecnológica da história. Neste quadro, é indicado como pode ser detectada certa proximidade entre o conceito de técnica em Milton Santos e a categoria de forças produtivas tal como mobilizada por Gerald Cohen. É apresentado o entendimento de que as forças produtivas, em específico, e a técnica, em geral, devem ser tomadas como elementos relevantes para a abordagem crítica em geografia, constituindo-se enquanto princípio fecundo de método na compreensão do espaço, permitindo que a singularidade de um objeto técnico – em sua forma e função específica – seja considerada com referência às práticas sociais que lhes dão vida, abrindo margem para visualização dos processos e estruturas sociais. Também, ao longo da exposição procurou-se responder a algumas críticas endereçadas à proposta de centralidade da técnica em geografia encontrada no trabalho de Milton Santos.
Genome-Wide Methylation Analysis Reveals a
KCNK3
-Prominent Causal Cascade on Hypertension
Authors: Huang Dandan , Shang Wenlong , Xu Mengtong , Wan Qiangyou , Zhang Jin , Tang Xiaofeng , Shen Yujun , Wang Yan , Yu Ying
Published: June 2024

BACKGROUND:

Despite advances in understanding hypertension’s genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease’s genetic mechanisms.

METHODS:

We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988
T/C
mutant mice using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the
Kcnk3
gene methylation highlighted the mutation’s role in hypertension.

RESULTS:

We discovered that DNA methylation–associated genetic effects, especially in non-cytosine-phosphate-guanine (non-CpG) island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type–specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in
Kcnk3
gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988
C/C
genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the
Kcnk3
gene by attenuating Nr2f2 (nuclear receptor subfamily 2 group F member 2) binding at the enhancer locus.

CONCLUSIONS:

Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation’s potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension’s molecular mechanisms and encourages personalized health care strategies.
Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF
Authors: Dewan Pooja , Shen Li , Pedro Ferreira João , Jhund Pardeep S. , Anand Inder S. , Chandra Alvin , Chiang Lu-May , Claggett Brian , Desai Akshay S. , Gong Jianjian , Lam Carolyn S.P. , Lefkowitz Martin P. , Maggioni Aldo P. , Martinez Felipe , Packer Milton , Redfield Margaret M. , Rouleau Jean L. , van Veldhuisen Dirk J. , Zannad Faiez , Zile Michael R. , Solomon Scott D. , McMurray John J.V.
Published: June 2024

BACKGROUND:

A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction).

METHODS:

In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events.

RESULTS:

Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19;
P
=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype.

CONCLUSIONS:

Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01920711.
Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease
Authors: Lima Posada Ixchel , Soulié Matthieu , Stephan Yohan , Palacios Ramirez Roberto , Bonnard Benjamin , Nicol Lionel , Pitt Bertram , Kolkhof Peter , Mulder Paul , Jaisser Frederic
Published: June 2024

Background

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO‐DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO‐DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes.

Methods and Results

We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD‐related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short‐term finerenone treatment decreased LV end‐diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity.

Conclusions

We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.
Multiplex Imaging for Cell Phenotyping of Early Human Atherosclerosis
Authors: Elishaev Maria , Li Boaz , Zhou Annie , Salim Kevin , Leeper Nicholas J. , Francis Gordon A. , Lai Chi , Wang Ying
Published: June 2024

Background

Previous studies using animal models and cultured cells suggest that vascular smooth muscle cells (SMCs) and inflammatory cytokines are important players in atherogenesis. Validating these findings in human disease is critical to designing therapeutics that target these components. Multiplex imaging is a powerful tool for characterizing cell phenotypes and microenvironments using biobanked human tissue sections. However, this technology has not been applied to human atherosclerotic lesions and needs to first be customized and validated.

Methods and Results

For validation, we created an 8‐plex imaging panel to distinguish foam cells from SMC and leukocyte origins on tissue sections of early human atherosclerotic lesions (n=9). The spatial distribution and characteristics of these foam cells were further analyzed to test the association between SMC phenotypes and inflammation. Consistent with previous reports using human lesions, multiplex imaging showed that foam cells of SMC origin outnumbered those of leukocyte origin and were enriched in the deep intima, where the lipids accumulate in early atherogenesis. This new technology also found that apoptosis or the expression of pro‐inflammatory cytokines were not more associated with foam cells than with nonfoam cells in early human lesions. More CD68
+
SMCs were present among SMCs that highly expressed interleukin‐1β. Highly inflamed SMCs showed a trend of increased apoptosis, whereas leukocytes expressing similar levels of cytokines were enriched in regions of extracellular matrix remodeling.

Conclusions

The multiplex imaging method can be applied to biobanked human tissue sections to enable proof‐of‐concept studies and validate theories based on animal models and cultured cells.
A checklist of eriophyoid species (Acari: Eriophyidae) on Zygophyllaceae with descriptions of two new species from Northeast Iran
Authors: HONARMAND ARASH , LOTFOLLAHI PARISA , XUE XIAO-FENG
Published: June 2024

During field survey of eriophyoid mites in northeast Iran (Razavi Khorasan, Iran, summer 2023), two new eriophyoid mite species (Acari: Eriophyoidea: Eriophyidae) on Zygophyllum atriplicoides Fisch. et C.A.Mey. subsp. atriplicoides (Zygophyllaceae) were discovered, illustrated and described herein. They are Aceria kalatiensis sp. nov., which caused rounded galls on both sides of the leaves, and Aculus sirzariensis sp. nov., which was vagrant on the same samples. Furthermore, we provided a checklist of eriophyoid mite species associated with Zygophyllaceae plants of the world.
A new species of the family Leucothoidae (Crustacea, Amphipoda) from the Mediterranean Sea, Paranamixis fishelsoni sp. nov.
Authors: KAIM-MALKA R.A.
Published: June 2024

A new Paranamixis species, is described based on an anamorph male (adult male on terminal stage), and on a leucomorph specimen which is the shape, in this genus, of the females and also of the males which have not reached the terminal stage. The presence of a Paranamixis species is recorded for the first time in the Mediterranean Sea. A key of the species known is given.