Colorectal cancer (CRC) is a common and highly metastatic cancer affecting people worldwide. Drug resistance and unwanted side effects are some of the limitations of current treatments for CRC. Naringenin (NAR) is a naturally occurring compound found in abundance in various citrus fruits such as oranges, grapefruits, and tomatoes. It possesses a diverse range of pharmacological and biological properties that are beneficial for human health. Numerous studies have highlighted its antioxidant, anti-cancer, and anti-inflammatory activities, making it a subject of interest in scientific research. This review provides a comprehensive overview of the effects of NAR on CRC. The study’s findings indicated that NAR: 1) interacts with estrogen receptors, 2) regulates the expression of genes related to the p53 signaling pathway, 3) promotes apoptosis by increasing the expression of proapoptotic genes (Bax, caspase9, and p53) and downregulation of the antiapoptotic gene Bcl2, 4) inhibits the activity of enzymes involved in cell survival and proliferation, 5) decreases cyclin D1 levels, 6) reduces the expression of cyclin-dependent kinases (Cdk4, Cdk6, Cdk7) and anti-apoptotic genes (Bcl2, x-IAP, c-IAP-2) in CRC cells. In vitro CDK2 binding assay was also performed, showing that the NAR derivatives had better inhibitory activities on CDK2 than NAR. Based on the findings of this study, NAR is a potential therapeutic agent for CRC. Additional pharmacology and pharmacokinetics studies are required to fully elucidate the mechanisms of action of NAR and establish the most suitable dose for subsequent clinical investigations.

Shelter-building insects are important ecosystem engineers, playing critical roles in structuring arthropod communities. Nonetheless, the influence of leaf shelters and arthropods on plant-associated microbiota remains largely unexplored. Arthropods that visit or inhabit plants can contribute to the leaf microbial community, resulting in significant changes in plant-microbe interactions. By artificially constructing leaf shelters, we provide evidence that shelter-building insects influence not only the arthropod community structure but also impact the phyllosphere microbiota. Leaf shelters exhibited higher abundance and richness of arthropods, leading to changes in the associated arthropod community composition. These shelters also altered the composition and community structure of phyllosphere microbiota, promoting greater richness and diversity of bacteria at the phyllosphere. In leaf shelters, microbial diversity increased with the richness and diversity of herbivores. These findings demonstrate the critical role of leaf shelters in structuring arthropod communities by facilitating colonization and influencing microbial communities through altered microhabitats and community interactions.

In Chlamydomonas, the directly light-gated, plasma membrane-localized (PM) cation channels channelrhodopsins ChR1 and ChR2 are the primary photoreceptors for phototaxis. Their targeting and abundance is essential for optimal movement responses. However, our knowledge how Chlamydomonas achieves this is still at its infancy. Here we show that ChR1 internalization occurs via light-stimulated endocytosis. Prior or during endocytosis ChR1 is modified and forms high molecular mass complexes. These are the solely detectable ChR1 forms in extracellular vesicles (EVs) and their abundance therein dynamically changes upon illumination. The ChR1-containing EVs are secreted via the PM and/or the ciliary base. In line with this, ciliogenesis mutants exhibit increased ChR1 degradation rates. Further, we establish involvement of two cysteine proteases in its turnover: CEP1, a papain-type C1A member, and a calpain. ΔCEP1 knock-out strains lack light-induced ChR1 degradation, whereas ChR2 degradation was unaffected. Low light stimulates CEP1 expression, which is regulated via phototropin, a SPA1 E3 ubiquitin ligase and cAMP. Further, mutant and inhibitor analyses revealed involvement of the small GTPase ARL11 and SUMOylation in ChR1 targeting to the eyespot and cilia. Our study thus defines the degradation pathway of this central photoreceptor of Chlamydomonas and identifies novel elements involved in its homeostasis and targeting.

Prescribing errors (PEs) can lead to patient harm. Prediction tools are available to detect patients at risk but are not ideal. We investigated whether doctors can identify hospitalized patients at risk of medication-related harm by assessing the prevalence of PEs. This matched case-control study was carried out on three clinical wards (Internal Medicine, Upper GI Surgery, and Otolaryngology & Oncology) in an academic hospital in the Netherlands. A total of 387 patients with 5191 prescriptions were included. A multidisciplinary in-hospital pharmacotherapeutic stewardship team detected 799 PEs affecting 279 patients (72.1%). Most (58.8%) PEs occurred during hospitalization. Doctors identified 40 patients (cases) as needing a clinical medication review (CMR). These patients were matched by age (10 years) and the number of prescriptions at the time of CMR (1), 1:1 with patients not selected for CMRs (controls). There were no significant differences in age, number of prescriptions, sex, renal function, or documented allergies or intolerances between the matched cases and controls or between controls and other patients who did not received a CMR. The incidence of PEs was higher among cases than controls, and more cases than controls had one or more PEs (97.5% versus 72.5% (OR=14.8, 95% CI [1.8 – 121.1], p=0.002)). The rate of PEs was three times higher in cases than in controls (IRR=3.0, 95% [2.3 – 4.0], p<0.001). In conclusion, clinical ward doctors can effectively identify patients with PEs thus at risk of medication-related harm. This may be a new and interesting selecting strategy for targeted PE-mitigating interventions.

Efficacy and safety of a 7-week immunotherapy protocol with aluminium hydroxide absorbed hymenoptera venomTo the Editor,Hymenoptera venom allergy can cause life threatening anaphylaxis in patients sensitised to wasp and bee venom. Venom immunotherapy is effective in 77%‐84% of patients treated with honeybee venom and in 91%‐96% of patients receiving vespid venom1. Adverse events are usually rare and mild, and symptoms occur in only 4.3%‐11.4% of patients during the updosing1.A variety of therapy regimes exist for the updosing phase, from conventional, rush, ultrarush or clustered modalities1,2. Current conventional protocols are time‐consuming for patients, and some patients decline the potentially life-saving treatment due to the time commitment required for immunotherapy. Adverse events appear to be less frequent in conventional protocols during the updosing phase compared to rush and ultrarush protocols1,2; however, patients may remain unprotected for weeks as it takes considerable time to reach the maintenance dose.The only licensed venom immunotherapy product in the UK is Alutard SQ® (ALK Abelló) for Vespula and Apidae venom. The SPC recommends updosing with a 7-week clustered protocol or 15- or 25-week conventional protocol.To enhance the acceptance of treatment and increase compliance, we reduced the length of the SPC protocol. Another significant factor was the COVID-19 pandemic, which significantly reduced outpatient capacity to comply with social distancing.Based on previous data using the same product3, we introduced a shorter updosing protocol with 8 injections in 7 weeks and monitored its efficacy and safety. We used this in a wider age range of patients, including one patient with indolent mastocytosis and more patients with severe sting reactions.Seventy‐four patients aged 17 to 85 years with a history of a systemic sting reaction to vespid and apidae stings grade 2-4 were included (Table 1). Further information about patient selection and the updosing protocol is in supplementary file S1.We managed to retain all the patients during updosing and maintenance, and no dose reduction was needed.During updosing, there were no objective systemic adverse reactions recorded. Only one objective systemic adverse reaction was documented during maintenance, which was mild and limited to the skin. There were 6 incidences of mild and subjective systemic reactions during updosing and maintenance, which included symptoms of feeling hot, dizzy and itchy. The symptoms were treated with additional antihistamines with no change in regime required. We had a lower incidence of systemic reactions at 1.4% compared to Schrautzer et al3, who reported objective systemic reactions in 3.9% of patients during just the updosing phase.9.5% of our patient cohort reported large localised reactions throughout both the updosing and maintenance phase, which generally only occurred once or twice during the full treatment course.The prevalence of cardiovascular disease and treatment with beta-blockers were not related to the occurrence of side effects.Reactions to field stings were monitored to assess efficacy as sting challenges are not performed in the UK. 20 patients had field stings and all reported localised reactions. Some patients were stung by multiple insects (such as one patient who was stung by 19 insects at one time) and this was more common in beekeepers.We have extended the work of Schrautzer et al3 and demonstrated the efficacy and safety of their 7-week protocol in a large group of patients in a real-world setting. We have also demonstrated safety and efficacy of the 7-week protocol for Alutard SQ® apidae immunotherapy. Our data includes a larger group of patients with more severe reactions. Interestingly, our data also shows a lower number of reactions to immunotherapy treatment.The quicker updosing protocol improved patients’ acceptance of treatment and increased the efficiency of our immunotherapy clinic in terms of time and cost for patients, and medical staff.

Objective: Clinical psychology, a pivotal aspect of psychology, combines research and practice. This study aims to assess the recent decade’s clinical psychology research, particularly post-COVID-19 paradigm shifts. Method: Analyzing 69,295 clinical psychology publications from 2010 to 2022 in the Web of Science database, we used advanced bibliometrics tools (CiteSpace and Mapequation) to scrutinize authorship networks, publishing trends, and research focus in the US, the field’s rigin. Results: We found a significant upswing in clinical psychology research prompted by the advent of the pandemic, particularly in the study of psychological trauma caused by issues such as family conflict, elder abuse, collective trauma, and so on. Clinical psychology research has been profoundly formed with a dynamic group of scholars and institutions, surrounding mainly higher education systems. Research participants are widely diverse, with a progressive focus transition to the populations on gender and race minorities, maternal, and adolescents. Mental disorder, such as PTSD, anxiety, and suicidal behaviors have caught more attention especially during the pandemic. Therapeutic approaches have long been another focus in clinical psychology, interventions such as mindfulness-based practice and AI-assisted technologies have started to gain prominence. Conclusions: This paper serves as the first large-scale bibliometrics analysis in clinical psychology, which offers an interdisciplinary collaboration potential with information science besides the originality of documenting publication trends in psychology. The integration of open data initiatives, machine learning, augmented reality, and virtual reality technologies shows promise in assessing mental health and fostering well-being, indicating an evolving landscape in clinical psychology research.

We are considered with the following nonlinear Schrödinger equation −∆ u+( λa( x)+1) u= f( u) ,x∈ V, on a locally finite graph G=( V,E), where V denotes the vertex set, E denotes the edge set, λ>1 is a parameter, f( s) is asymptotically linear with respect to s at infinity, and the potential a: V→[0 ,+∞) has a nonempty well Ω. By using variational methods we prove that the above problem has a ground state solution u λ for any λ>1. Moreover, we show that as λ→∞, the ground state solution u λ converges to a ground state solution of a Dirichlet problem defined on the potential well Ω.

A fifteen-year-old warmblood gelding was presented with recurrence of a histologically confirmed osteosarcoma of the left second and third metacarpal bones three years after initial diagnosis and treatment. Initially, surgical excision was performed, followed by local injection of carboplatin 11 weeks later. The horse was sound after surgery and was used for low level dressage and jumping. Three years later, the horse developed acute onset of lameness in the left forelimb and a painful soft tissue swelling at the proximomedial metacarpal region. Radiographs showed a spiculated periosteal reaction on the medial aspect of the third metacarpal bone, indicating re-activation of the lesion. Stereotactic radiation therapy was performed with a protocol consisting of three fractions under general anaesthesia (Mo-We-Fr schedule), and a total dose of 30 Gy. The technique used was volumetric modulated arc therapy guided by cone beam computed tomography for daily positioning. Following the radiation therapy, the horse became sound at walk and one month later, it became sound at trot. Follow-up by veterinary examination eighteen months after final treatment revealed no lameness at walk and trot, and a stable radiographic appearance.

Numerous challenges hinder the development of neuroprotective treatments for Parkinson’s disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α-synuclein is widely considered the most relevant model, however this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α-synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of AAV-α-synuclein and FN075 into the rat brain can replicate α-synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson’s disease. Rats received a unilateral injection of AAV-α-synuclein (or AAV-GFP) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post-mortem. As anticipated, AAV-α-synuclein led to extensive overexpression of human α-synuclein throughout the nigrostriatal pathway, as well as elevated levels of pathological and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α-synuclein pathology. Furthermore, despite the extensive α-synuclein pathology, neither administration of AAV-α-synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson’s disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson’s disease.

Background: Obesity has been associated with human obstructive sleep apnoea and canine brachycephalic obstructive airway syndrome. To the authors’ knowledge the effect of body condition score (BCS) on structures of the oropharynx , nasopharynx and upper airway of the horse has not been investigated. Objectives: To investigate the effect of BCS on tongue area and height, soft palate angle and basihyoid depth in the horse. Study Design: Retrospective, analytical, cross-sectional. Methods: Computed tomographic (CT) images of the head of 44 horses were assessed. DICOM viewing software was used to measure head length, basihyoid-skin depth, soft palate angle (SPA), midline tongue area and dorsoventral height (DVH) of the tongue in two locations. BCS were assigned at the time of CT examinations. Results: Increased BCS led to an increased mean SPA (mean difference=2.56 ˚ ; P=0.019) and increased median basihyoid depth (mean difference=0.246cm; P=0.006). Following adjustments made for the effect of head length on tongue measures, significant correlation was identified between SPA and tongue area (Spearman’s r=0.544; P=0.007); SPA and DVH of the tongue at the level of the hard palate (Spearman’s r=0.562; P=0.004) and SPA and DVH of the tongue at the lingual process of the basihyoid bone (Spearman’s r=0.690; P<0.001). No significant correlation was identified between variables with sex or age of horses. Conclusions: Increased BCS increases SPA and basihyoid bone depth. Increases in tongue size measurements increase SPA. Results from this study warrant further investigation into the clinical significance of the effects of BCS on the upper airways of the horse.

The importance of fine-root diameter for ecosystem functioning is increasingly recognized; yet, much remains to be learned about the variation in fine-root diameter at large scale. We conducted an analysis of fine-root diameter for 1,163 plant species to detect root diameter patterns in relation to resource availability (e.g. carbon, nitrogen and water), stress intensity (e.g. plant/soil biodiversity, soil bulk density) and temperature. First- to fourth-order root diameter showed non-linear relationships with latitude and/or mean annual temperature (except for first-order root diameter). The diameter of five root orders decreased with increasing mean annual precipitation, but increased with net primary production (NPP), which was the strongest determinant of fine-root diameter. Increasing soil biodiversity was associated with decreasing root diameter of fourth- to fifth-order roots while increased plant biodiversity was associated with decreasing diameter of first- to third-order roots. Total soil nitrogen had a positive effect on first-order root diameter, but a negative effect on fourth- and fifth-order root diameter. The patterns reversed for total soil phosphorus. First- to third-order and fifth-order root diameters increased with increasing soil bulk density. Second- to fourth-order root diameter increased with soil pH. Overall, the variables related to climate, biology and soil explained 44% to 63% of the total variance in the diameter of the different root orders. The unique patterns of plasticity observed in fine-root diameter across root orders in response to varying environmental conditions contributes to a diversification of strategies for nutrient/water acquisition and transport under climate change.

Gut bacterial communities provide flexibility to hosts during dietary changes. Despite the increasing number of studies exploring the associations between broader dietary guilds of mammalian hosts and their gut bacteria, it is generally unclear how diversity and variability in consumed diets link to gut bacteria in wild non-primate mammals. Here we contribute to filling this gap by exploring consumed diets and gut bacterial community compositions with metabarcoding of faecal samples for two African mammals, Civettictis civetta and Genetta spp., from the family Viverridae. For each individual sample, we characterised bacterial communities and identified dietary taxa by sequencing vertebrate, invertebrate, and plant markers. This led us to establish diet compositions that diverged from what has previously been found from visual identification methods. Specifically, while the two genera have been categorised into the same dietary guild, we detected more animal dietary items than plant items in C. Civetta, while in Genetta spp. we observed an opposite pattern. We further found that individuals with similar diets have similar gut bacterial communities in both species. This association tended to be driven by specific associations of dietary items to specific gut bacterial taxa, rather than entire communities, implying diet-driven selection for specific gut microbes in individual wild hosts. Our findings underline the importance of molecular tools for improving characterisations of wild mammalian diets and highlight the opportunities for simultaneously disentangling links between diets and gut symbionts. Such insights can inform robustness and flexibility in host-microbe symbioses to dietary change associated with seasonal and habitat change.

Tree transpiration dynamics and mechanisms in karst habitats are not fully understood due to the heterogeneous environmental features and complex species composition. Two common coexisting tree species, Mallotus philippensis and Celtis biondii, were examined in soil- and rock-dominated (SD and RD) karst habitats. Soil moisture, plant transpiration, root distribution, and leaf water potential were measured over two years (2021 and 2022). The mean water content was significantly lower in the RD than in the SD habitat. Transpiration patterns also differed between habitats, although species-specific distinctions were driven by leaf and root physiological traits. M. philippensis showed an isohydric tendency in both habitats and a lower density of fine roots, mostly in the soil zone, in the RD habitat. The transpiration of M. philippensis followed the variation in soil moisture, being lower in the RD habitat. Conversely, an anisohydric tendency in both habitats and a higher density of fine roots in both the soil and bedrock zones in the RD habitat were found in C. biondii. This species showed higher transpiration in the RD habitat, arising from ample water availability from soil and epikarst. Our findings reveal the regulatory mechanisms of species-specific root-zone water availability in transpiration patterns across karst habitats.

Influenza circulation was significantly affected in 2020–21 by the COVID-19 pandemic. During this time, few influenza cases were recorded. However, in the summer of 2021–22, an increase in atypical influenza cases was observed, leading to the resurgence of influenza in the southernmost state of Brazil, Rio Grande do Sul (RS). The present study aimed to identify FLUAV, FLUBV, and SARS-CoV-2 circulation and characterize influenza genomes in suspected COVID-19 patients using high-throughput sequencing technology. Respiratory samples (n = 694) from patients in RS were selected between July 2021 and August 2022. The samples were typed reverse transcriptase real-time PCR (RT-qPCR) and showed 32.13% (223/694) of the samples to be positive for SARS-CoV-2, 7.06% for FLUAV (49/694). FLUBV was not detected. RT-qPCR data also showed 0.57% of the cases had FLUAV and SARS-CoV-2 co-infections. Whole genome sequencing of the FLUAV positive specimens produced 15 complete genomes of H3N2 subtype with phylogenetic placement in the 3C.2a1b.2a.2a.3 subclade. Mutation analysis showed 73 amino acid substitutions in addition to several nonsynonymous mutations. The detected percentage of FLUAV (7.06%) is relatively similar to the total number of flu cases requiring hospitalization in RS state (8.9%), including those admitted to intensive care units for severe complications. This study provides insights into influenza virus circulation in the south of Brazil during the Omicron wave of the COVID-19 pandemic and reinforces the importance of H3N2 as a major driver of severe respiratory disease in the region along with the SARS-CoV-2 Omicron wave at the beginning of 2022.

Abstract Background: Health workforce supply is critical to ensuring the delivery of essential healthcare, and may be enhanced via mechanisms which alter the scopes of practice of health professions. The aim of this paper is to study the collective perspectives of allied health decision-makers on factors which influence their development and implementation of advanced and extended scope of practice initiatives, and the timing/catalyst and application of their decision-making. Methods: A grounded-theory, qualitative study of the experiences of allied health directors and senior managers across two Australian jurisdictions. Results: Twenty allied health decision-makers met study eligibility criteria. Data coding of interview transcripts identified 14 factors specific to scope of practice change, spanning rational (n=8) and non-rational (n=6) decision-making approaches. Leadership, Governance, Organisational need, Resourcing, Knowledge & Skills – clinical, Supporting resources, Knowledge & skills – change and Sustainability were identified as being rational and enabling in and of themselves, with Leadership seen as being most influential. Comparatively, the non-rational factors of Socio-economic & political environment, Perceived patient need, Organisational environment, Change culture & appetite, Perceived professional territorialism and Actual professional territorialism were more varied, and primarily influenced the timing/catalyst and application of decision-making. Conclusion : Allied health decision-makers hold a complex, systems-level understanding of scope of practice change. Whilst rational decision criteria were predominant and seen to enable scope change, non-rational influences reflected greater variation in decision timing/catalyst and application, thus emphasising the human dimensions of decision-making. Further research is required to better understand how decision-makers integrate and weight decision-making factors to inform the development of structured decision tools.

A large and growing corpus of epidemiologic studies suggests that the population-level burden of pediatric FA is not equitably distributed across major sociodemographic groups, including race, ethnicity, household income, parental educational attainment, sex). As is the case for more extensively studied allergic disease states such as asthma and atopic dermatitis) epidemiologic data suggest that FA may be more prevalent among certain populations experiencing lower socioeconomic status (SES), particularly those with specific racial and ethnic minority backgrounds living in highly urbanized regions. Emerging data also indicate that these patients may also experience more severe FA-related physical health, psychosocial and economic outcomes relating to chronic disease management. However, many studies that have identified sociodemographic inequities in FA burden are limited by cross-sectional designs that are subject to numerous biases, which can reduce the epidemiologic utility of the resulting estimates. Compared to cross-sectional study designs or cohorts that are recruited during childhood, birth cohorts can offer advantages relative to other study designs when investigators seek to understand causal relationships between exposures occurring during the prenatal or postnatal period and the atopic disease status of individuals later in life. Numerous birth cohorts have been established across recent decades, which include evaluation of food allergy-related outcomes, and a subset of these also have measured sociodemographic variables that, together, have the potential to shed light on the existence and possible etiology of sociodemographic inequities in food allergy. This manuscript attempts to survey the current state of this birth cohort literature and draw insights regarding what is currently known, and what further information can potentially be gleaned from thoughtful examination and further follow-up of ongoing birth cohorts across the globe.

Adaptation is defined as reduced neural activation following repeated stimulus presentation. While numerous previous electroencephalogram studies used either one repetition or multiple repetitions to elicit adaptation in event-related potentials, the adaptation patterns under controlled expectations manifested in the two main auditory components, N1 and P2, are still largely unknown. In addition, multiple repetitions were used in mismatch negativity experiments to measure deviance detection, but how adaptation in different time points contributes to the mismatch negativity remains unclear. Therefore, in the present study, 37 healthy adults participated in an electroencephalogram experiment with a pure tone roving paradigm and a random stimulus arrangement to maintain expectations. The amplitudes were traced along with the first ten tones in the auditory event-related potentials components, N1 and P2, to examine the adaptation patterns. Results showed an L-shaped adaptation in the N1 with a large decrease after the first repetition (N1 initial adaptation), and a continuous, linear amplitude increase in the P2 even after the first repetition (P2 subsequent adaptation), possibly indicating memory trace formation. Regression results showed that the peak amplitudes of the N1 initial adaptation and the P2 subsequent adaptation significantly explained the variance in the mismatch negativity amplitude. The results indicate distinct adaptation patterns for multiple repetitions in different components and suggest that the mismatch negativity combines two processes as indicated by the initial adaptation in the N1 and a continuous memory trace effect in the P2. Separating the two processes may be relevant for models of cognitive processing and clinical disorders.

Trace elements and minerals can be important for physiological and biochemical functions in aquatic organisms and are also permanently retained in metabolically inert structures in fish, such as otoliths, which can be examined to reconstruct environmental history. Despite the importance of trace elements for biological function and environmental reconstruction, their distribution and dynamics in river systems is poorly understood. The objective of our study was to quantify trace element concentration data from across 14 river basins in Georgia, USA to create elemental concentration profiles and illustrate how spatial changes in water chemistry can be used to construct research hypotheses or make management decisions using results from chemical analyses on hard calcified parts of fish. Principal component analysis revealed substantial variation in water chemistry among and with river basins. Pairwise comparisons of Sr:Ca and Ba:Ca ratios were useful in quantifying specific differences among river systems within river basins. These data will be useful for establishing a baseline for long-term water chemistry monitoring and provides a framework for future fish chemistry research.