Purpose Prior approval for reimbursement is a cost containment policy, aimed at reducing demand. It has been employed in Ireland to address financial challenges due to the shift from warfarin to Direct Oral Anticoagulant (DOACs). Studies assessing the effectiveness of this policy are limited. Thus, we aimed to examine the effectiveness of prior approval for reimbursement of DOACs (apixaban, rivaroxaban) as a cost containment policy in Ireland. Methods The Irish Health Service Executive-Primary Care Reimbursement Service database was used in this cross-sectional study. We examined the prescribing frequencies and associated costs of the oral anticoagulants; ((OACs) apixaban, rivaroxaban, and warfarin) listed in the top 100 most frequently prescribed drugs, between 2018 and 2021. Interrupted time series Poisson regression was used to assess the impact of removing the approval requirement of apixaban in September 2019 followed by the other DOACs in November 2020. Results The prescribing frequency of OACs increased by almost 20% from 2018-2021. This study showed there were significant differences in the proportion of OACs prescribed among the Community Drug Schemes. A statistically significant decreased use of apixaban (<1%, p<0.05) occurred when prior approval was removed for all DOACs. Conclusions The removal of prior approval for reimbursement of DOACs in Ireland had a minimal impact on the prescribing frequency trends of the OACs. Future use of these potentially useful policies by healthcare systems requires careful consideration of drug type, approval criteria and length of time the policy remains in place to minimise any negative effects associated with their use.

Over the past decade, increasing off-label use of quetiapine has been reported worldwide from various sources. We wanted to investigate how this is reflected in therapeutic drug monitoring (TDM) data. Requisitions for serum concentration measurements of quetiapine from a TDM service in Central Norway during 2001-2019 were obtained, and analyzed for trends in quetiapine doses, serum concentrations, demographics and indicators of diagnoses. 19759 samples from 7459 individuals were included. Daily doses of quetiapine decreased by 24 mg per year (95% CI -25.61 - -21.48, p<0.001, N=4505). A corresponding decrease in quetiapine serum concentrations was not seen. The proportion of requisitions with diagnoses indicating reimbursable use, i.e. within approved indications, was 13 % for the whole study period. Mean daily doses were slightly higher in the reimbursable group, but declined over time in these samples, as well. To our understanding, these results provide additional documentation of increasing low-dose usage of quetiapine, and signal both increasing off-label use, as well as possibly higher dose-intake than prescribed and incorrect filing of reimbursable use in this population. There is a continued need for investigation and characterization of quetiapine use and prescription practices, and the extent of and motivations for off-label prescription of the drug.

Invasive species are one of the main threats to global biodiversity and, within marine ecosystems, tunicates feature some prominent examples. Styela plicata is an ascidian species inhabiting harbors in all temperate oceans and seas, thus being considered a thriving invasive species. However, this species’ adaptive mechanisms, introduction history, and population structure have never been completely elucidated. Here, by genotyping 87 S. plicata individuals from 18 localities worldwide with 2b-RADseq, we confirm the presence of four chromosome inversions, demonstrate population structuring on this species, detect local adaptation signals, and infer historical demographic events. The locality of North Carolina constitutes an utterly unrelated population, Atlanto-Mediterranean and Pacific localities constitute their own genetic clusters, and the South Carolina locality presents an intermediate genetic position between North Carolina and the other two groups. For each biogeographic population we highlight substructuring, being the most evident the split between North Atlantic+Mediterranean and the South Atlantic localities. We identify genomic drivers for adaptation, with functions involved with cell processes, metabolism, development, and ion transport, among others. We model ancient effective population sizes, providing evidence on three main bottlenecks that could correspond to different introduction events. Finally, hybridization tests point to South Carolina having a hybrid origin, likely resulting from a secondary contact between North Carolina and other ancient populations. Overall, this study highlights the complex historical processes of S. plicata, which have led this species to its current distribution, population structure, and local adaptation footprint in oceans worldwide.

Molecular Ecology News and Views

The chief objective of the present investigation is to study experimentally the hydraulic and thermal performance of a corrugated tube with copper foam cylindrical inserts (MFCI) containing a new types of inserts with the purpose to improve the procedure of heat transfer, which gives an elevated thermal enhancement factor (PEF) more than that of smooth tube beneath the similar operating circumstances. Also, in this paper, the study of the effect on the number of cylindrical insert was made from metal foam (10 PPI and porosity 0.9) on the Nusselt no. and Nusselt no. ratio as a double heat exchanger furnished with the suggested MFCI with various values of Reynolds numbers ranges from (1600) to (4000) via using water as the test fluid. The investigational outcomes revealed an enhancement in heat transfer as well as thermal performance of the corrugated tube with MFCI which being significantly augmented in comparison to those for smooth tube. Additionally, the average rise into the value of heat transfer is within (74%) and (90%) at the test range, relying upon the number of cylindrical inserts as well as Reynolds no., whereas the max. thermal performance is obtained to be around (2.4) for utilizing the corrugated tube having (4) cylindrical inserts at low Reynolds no. Furthermore, the outcome of the loss of pressure manifested that the corrugated tube’s mean friction factor is within 96% and 97% more than the smooth tube.

Quercus chungii is an endemic tree species in China, rare and endangered in subtropical areas of China. Understanding its population structure and temporal dynamics is crucial for conserving and restoring Q. chungii population and its associated ecosystems. However, large knowledge gaps remain about its population structure and temporal change, and its key demographic rates across size classes. In this study, we investigated the population structures of Q. chungii in 2013 and 2023 in a nature reserve specifically established to better conserve Q. chungii and its associated ecosystems. We found that Q. chungii increased in its overall abundance, frequency and tree size in the past decade, suggesting active regeneration and fast growth rate of this species and the effectiveness of past conservation efforts. The age structure in 2023 shows a pyramid shape, with a sharp decline in the numbers of individuals from germinated seeds to seedlings and from seedlings to saplings. These lead to the low numbers of seedlings and saplings and high age-specific death probabilities at the early developmental stages. These results indicate potential risks of future population decline. These risks may have already manifested over the past decade, as a high mortality rate during the seedling-to-sapling transition could be one of the primary reasons contributing to the decreased proportion of saplings in 2023 compared to 2013. We propose that future studies may benefit from in-depth studies on the regeneration processes of Q. chungii by considering seed predation and germination under changing climate. This study improves the prediction of population development of Q. chungii and provide theoretical guidance for the conservation of Q. chungii.

Objective To identify phenotypes of pain in patients with endometriosis and to investigate their associations with predictors and quality of life (QoL). Design Population-based study. Setting A referral university center in Quebec City, Canada. Population or Sample A total of 352 patients aged 18‒50 years and diagnosed with endometriosis. Methods Latent class analysis (LCA) was used to identify pain phenotypes. To assess the associations, the three-step approach of LCA was applied. Main Outcome Measures Pain phenotypes, predictors of pain phenotypes, QoL. Results A total of 352 patients were included in the analyses. The diagnosis of endometriosis was either based on histology (N=135), imaging (N=106) or clinical presentation (N=111). The optimal model identified two distinct and homogeneous phenotypes of patients with endometriosis. The two groups had distinct clinical presentations, one with more severe and frequent pain symptoms and poorer quality of life (54%); the other with mild and less frequent pain symptoms (46%). Predictors of a high pain phenotype were a previous treatment failure, use of pain killers, a family history of endometriosis, a low annual family income, and pain comorbidities such as painful bladder, fibromyalgia, migraines, low back pain, irritable bowel syndrome, anxiety, and depression or mood disorders. The presence of endometrioma was predictive of the low pain phenotype. Phenotype membership was associated with distinct quality of life profiles (p<0.001). Conclusion Patients with endometriosis and pelvic pain can be grouped into two distinct and homogeneous phenotypes. Phenotypes membership correlates with quality of life and can be predicted with the patients’ characteristics. These findings will need to be validated in other populations and may inform the development of more specialized or personalized interventions based on the pain phenotypes.

Concomitant inferior sinus venosus atrial septal defect and hypoplasia of the posterior mitral valve leaflet in a 65-year-old female with a history of surgical ostium secundum atrial septal defect repair decades ago. Transesophageal echocardiography with bubble study using agitated saline contrast and cardiac magnetic resonance confirmed the previously undetected diagnosis

Background Cystic fibrosis (CF) is a multisystemic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene, resulting in defective synthesis or function of the CFTR protein. Historically, CF treatment focused on managing symptoms and complications. Fortunately, modulator drugs are now available to directly target the defective CFTR protein. However, in some countries, such as Turkey, these drugs are not covered by social insurance. Consequently, many CF patients face barriers to accessing modulatory therapies or must interrupt their treatment. This study demonstrates the impact of interrupting modulator therapy on pulmonary function, emphasizing the need for uninterrupted continuous treatment. Methods In this study, 39 CF patients receiving elexacaftor-tezacaftor-ivacaftor (ETI) at our clinic were retrospectively analyzed. Among the patients, 18 experienced one or more interruptions, ranging from 15 to 210 days during ETI treatment. We analyzed pulmonary function test results from 27 interruption periods. Results At the beginning of the interruption, the mean percent predicted FEV1 (ppFEV1) was 69.59 ± 25.87%, which decreased to 64.96 ± 24.52% by the end of the interruption. There was a significant decrease with a mean change of 4.62 ± 8.49 (p = 0.008). However, no significant correlation was found between the interruption duration and FEV1 change. Conclusion Our results demonstrate that pulmonary functions are adversely affected by interruption periods, regardless of their duration. Even short interruptions have a significant impact on pulmonary functions. This underscores the need for uninterrupted continuation of modulatory treatment and for improved policies to ensure equitable access to treatment.

1. Biodiversity and ecosystem multifunctionality are currently hot topics in ecological research. However, little is known about the role of multitrophic diversity in regulating various ecosystem functions, which limits our ability to predict the impact of biodiversity loss on human well–being and ecosystem multifunctionality. 2. In this study, multitrophic diversity was divided into three categories: plant, animal, and microbial communities (i.e., plant diversity, rodent diversity, bacterial and fungal diversity). Also, 15 ecosystem functions were divided into four categories–water conservation, soil fertility, nutrient cycling and transformation, and community production–to evaluate the significance of biotic and abiotic variables in maintaining ecosystem multifunctionality. 3. Results indicated that species diversity at multiple trophic levels had a greater positive impact on ecosystem multifunctionality than species diversity at a single trophic level. Notably, the specific nature of this relationship depended on the niche breadths of plants, indicating that plants were key indicators linking above and below ground trophic levels. Abiotic factors such as altitude and pH directly acted on ecosystem multifunctionality and could explain changes in ecosystem functions. 4. Overall, our study offers valuable insights into the critical role of multitrophic species diversity in preserving ecosystem multifunctionality within alpine grassland communities, as well as strong support for the importance of biodiversity protection.

Human activity and climate change are widely considered to be main responsible for Galliformes bird extinction. Due to a decline in population, the Reeves’s Pheasant (Syrmaticus reevesii), a member of the Galliformes family, was recently elevated to first-class national protected status in China. However, determining their factor on extinction and provide remedy is challenging owing to the lack of long-term data with high spatial and temporal resolution. Here, based on national field survey we used habitat suitability models and integrated data on geographical environment, road development, land-use and climate change to predict potential changes from 1995 to 2050 in the distribution and connectivity of Reeves’s Pheasant habitat. Furthermore, ecological corridors were identified using the Minimum Cumulative Resistance (MCR) model. The priority of building ecological corridors was then determined by combining the ecological source and the network cost-weight importance index. The study results indicate that both intensified land-use and climate change were associated with the increased habitat loss of the Reeves’s Pheasant. In more recent decades, road construction and land-use changes have been linked to a rise in local extinction, and future climate change is predicted to cause the habitat to become even more fragmented and lose 89.58% of its total area. The ecological corridor for Reeves’s Pheasant will continue to decline by 88.55%. To counteract the negative effects of human activity and climate change on Reeves’s Pheasant survivorship, we recommend taking immediate action. This includes bolstering cooperation amongst provincial governments, restoring habitats, and creating ecological corridors amongst important habitat.

Tick-borne encephalitis virus (TBEV) can cause life-threatening CNS infection. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuro infection and neuroinflammation. In this study, we applied an untargeted metabolomics screen of CSF samples to investigate the metabolites profile and explore biomarkers for TBEV infection. By analyzing CSF samples from 77 patients with TBEV infection and 23 without TBEV infection, tryptophan metabolism and Citrate cycle were found to be the top important metabolic pathways in differentiating the control and case groups; acetoacetate, 5’-deoxy-5’-(methylthio)-adenosine, 3-methyl-2-oxobutanoic acid,etc. were identified to be metabolic biomarkers（| log 2 FC|>1,VIP>1,FDR<0.05）in CSF and clearly separated the TBEV infection from the non-infected samples. Moreover, four metabolites were identified to be associated with fatal outcome, including kynurenic acid, 5-hydroxyindole-3-acetic acid, DL-tryptophan, indole-3-acrylic acid, demonstrating the potential predictive biomarkers for severe TBEV infection. This study explored the metabolic profile of TBEV infection both in CSF samples and identified candidate biomarkers for TBEV infection, which might be useful in target screening for differential diagnosis and therapeutic inter-vention.

Background: Approximately 1% of Sweden’s 90,000 annual deaths are caused by poisoning. In this study we aim to describe this poisoning population’s characteristics, autopsy frequency, and results of toxicology testing. Method: A national cohort study based on Swedish national registers. All deceased patients older than 18 years with poisoning as the cause of death registered between 1 th January 2000 to 31 th December 2021 were included. Causes of death according to primary ICD-10-code were analysed along with the substances found in forensic chemistry testing. Results: There were 27,057 poisonous deaths during the study periods 2,018,495 total adult deaths. Patients deceased due to poisoning had a median age of 53 years and 18,838 (70%) were men. A private home was the most reported location of death (52%). In total did 23,260 (87%) undergo some sort post-mortem examination. Drugs (synthetic narcotics, opioids, heroin) caused 12,448 (46%) deaths and alcohols explained 9,056 cases (33%). Positive toxicological tests were found in 22,550 (83%) of the subjects. The most common separate substances were ethanol, zopiclone and, nordazepam. Conclusion: Poisoning causes 1.3% of Swedish deaths. Men in their fifties are the most common victims and their death are often cause by synthetic narcotics, other opioids, or alcohol. The autopsy frequency is lower than expected for poisonous deaths.

This paper presents an AI-based framework designed for learning and regenerating analog circuits from academic papers. The framework comprises four distinct modules: circuit extractor, table extractor, text extractor, and simulation executor. The circuit extractor module utilizes deep learning object detection to identify devices and their associated textual descriptions while extracting interconnections between devices. The table extractor module handles textual and image-based tables, extracting device parameters and simulation data. The text extractor module leverages Optical Character Recognition (OCR) and AI models to extract supplementary information. The simulation executor employs this information to conduct simulations and optimize circuit performance. In our experiments, our method effectively extracts multimodal circuit design information, achieving an average accuracy of up to 97% in target detection within the circuit extractor module. The improved performance during the simulation process further validates the effectiveness of our framework.

Chalcones are α,β-unsaturated ketones, naturally produced as flavonoids and isoflavonoids precursors. Their privileged chemical structure enables their conjugation with different groups, aiming to improve their chemical properties and biological activities. Chalcone-sulfonamide hybrids display a range of biological activities and have been widely investigated for their anticancer potential, being considered promising molecules for cancer treatment. This systematic review aimed to summarize the information available in the literature about the anticancer potential of chalcones-sulfonamides in vitro and in vivo and their mechanisms of action. An electronic search was performed across scientific databases (PubMed, Web of Science, Emabase, and Scopus), and two blinded authors selected the studies according to the inclusion and exclusion criteria. The search yielded 1,467 articles, of which 18 were considered eligible for the review. Our analysis demonstrated that chalcones-sulfonamides are mainly obtained by Claisen-Schmidt condensation and can receive several functional groups, directly affecting their activity. Chemical substitutions often involve the addition of methoxy or chlorine groups at different positions of the molecule. Chalcones-sulfonamides demonstrated relevant cytotoxic potential in vitro and reduced tumor growth in vivo. The mechanisms underlying these effects involve oxidative stress, increased intracellular Reactive Oxygen Species (ROS), and DNA damage. The oxidative stress induced by chalcones-sulfonamides also seems to contribute to the inhibition of Carbonic Anhydrase, which is frequently overexpressed in cancer cells. Altogether, chalcones-sulfonamides may lead to cell death by different pathways, predominantly via apoptosis or necroptosis.

Title: A Diagnostic Challenge: Leukemia Cutis Masquerading as Infantile Hemangioma

Background Neuroendocrine tumors (NETs), although rare, are considered one of the most common gastrointestinal and bronchopulmonary pediatric neoplasms. We aimed to determine the incidence, tumor characteristics, management, and outcome of NETs and explore the role of genetic predisposition in a Danish pediatric population. Methods Using the Danish National Pathology Registry, we conducted a nationwide retrospective study including all Danish children aged ≤18 years diagnosed with a pathology-proven NET between 1995 and 2020. Results We identified 220 patients, with a 1.89:1 girl to boy ratio. The yearly incidence for Danish pediatric NETs was 6.84 per 1 million children, with no significant change in incidence throughout the observation period. NETs were located in the appendix (93.2%), the pulmonary system (4.5%) and pancreas (2.3%). One recurrence was noted in the pancreas in a genetically predisposed patient with multiple neuroendocrine neoplasia type 1 (MEN1), resulting in an overall recurrence rate of 0.5% (0% in appendiceal NETs; 0% in bronchopulmonary NETs; 20.0% in pancreatic NETs). No NET-related mortality was registered. Four patients had a known predisposing genetic condition, one appendiceal NET and neurofibromatosis type 1, and three pancreatic NETs associated with MEN1. Postsurgical surveillance regimes, choice of tumor markers, and imaging modality varied throughout the study period. Conclusions We confirmed a stable incidence of pediatric NETs during the study period. The overall recurrence rate was 0.5% and no NET-related mortality was observed. Known genetic predisposition was present in 1.8% of patients. Future guidelines should consider the apparent indolent nature and excellent prognosis of these tumors.

Following the increased mass mortality of Pinna nobilis populations in the Mediterranean, reliable protocols for the transport, maintenance and controlled reproduction of this highly endangered species were drawn up within the European Life Pinna project. To test these protocols the large Pinnidae Atrina fragilis, which shares similar habits to P. nobilis has been used. In December 2022, a transport trial of nine specimens of A. fragilis from Trieste (NE Italy) to Camogli (NW Italy) was carried out. Two positioning (vertical and horizontal) of the specimens were tested inside the transport box. In the laboratory, after acclimatisation, the specimens were placed inside three tanks and fed three times a week with a mix of live microalgae and artificial feed. The transport and maintenance protocols tested on A. fragilis were then applied to 11 P. nobilis collected in the Venice lagoon (NE Italy) and transported to the laboratory in June 2023. Due to the possible infection with Haplosporidium pinnae, considered one of the main etiological agents of mass mortality, P. nobilis the individuals were evaluated through molecular analyses during their stay in the tank. Furthermore, these specimens were used as breeders: they spontaneously released already fertilized eggs, as a consequence of transport stress. Rapid larval development stopped at the early veliger stage and the larvae were fed three times a week with a mixture of microalgae. After the reproduction period, the four specimens survived 6 months in the laboratory, and constantly tested negative for H. pinnae, were transplanted to the Capo Mortola Marine Protected Area (Liguria, Italy) and monitored monthly.