bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy of frozen section remote subspecialty consultation using real-time telepathology and whole-slide imaging in gynecologic cases
Authors: Treece Charisse Liz B , Filipek Jennifer , Makker Jitin , Moatamed Neda A , Rodriguez Erika F
Published: August 2023

Objectives

Intrapathology consultation is recommended for complex cases during frozen section (FS) as routine practice. In our institution, solicited second opinions were traditionally provided by in-person consultation (IPC). Whole-slide imaging (WSI) was implemented in 2018 as an alternative but replaced by videoconferencing in 2020. Here, we assess the accuracy of remote FS consultation using these digital modalities vs IPC.

Methods

Gynecologic FS cases over a 4-year period overseen by 2 intraoperative consultants were grouped by consultation method: (1) IPC, (2) WSI, and (3) videoconferencing. Accuracy was determined by concordance between the FS and final report diagnoses. Turnaround time between the 3 groups was analyzed using SPSS statistical software (IBM).

Results

Using WSI and videoconferencing, 100% concordance was observed, while the IPC group had a 98.5% concordance rate. Videoconferencing, however, showed longer turnaround times (mean, 45.59 minutes) than IPC (mean, 33.36 minutes). Although turnaround time positively correlated with the number of FS specimens, blocks, and H&E slides per case, no statistically significant differences in the number of specimens, blocks, and H&E slides generated were found among the consultation methods.

Conclusions

Even though turnaround time using videoconferencing is longer, the accuracy of WSI and videoconferencing for remote FS consultation is equivalent to IPC. It is therefore a safe method for conducting intrapathology FS consultation in challenging surgical cases.
Hypomyelination, hypodontia and craniofacial abnormalities in a Polr3b mouse model of leukodystrophy
Authors: Michell-Robinson Mackenzie A , Watt Kristin E N , Grouza Vladimir , Macintosh Julia , Pinard Maxime , Tuznik Marius , Chen Xiaoru , Darbelli Lama , Wu Chia-Lun , Perrier Stefanie , Chitsaz Daryan , Uccelli Nonthué A , Liu Hanwen , Cox Timothy C , Müller Christoph W , Kennedy Timothy E , Coulombe Benoit , Rudko David A , Trainor Paul A , Bernard Geneviève
Published: August 2023

RNA polymerase III (Pol III)-related hypomyelinating leukodystrophy (POLR3-HLD), also known as 4H leukodystrophy, is a severe neurodegenerative disease characterized by the cardinal features of hypomyelination, hypodontia and hypogonadotropic hypogonadism. POLR3-HLD is caused by biallelic pathogenic variants in genes encoding Pol III subunits. While approximately half of all patients carry mutations in POLR3B encoding the RNA polymerase III subunit B, there is no in vivo model of leukodystrophy based on mutation of this Pol III subunit.

Here, we determined the impact of POLR3BΔ10 (Δ10) on Pol III in human cells and developed and characterized an inducible/conditional mouse model of leukodystrophy using the orthologous Δ10 mutation in mice. The molecular mechanism of Pol III dysfunction was determined in human cells by affinity purification-mass spectrometry and western blot. Postnatal induction with tamoxifen induced expression of the orthologous Δ10 hypomorph in triple transgenic Pdgfrα-Cre/ERT; R26-Stopfl-EYFP; Polr3bfl mice. CNS and non-CNS features were characterized using a variety of techniques including microCT, ex vivo MRI, immunofluorescence, immunohistochemistry, spectral confocal reflectance microscopy and western blot. Lineage tracing and time series analysis of oligodendrocyte subpopulation dynamics based on co-labelling with lineage-specific and/or proliferation markers were performed.

Proteomics suggested that Δ10 causes a Pol III assembly defect, while western blots demonstrated reduced POLR3BΔ10 expression in the cytoplasm and nucleus in human cells. In mice, postnatal Pdgfrα-dependent expression of the orthologous murine mutant protein resulted in recessive phenotypes including severe hypomyelination leading to ataxia, tremor, seizures and limited survival, as well as hypodontia and craniofacial abnormalities. Hypomyelination was confirmed and characterized using classic methods to quantify myelin components such as myelin basic protein and lipids, results which agreed with those produced using modern methods to quantify myelin based on the physical properties of myelin membranes. Lineage tracing uncovered the underlying mechanism for the hypomyelinating phenotype: defective oligodendrocyte precursor proliferation and differentiation resulted in a failure to produce an adequate number of mature oligodendrocytes during postnatal myelinogenesis.

In summary, we characterized the Polr3bΔ10 mutation and developed an animal model that recapitulates features of POLR3-HLD caused by POLR3B mutations, shedding light on disease pathogenesis, and opening the door to the development of therapeutic interventions.
Effect of chilling on the spring emergence of overwintering Eurytoma maslovskii (Eurytomidae: Hymenoptera)
Authors: Nguyen Hai Nam , Hong Ki-Jeong
Published: August 2023

This study investigated the effect of chilling temperature and duration on diapause termination in Eurytoma maslovskii, a major apricot pest in Korea and China. The experimental insects were sampled in mid-autumn. Overwintering larvae were subjected to a temperature range at −16, −4, 2, 9, 13 °C for 12 wk (a temperature of 19 °C was used for nonchilled control), and then exposed to cold temperature (2 °C) for different durations (from 1 to 16, 19, and 22 wk) at different times (20 September and 30 November) to determine adult emergence, prolonged larval diapause, and development rate postchilling. The results demonstrated a strong association between chilling temperature and duration with the emergence of E. maslovskii. It was observed that diapause may be terminated after at least 6 wk in the cold. However, the rate only reached a higher significance after 10 wk or longer duration of chilling. The optimal chilling temperature ranged from 2 to 9 °C. Late autumn chilling (mid-September) did not differ from winter chilling (late November). The postdiapause development rate of E. maslovskii was determined to be affected by the chilling duration and could be described by a 3-parameter probability density Weibull function. These results suggest that winter conditions play a crucial role in the phenology of E. maslovskii in spring.
Recommendations for statin management in primary prevention: disparities among international risk scores
Authors: Mancini G B John , Ryomoto Arnold , Yeoh Eunice , Brunham Liam R , Hegele Robert A
Published: August 2023

Background and Aims

Statin recommendations in primary prevention depend upon risk algorithms. Moreover, with intermediate risk, risk enhancers and de-enhancers are advocated to aid decisions. The aim of this study was to compare algorithms used in North America and Europe for the identification of patients warranting statin or consideration of risk enhancers and de-enhancers.

Methods

A simulated population (n = 7680) equal in males and females, with/without smoking, aged 45–70 years, total cholesterol 3.5–7.0 mmol/L, high-density lipoprotein cholesterol 0.6–2.2 mmol/L, and systolic blood pressure 100–170 mmHg, was evaluated. High, intermediate, and low risks were determined using the Framingham Risk Score (FRS), Pooled Cohort Equation (PCE), four versions of Systematic Coronary Risk Evaluation 2 (SCORE2), and Multi-Ethnic Study of Atherosclerosis (MESA) algorithm (0–1000 Agatston Units).

Results

Concordance for the three levels of risk varied from 19% to 85%. Both sexes might be considered to have low, intermediate, or high risk depending on the algorithm applied, even with the same burden of risk factors. Only SCORE2 (High Risk and Very High Risk versions) identified equal proportions of males and females with high risk. Excluding MESA, the proportion with moderate risk was 25% (SCORE2, Very High Risk Region), 32% (FRS), 39% (PCE), and 45% (SCORE2, Low Risk Region).

Conclusion

Risk algorithms differ substantially in their estimation of risk, recommendations for statin treatment, and use of ancillary testing, even in identical patients. These results highlight the limitations of currently used risk-based approaches for addressing lipid-specific risk in primary prevention.
Frailty and outcomes in heart failure patients from high-, middle-, and low-income countries
Authors: Leong Darryl P , Joseph Philip , McMurray John J V , Rouleau Jean , Maggioni Aldo P , Lanas Fernando , Sharma Sanjib K , Núñez Julio , Mohan Bishav , Celik Ahmet , Abdullakutty Jabir , Ogah Okechukwu S , Mielniczuk Lisa M , Balasubramanian Kumar , McCready Tara , Grinvalds Alex , Yusuf Salim
Published: August 2023

Background and Aims

There is little information on the incremental prognostic importance of frailty beyond conventional prognostic variables in heart failure (HF) populations from different country income levels.

Methods

A total of 3429 adults with HF (age 61 ± 14 years, 33% women) from 27 high-, middle- and low-income countries were prospectively studied. Baseline frailty was evaluated by the Fried index, incorporating handgrip strength, gait speed, physical activity, unintended weight loss, and self-reported exhaustion. Mean left ventricular ejection fraction was 39 ± 14% and 26% had New York Heart Association Class III/IV symptoms. Participants were followed for a median (25th to 75th percentile) of 3.1 (2.0–4.3) years. Cox proportional hazard models for death and HF hospitalization adjusted for country income level; age; sex; education; HF aetiology; left ventricular ejection fraction; diabetes; tobacco and alcohol use; New York Heart Association functional class; HF medication use; blood pressure; and haemoglobin, sodium, and creatinine concentrations were performed. The incremental discriminatory value of frailty over and above the MAGGIC risk score was evaluated by the area under the receiver-operating characteristic curve.

Results

At baseline, 18% of participants were robust, 61% pre-frail, and 21% frail. During follow-up, 565 (16%) participants died and 471 (14%) were hospitalized for HF. Respective adjusted hazard ratios (95% confidence interval) for death among the pre-frail and frail were 1.59 (1.12–2.26) and 2.92 (1.99–4.27). Respective adjusted hazard ratios (95% confidence interval) for HF hospitalization were 1.32 (0.93–1.87) and 1.97 (1.33–2.91). Findings were consistent among different country income levels and by most subgroups. Adding frailty to the MAGGIC risk score improved the discrimination of future death and HF hospitalization.

Conclusions

Frailty confers substantial incremental prognostic information to prognostic variables for predicting death and HF hospitalization. The relationship between frailty and these outcomes is consistent across countries at all income levels.
Dramatic difference in rate of chromosome number evolution among sundew (Drosera L., Droseraceae) lineages
Authors: Mohn Rebekah A , Zenil-Ferguson Rosana , Krueger Thilo A , Fleischmann Andreas S , Cross Adam T , Yang Ya
Published: August 2023

Chromosome number change is a driver of speciation in eukaryotic organisms. Carnivorous sundews in the plant genus Drosera L. exhibit single chromosome number variation both among and within species, especially in the Australian Drosera subg. Ergaleium D.C., potentially linked to atypical centromeres that span much of the length of the chromosomes. We critically reviewed the literature on chromosome counts in Drosera, verified the taxonomy and quality of the original counts, and reconstructed dated phylogenies. We used the BiChrom model to test whether rates of single chromosome number increase and decrease, and chromosome number doubling differed between D. subg. Ergaleium and the other subgenera and between self-compatible and self-incompatible lineages. The best model for chromosome evolution among subgenera had equal rates of chromosome number doubling but higher rates of single chromosome number change in D. subg. Ergaleium than in the other subgenera. Contrary to expectation, self-incompatible lineages had a significantly higher rate of single chromosome loss than self-compatible lineages. We found no evidence for an association between differences in single chromosome number changes and diploidization after polyploidy or centromere type. This study presents an exemplar for critically examining published cytological data and rigorously testing factors that may impact the rates of chromosome number evolution.
Pyronaridine: a review of its clinical pharmacology in the treatment of malaria
Authors: Chu Wan-Yu , Dorlo Thomas P C
Published: August 2023

Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.
A method to automate the discharge summary hospital course for neurology patients
Authors: Hartman Vince C , Bapat Sanika S , Weiner Mark G , Navi Babak B , Sholle Evan T , Campion Thomas R
Published: August 2023

Objective

Generation of automated clinical notes has been posited as a strategy to mitigate physician burnout. In particular, an automated narrative summary of a patient’s hospital stay could supplement the hospital course section of the discharge summary that inpatient physicians document in electronic health record (EHR) systems. In the current study, we developed and evaluated an automated method for summarizing the hospital course section using encoder-decoder sequence-to-sequence transformer models.

Materials and Methods

We fine-tuned BERT and BART models and optimized for factuality through constraining beam search, which we trained and tested using EHR data from patients admitted to the neurology unit of an academic medical center.

Results

The approach demonstrated good ROUGE scores with an R-2 of 13.76. In a blind evaluation, 2 board-certified physicians rated 62% of the automated summaries as meeting the standard of care, which suggests the method may be useful clinically.

Discussion and conclusion

To our knowledge, this study is among the first to demonstrate an automated method for generating a discharge summary hospital course that approaches a quality level of what a physician would write.
GPR120 Gene expression and activity in subcutaneous and intramuscular adipose tissues of Angus crossbred steers
Authors: Westbrook Lindsay , Johnson Bradley J , Gang Gyoungok , Toyonaga Kentaro , Young Kang Eun , Smith Stephen B
Published: August 2023

We hypothesized that media long-chain fatty acids (LCFA) would more greatly depress cyclic adenosine monophosphate (cAMP), glycerol, and free fatty acid (FFA) concentrations in subcutaneous (s.c.) adipose tissue than in intramuscular (i.m.) adipose tissue via G protein-coupled receptor 120 (GPR120). The GPR120 receptor binds to LCFA, which reduces cAMP production, thereby causing a depression in lipolysis. Fresh ex vivo explants of s.c. and i.m. adipose tissue from the fifth to eighth longissimus thoracic rib muscle section of 8, 22-mo-old Angus crossbred steers were transferred immediately to 6-well culture plates containing 3 mL of Krebs–Henseleit buffer/Hepes/5 mM glucose. Samples were preincubated with 0.5 mM theophylline plus 10 μM forskolin for 30 min, after which increasing concentrations of acetate or propionate (volatile fatty acids, VFA) (0, 1, 5, and 10 mM) in the absence or presence of 100 µM oleate (18:1n-9) or 100 μM palmitate (16:0) (LCFA) were added to the incubation media and incubated an additional 30 min. Main effects of adipose tissue depot (i.m. vs. s.c) and VFA (acetate vs. propionate) for adipose tissue concentrations of forskolin-stimulated cAMP were P = 0.747 and P = 0.106, respectively. The addition of LCFA to the media depressed adipose tissue concentrations of cAMP (P = 0.006) (LCFA main effects). The Tissue × VFA × LCFA interaction was not significant for any dependent variable (P ≥ 0.872). Therefore, concentrations of cAMP, glycerol, and FFA were analyzed separately for i.m. and s.c. adipose tissue by split-plot analysis. Concentrations of cAMP, glycerol, or FFA in i.m. and s.c. adipose tissue were not affected by increasing concentrations of VFA (P ≥ 0.497). Media LCFA had no effect on i.m. adipose tissue cAMP (P = 0.570) or glycerol (P = 0.470) but depressed i.m. adipose tissue FFA (P < 0.001). In s.c. adipose tissue, LCFA decreased concentrations of cAMP (P = 0.042) and glycerol (P = 0.038), but increased FFA concentration (P = 0.026). Expression of GPR120 (P = 0.804) and stearoyl-CoA desaturase (P = 0.538) was not different between s.c. adipose tissue and i.m. adipose tissue. The binding of VFA to the GPR43 receptor depresses cAMP production, thereby attenuating lipolysis, but GPR43 mRNA was undetectable in those adipose tissue samples. These results provide evidence for functional GPR120 receptors in s.c. adipose tissue but question the role of GPR43 in the accumulation of adipose tissue lipids in growing steers.
Differentiating Childhood Traumas in Inflammatory Bowel Disease
Authors: Gnat Lauren , Mihajlovic Valentina , Jones Krista , Tripp Dean A
Published: August 2023

Background

Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract. Research on inflammatory bowel disease has shown a connection to childhood traumatic events. However, few studies have focused on specific types of traumatic experiences and the impact of confiding in others on disease-related outcomes. This comparative, cross-sectional study expected that: (1) patients would report higher prevalence rates of childhood traumas than healthy controls; (2) healthy controls would report fewer and less severe traumatic experiences than patients and less confiding in others compared to patients; (3) childhood trauma severity would be indirectly related to depressive symptoms through resilience and confiding in others would moderate this relationship.

Methods

Participants completed an online survey; an inflammatory bowel disease patient group (N = 195, Mage = 40.48, 76.4% female) was compared to a similarly recruited sample of healthy controls (N = 190, Mage = 31.16, 59.5% female).

Results

Patients reported a higher prevalence of experiencing sexual traumas (P = .031), major upheavals (i.e., disruptions) (P = .048), and violence (P = .050) than controls. Patients had significantly higher total trauma severity odds ratios (OR 0.89, 95% CI[0.81,0.97]) and significantly lower total confiding in other odds ratios than controls (OR 1.09, 95% CI[1.02,1.16]). Childhood trauma severity was indirectly related to depressive symptoms through resilience, b = .05, SE = 0.09, 95% CI[0.01,0.09]; however, confiding did not moderate this relationship.

Conclusions

Patients reported more sexual, disruptive, and violent traumas. Although confiding did not act as a moderator, trauma was related to depressive symptoms through resilience.
NGOs Shaping Public Participation Through Law: The Aarhus Convention and Legal Mobilisation
Authors: Abbot Carolyn , Lee Maria
Published: August 2023

This article explores the relative neglect by environmental NGOs—at least until recently—of the middle, public participation, pillar of the Aarhus Convention. This can be seen in litigation, as well as in political advocacy, both domestically and at the international (Aarhus) level. Interviews with some key actors in this area and analysis of published documents provide insights into NGO decision-making. The limits of law become clear—Aarhus rights are made real only through the commitment of governments and civil society. A nuanced combination of internal and external factors contributes to explaining the lack of NGO attention to Aarhus’ middle pillar. We may also see some indications that NGOs envisage participation as a process properly dominated by expertise. This is far from uniform, however, and other parts of the community clearly appreciate and value the significance of lay participation in the environmental arena.
Adolescents’ Perspectives on Skateboarding and Injury Risk: The Benefits Outweigh the Risks
Authors: Seasons Mackenzie , Morrongiello Barbara A
Published: August 2023

Objective

Skateboarding is an increasingly popular sport among youth, despite the fact that children and adolescents are the age groups most frequently injured when skateboarding. A greater understanding of the psycho-social factors that motivate participation in skateboarding, including why youth return to the sport after serious injury from skateboarding, is needed to inform injury prevention efforts. This study addressed that gap in knowledge.

Methods

Twenty-six Canadian adolescent skateboarders 14–17 years of age (20 males and 6 females) who had previously sustained medically attended injuries while skateboarding participated in individual interviews to explore their perspectives on skateboarding and injury risk, including reasons for returning to the sport after injury.

Results

Thematic analyses revealed that participants perceived many unique benefits from skateboarding, including interpersonal benefits, mental and physical health benefits, pleasure, personal growth, and identity development. Participants uniformly identified that a major drawback was the risk of injury, with trickle-down effects of injury including a loss of social contacts (e.g., missing friends), challenges to individual identity from not participating, and injury-specific negative outcomes (e.g., pain, physical limitations). When exploring reasons participants returned to the sport and to the trick or activity that precipitated their injury, the primary theme identified was that the benefits of skateboarding significantly outweighed the costs associated with potential re-injury.

Conclusion

Results paint a nuanced picture of psycho-social factors that impact youths’ skateboarding and decisions to return to the sport after injury. Implications for injury prevention are discussed.
Frequency of antithyroid antibodies in patients with primary biliary cholangitis
Authors: Ghozzi Mariam , Mankai Amani , Chedly Zeineb , Mlika Ikram , Manoubi Wiem , Melayah Sarra , Ghedira Ibtissem
Published: August 2023

Objective

Primary biliary cholangitis (PBC) is an autoimmune disease of liver that may be associated with other conditions, including autoimmune thyroid diseases. We aimed to investigate the frequency of anti-thyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (TG-Ab), and anti–thyrotropin receptor antibodies (TSHR-Ab) in Tunisian patients with PBC.

Methods

Sera of 80 patients with PBC were collected over a 9-year period. A total of 189 healthy blood donors (HBD) were included in the control group. Measurements of TPO-Ab and TG-Ab were performed using indirect enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess TSHR-Ab.

Results

Antithyroid antibodies (ATA) were significantly more frequent in PBC patients than in the control group (13.7% vs 1.6%; P < 10−3). Out of 11 patients with ATA, 10 (90.9%) were female. Nine patients and 2 HBD had TPO-Ab (11.2% vs 1%; P < 10−3). TG-Ab were more frequent in patients than in healthy subjects but the difference was not statistically significant (6.2% vs 1.6%; P = .1). TPO-Ab and TG-Ab were present together in 3 patients (3.7%). TSHR-Ab were absent in patients and controls.

Conclusion

This study shows that PBC is associated with a high frequency of ATA but not TG-Ab or TSHR-Ab.
Morphological Characterization of the Antennal Sensilla of the Legume Pod Borer, Maruca vitrata (Fabricius) (Lepidoptera: Crambidae)
Authors: Pathour Rajendra Shashank , Rani Abalavadi Thammaiah , Devi Salam Rita , Meshram Naresh Manohar
Published: August 2023

Maruca vitrata (Fabricius) is an important lepidopteran pest of legumes in the tropics and subtropics. Here, we studied the ultrastructural organization of its antennal sense organs using scanning electron microscopy. The antennae of both sexes of M. vitrata were filiform with the number of flagellar segments varying from 72 to 84. Nine major morphological types of sensilla were observed on male and female antennae: sensilla trichodea (ST), sensilla basiconica (SB), sensilla auricillica (SA), sensilla chaetica (SCh), sensilla coeloconica (SCoe), sensilla cylindrica (SCy), sensilla squamiformia (SSq), sensilla styloconica (SSt), and Böhm sensilla (BS). Three of these sensilla types (SB, SSq, and BS) are newly reported for M. vitrata. Morphological observations revealed that four types are multiporous (ST, SB, SA, and SCoe), two types are uniporous (SCh and SCy), and three types are aporous (SSq, SSt, and BS). The average length of male ST was longer than that of the female. Sensilla cylindrica were observed only on male antennae, indicating sexual dimorphism. This study aims to provide some basic evidence for further studies on the mechanism of insect–plant chemical communication and future semiochemical-based management strategies of the major legume pest M. vitrata.
Immunohistochemical Analysis of Olfactory Sensory Neuron Populations in the Developing Olfactory Organ of the Guppy, Poecilia reticulata (Cyprinodontiformes, Poecilidae)
Authors: Bettini Simone , Lazzari Maurizio , Milani Liliana , Maurizii Maria Gabriella , Franceschini Valeria
Published: August 2023

Olfaction is fundamental for sensing environmental chemicals and has obvious adaptive advantages. In fish, the peripheral olfactory organ is composed of lamellae in which the olfactory mucosa contains three main categories of olfactory sensory neurons (OSNs) as follows: ciliated (cOSNs), microvillous (mOSNs), and crypt cells. We studied the appearance of these different OSNs during development of Poecilia reticulata, given its growing use as animal model system. We performed immunohistochemical detection of molecular markers specific for the different OSNs, carrying out image analyses for marked-cell counting and measuring optical density. The P. reticulata olfactory organ did not show change in size during the first weeks of life. The proliferative activity increased at the onset of secondary sexual characters, remaining high until sexual maturity. Then, it decreased in both sexes, but with a recovery in females, probably in relation to their almost double body growth, compared to males. The density of both cOSNs and mOSNs remained constant throughout development, probably due to conserved functions already active in the fry, independently of the sex. The density of calretinin-positive crypt cells decreased progressively until sexual maturity, whereas the increased density of calretinin-negative crypt cell fraction, prevailing in later developmental stages, indicated their probable involvement in reproductive activities.
On Earth’s habitability over the Sun’s main-sequence history: joint influence of space weather and Earth’s magnetic field evolution
Authors: Varela J , Brun A S , Strugarek A , Réville V , Zarka P , Pantellini F
Published: August 2023

The aim of this study is to analyse the Earth habitability with respect to the direct exposition of the Earth atmosphere to the solar wind (SW) along the Sun’s evolution on the main sequence including the realistic evolution of the space weather conditions and the Earth magnetic field. The MHD code PLUTO in spherical coordinates is applied to perform parametric studies with respect to the SW dynamic pressure and the interplanetary magnetic field intensity for different Earth magnetic field configurations. Quiet space weather conditions may not impact the Earth habitability. On the other hand, the impact of interplanetary coronal mass ejections (ICME) could lead to the erosion of the primary Earth atmosphere during the Hadean eon. A dipolar field of 30 μT is strong enough to shield the Earth from the Eo-Archean age as well as 15 and 5 μT dipolar fields from the Meso-Archean and Meso-Proterozoic, respectively. Multipolar weak field period during the Meso-Proterozoic age may not be a threat for ICME-like space weather conditions if the field intensity is at least 15 μT and the ratio between the quadrupolar (Q) and dipolar (D) coefficients is $\frac{Q}{D} \le 0.5$. By contrast, the Earth habitability in the Phanerozoic eon (including the present time) can be hampered during multipolar low field periods with a strength of 5 μT and $\frac{Q}{D} \ge 0.5$ associated with geomagnetic reversals. Consequently, the effect of the SW should be considered as a possible driver of Earth’s habitability.
DONSON facilitates Cdc45 and GINS chromatin association and is essential for DNA replication initiation
Authors: Kingsley Georgia , Skagia Aggeliki , Passaretti Paolo , Fernandez-Cuesta Cyntia , Reynolds-Winczura Alicja , Koscielniak Kinga , Gambus Agnieszka
Published: August 2023

Faithful cell division is the basis for the propagation of life and DNA replication must be precisely regulated. DNA replication stress is a prominent endogenous source of genome instability that not only leads to ageing, but also neuropathology and cancer development in humans. Specifically, the issues of how vertebrate cells select and activate origins of replication are of importance as, for example, insufficient origin firing leads to genomic instability and mutations in replication initiation factors lead to the rare human disease Meier-Gorlin syndrome. The mechanism of origin activation has been well characterised and reconstituted in yeast, however, an equal understanding of this process in higher eukaryotes is lacking. The firing of replication origins is driven by S-phase kinases (CDKs and DDK) and results in the activation of the replicative helicase and generation of two bi-directional replication forks. Our data, generated from cell-free Xenopus laevis egg extracts, show that DONSON is required for assembly of the active replicative helicase (CMG complex) at origins during replication initiation. DONSON has previously been shown to be essential during DNA replication, both in human cells and in Drosophila, but the mechanism of DONSON’s action was unknown. Here we show that DONSON’s presence is essential for replication initiation as it is required for Cdc45 and GINS association with Mcm2–7 complexes and helicase activation. To fulfil this role, DONSON interacts with the initiation factor, TopBP1, in a CDK-dependent manner. Following its initiation role, DONSON also forms a part of the replisome during the elongation stage of DNA replication. Mutations in DONSON have recently been shown to lead to the Meier-Gorlin syndrome; this novel replication initiation role of DONSON therefore provides the explanation for the phenotypes caused by DONSON mutations in patients.
HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers
Authors: Morozov Viacheslav M , Riva Alberto , Sarwar Sadia , Kim Wan-Ju , Li Jianping , Zhou Lei , Licht Jonathan D , Daaka Yehia , Ishov Alexander M
Published: August 2023

Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.3 in prostate cancer (PC), we found that knockout (KO) of H3.3 chaperone HIRA suppresses PC growth in vitro and in xenograft settings, deregulates androgen-induced gene expression and alters androgen receptor (AR) binding within enhancers of target genes. H3.3 affects transcription in multiple ways, including activation of p300 by phosphorylated H3.3 at Ser-31 (H3.3S31Ph), which results in H3K27 acetylation (H3K27Ac) at enhancers. In turn, H3K27Ac recruits bromodomain protein BRD4 for enhancer-promoter interaction and transcription activation. We observed that HIRA KO reduces H3.3 incorporation, diminishes H3.3S31Ph and H3K27Ac, modifies recruitment of BRD4. These results suggest that H3.3-enriched enhancer chromatin serves as a platform for H3K27Ac-mediated BRD4 recruitment, which interacts with and retains AR at enhancers, resulting in transcription reprogramming. In addition, HIRA KO deregulates glucocorticoid- (GR) driven transcription of genes co-regulated by AR and GR, suggesting a common H3.3/HIRA-dependent mechanism of nuclear receptors function. Expression of HIRA complex proteins is increased in PC compared with normal prostate tissue, especially in high-risk PC groups, and is associated with a negative prognosis. Collectively, our results demonstrate function of HIRA-dependent H3.3 pathway in regulation of nuclear receptors activity.
A comprehensive analysis of translational misdecoding pattern and its implication on genetic code evolution
Authors: Katoh Takayuki , Suga Hiroaki
Published: August 2023

The universal genetic code is comprised of 61 sense codons, which are assigned to 20 canonical amino acids. However, the evolutionary basis for the highly conserved mapping between amino acids and their codons remains incompletely understood. A possible selective pressure of evolution would be minimization of deleterious effects caused by misdecoding. Here we comprehensively analyzed the misdecoding pattern of 61 codons against 19 noncognate amino acids where an arbitrary amino acid was omitted, and revealed the following two rules. (i) If the second codon base is U or C, misdecoding is frequently induced by mismatches at the first and/or third base, where any mismatches are widely tolerated; whereas misdecoding with the second-base mismatch is promoted by only U-G or C-A pair formation. (ii) If the second codon base is A or G, misdecoding is promoted by only G-U or U-G pair formation at the first or second position. In addition, evaluation of functional/structural diversities of amino acids revealed that less diverse amino acid sets are assigned at codons that induce more frequent misdecoding, and vice versa, so as to minimize deleterious effects of misdecoding in the modern genetic code.
Evaluation of tissue depth, captive bolt penetration force and energy, and potential for bolt-thalamus contact in cadaver heads from physically castrated market barrows and immunocastrated boars
Authors: Hamilton Emma M , Anderson Karly N , Kirk Ashlynn A , Bishop Katherine D , Shakal Joseph S , Vogel Kurt D
Published: August 2023

The main objective of this study was to describe tissue thicknesses of cadaver heads from physically castrated market barrows (PC MARKET BARROWS) and immunocastrated boars (IC BOARS) at the frontal penetrating captive bolt (PCB) placement. Other objectives were to describe differences in bolt force and energy requirements to penetrate and describe potential for bolt-thalamus contact. Forty-four heads were obtained from PC MARKET BARROWS (n = 22) and IC BOARS (n = 22) of similar age and size that were rendered insensible with CO2. Mean HCW was 117.32 ± 3.52 kg. Snout to poll distance (cm) and maximum deflection distance (cm) were collected in duplicate. Heads were split at midline with a bandsaw and soft tissue and cranial thicknesses were measured with a digital caliper. Images of each cut surface were collected to evaluate the potential for thalamic damage. Tissue samples were retained from each half of each head and a universal tester was used to determine maximum force and energy of bolt penetration. There was no evidence to support a significant difference (P > 0.05) in tissue thicknesses between PC MARKET BARROWS and IC BOARS. Maximum deflection distance (maximum distance from a straight edge that was placed from the tip of the snout to the poll of the head) was not different (P = 0.10) between PC MARKET BARROWS (3.31 ± 0.10 cm) and IC BOARS (3.08 ± 0.10 cm). There was no evidence to support a difference (P = 0.77) in maximum force between PC MARKET BARROWS (7130.32 ± 483.23 N) and IC BOARS (6974.60 ± 463.70 N). There was also no evidence to support a difference (P = 0.62) in maximum energy between PC MARKET BARROWS (33.37 ± 2.77 J) and IC BOARS (32.04 ± 2.50 J). For PC MARKET BARROWS, there was a difference (P = 0.05) between the number of heads where the thalamus was located within the theoretical plane of bolt travel for market placement (21/21) versus mature placement (16/21). For IC BOARS, the number of heads where the thalamus was located within the plane of theoretical bolt path was not different between the two PCB placements (19/21 each). Overall, the data suggest that tissue profiles of PC MARKET BARROWS and IC BOARS do not differ at the frontal PCB placement site and the mechanical tools that are effective for PC MARKET BARROWS should also be effective for IC BOARS.
Delayed Treatment of Bloodstream Infection at Admission is Associated With Initial Low Early Warning Score and Increased Mortality
Authors: Fischer Christian P. , Kastoft Emili , Olesen Bente Ruth Scharvik , Myrup Bjarne
Published: August 2023

OBJECTIVES:

To identify factors associated with antibiotic treatment delay in patients admitted with bloodstream infections (BSIs).

DESIGN:

Retrospective cohort study.

SETTING:

North Zealand Hospital, Denmark.

PATIENTS:

Adult patients with positive blood cultures obtained within the first 48 hours of admission between January 1, 2015, and December 31, 2015 (n = 926).

MEASUREMENTS AND MAIN RESULTS:

First recorded Early Warning Score (EWS), patient characteristics, time to antibiotic treatment, and survival at day 60 after admission were obtained from electronic health records and medicine module. Presence of contaminants and the match between the antibiotic treatment and susceptibility of the cultured microorganism were included in the analysis. Data were stratified according to EWS quartiles. Overall, time from admission to prescription of antibiotic treatment was 3.7 (3.4–4.0) hours, whereas time from admission to antibiotic treatment was 5.7 (5.4–6.1) hours. A gap between prescription and administration of antibiotic treatment was present across all EWS quartiles. Importantly, 23.4% of patients admitted with BSI presented with an initial EWS 0–1. Within this group of patients, time to antibiotic treatment was markedly higher among nonsurvivors at day 60 compared with survivors. Furthermore, time to antibiotic treatment later than 6 hours was associated with increased mortality at day 60. Among patients with an initial EWS of 0–1, 51.3% of survivors received antibiotic treatment within 6 hours, whereas only 19.0% of nonsurvivors received antibiotic treatment within 6 hours.

CONCLUSIONS:

Among patients with initial low EWS, delay in antibiotic treatment of BSIs was associated with increased mortality at day 60. Lag from prescription to administration may contribute to delayed antibiotic treatment. A more frequent reevaluation of patients with infections with a low initial EWS and reduction of time from prescription to administration may reduce the time to antibiotic treatment, thus potentially improving survival.
Efficacy of Milrinone and Dobutamine in Cardiogenic Shock: An Updated Systematic Review and Meta-Analysis
Authors: Abdel-Razek Omar , Di Santo Pietro , Jung Richard G. , Parlow Simon , Motazedian Pouya , Prosperi-Porta Graeme , Visintini Sarah , Marbach Jeffrey A. , Ramirez F. Daniel , Simard Trevor , Labinaz Marino , Mathew Rebecca , Hibbert Benjamin
Published: August 2023

OBJECTIVES:

Inotropic support is commonly used in patients with cardiogenic shock (CS). High-quality data guiding the use of dobutamine or milrinone among this patient population is limited. We compared the efficacy and safety of these two inotropes among patients with low cardiac output states (LCOS) or CS.

DATA SOURCES:

MEDLINE, Embase, and Cochrane Central Register of Controlled Trials were searched up to February 1, 2023, using key terms and index headings related to LCOS or CS and inotropes.

DATA EXTRACTION:

Two independent reviewers included studies that compared dobutamine to milrinone on all-cause in-hospital mortality, length of ICU stay, length of hospital stay, and significant arrhythmias in hospitalized patients.

DATA SYNTHESIS:

A total of eleven studies with 21,084 patients were included in the meta-analysis. Only two randomized controlled trials were identified. The primary outcome, all-cause mortality, favored milrinone in observational studies only (odds ratio [OR] 1.19 (95% CI, 1.02–1.39; p = 0.02). In-hospital length of stay (LOS) was reduced with dobutamine in observational studies only (mean difference –1.85 d; 95% CI –3.62 to –0.09; p = 0.04). There was no difference in the prevalence of significant arrhythmias or in ICU LOS.

CONCLUSIONS:

Only limited data exists supporting the use of one inotropic agent over another exists. Dobutamine may be associated with a shorter hospital LOS; however, there is also a potential for increased all-cause mortality. Larger randomized studies sufficiently powered to detect a difference in these outcomes are required to confirm these findings.
Dexmedetomidine Versus Remifentanil Monitored Anesthesia Care During Endothelial Keratoplasty: A Retrospective Study
Authors: Mencucci Rita , De Vitto Chiara , Cennamo Michela , Pierucci Samuela , Adembri Chiara
Published: August 2023

Purpose:

Descemet's membrane endothelial keratoplasty (DMEK) is usually performed under topical or locoregional anesthesia; a sedation is often required. Several drugs are administered but undesirable side effects limit the use of each medication. Dexmedetomidine (DEX), a sedative-analgesic, has minimal respiratory depressant effects, and its use in DMEK surgery has not been reported. This study compares the use of DEX versus Remifentanil (REMI) during DMEK.

Methods:

Retrospective, observational, single-center study. Forty-two patients received sedation with DEX or REMI. Heart rate, blood pressure, oxygen saturation were always recorded during the procedure. The degree of sedation was evaluated using the Ramsay sedation scale; preoperative evaluation of anxiety disorders was carried out with the Hospital Anxiety and Depression Scale, while patients' and surgeon's satisfaction was evaluated using the 7-point Likert-like verbal rating scale.

Results:

Baseline demographic and clinical characteristics, as well as the baseline anxiety trait were similar for the 2 groups. Patients and surgeons reported higher satisfaction scores with DEX compared to patients receiving REMI (P < 0.01; P < 0.001). The intraoperative Ramsay score was 3 in 62% of patients in Group DEX and 23% in Group REMI; conversely, it was 2 in 38% of DEX Group and 77% in REMI Group (P < 0.02). No statistical difference in the hemodynamic and respiratory parameters between the 2 groups was recorded.

Conclusions:

With similar stability of hemodynamic and respiratory parameters, Dexmedetomedine provided a deeper sedation than REMI without respiratory depression, resulting in better surgical performance in terms of the patients' and the surgeon's satisfaction, thus suggesting a possible role for sedation during DMEK surgery.
Correlation of Manifest Refraction and Simulated Keratometry to Tomography Characteristics in Patients With Keratoconus
Authors: Greenstein Steven A. , Yu Austin S. , Wawrzusin Peter , Ando Airi , Chung Daniel , Garvey Nicholas , Su Becky , Hersh Peter S. , Gelles John D.
Published: August 2023

Objectives:

To report on baseline refractive and keratometric values and their correlation with tomographic characteristics of eyes with keratoconus (KC).

Methods:

Retrospective chart review of patients treated in a single-center cornea and refractive surgery practice. Baseline topographic measurements were reviewed for 1,012 keratoconic eyes of 586 patients between 2008 and 2018. The manifest refraction, thinnest pachymetry (Pthin), corneal astigmatism (Kastig), and the maximum (Kmax), steep (Ksteep), flat (Kflat), and mean (Kmean) keratometry were analyzed. The location of Kmax (x, y) was used to determine central (<1 mm), paracentral (1–3 mm), pericentral (3–5 mm), or peripheral (>5 mm) cone locations.

Results:

In the entire cohort, the mean manifest sphere was −2.2±4.4 diopters (D) and the cylinder was −3.2±2.3 D. In total, 48.6% of patients had against the rule (ATR) manifest astigmatism (Mastig). The average Kastig was 3.8±2.7 D, and unlike the manifest axis, 50.2% of patients had with the rule (WTR) Kastig. Patients with a Kmax less than 50 D had an Mastig of −1.9±1.6 D, 45.9% of which was ATR Mastig. With respect to baseline tomography measurements, Kmax, Ksteep, Kflat, and Kmean were 58.0±9.4, 50.6±6.5, 46.8±5.9, and 48.6±6.1 D, respectively. There was a weak correlation between Kmax and simulated keratometry (Ksteep, Kflat, and Kmean) for patients with a Kmax less than 60 D.

Conclusions:

Simulated keratometry is poorly correlated with KC severity until the disease is more severe. Mastig ≥2 D and ATR Mastig were correlated with KC at all levels of severity. Mastig ≥2 D and ATR Mastig may serve as a simple, inexpensive, and widely available indicator for topographic analysis to identify possible KC and suggest further workup; however, further prospective studies are needed to confirm its utility.
Intraocular Pressure and Myopia Progression, Axial Length Elongation in Rural Chinese Children
Authors: Lin Jue , Vasudevan Balamurali , Gao Tie Ying , Zhou Hong Jia , Ciuffreda Kenneth J. , Liang Yuan Bo , Lin Zhong
Published: August 2023

SIGNIFICANCE

This study reported the relationship between intraocular pressure (IOP) and myopia progression, which helps to understand more comprehensively whether IOP can be an important reference factor to intervene in the progression of myopia.

PURPOSE

This study aimed to investigate the association between IOP and myopia progression as well as axial length elongation in rural Chinese children.

METHODS

A total of 598 (598 of 878 [68.1%]) children (6 to 17 years) from the baseline Handan Offspring Myopia Study who completed a 3.5-year follow-up vision examination were included. Ocular examinations at both visits included cycloplegic autorefraction, IOP, and axial length measurements.

RESULTS

Children with myopia had the highest baseline IOP of the three refractive groups (14.13 ± 1.31, 13.78 ± 1.71, and 13.59 ± 1.64 mmHg in myopes, emmetropes, and hyperopes, respectively, P = .002). However, IOPs showed no significant difference between eyes with or without newly developed myopia (13.63 ± 1.68 vs. 13.89 ± 1.68, P = .16), with or without faster myopia progression (13.75 ± 1.61 vs. 13.86 ± 1.63, P = .46), or with axial length elongation (13.80 ± 1.61 vs. 13.76 ± 1.64, P = .80). The multivariate regression analysis demonstrated that neither baseline refractive error (β = −0.082, P = .13) nor baseline axial length (β = −0.156, P = .08) was associated with baseline IOP.

CONCLUSIONS

Myopic eyes have slightly higher IOP compared with emmetropic and hyperopic eyes, although it was not clinically significant. However, IOP was not found to be associated with either myopia progression or axial length elongation in this cohort sample of rural Chinese children.