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Plants enter their reproductive phase when the environmental conditions are favourable for the successful production of progeny. The transition from vegetative to reproductive phase is influenced by several environmental factors including ambient temperature. In the model plant Arabidopsis thaliana, SHORT VEGETATIVE PHASE (SVP) is critical for this pathway; svp mutants cannot modify their flowering time in response to ambient temperature. SVP encodes a MADS-box transcription factor that directly represses genes that promote flowering. SVP binds DNA in complexes with other MADS-box transcription factors, including FLOWERING LOCUS M (FLM), which acts with SVP to repress the floral transition at low temperatures. Small temperature changes post-transcriptionally regulate FLM through temperature-dependent alternative splicing (TD-AS). As ambient temperature increases, the predominant FLM splice isoform shifts to encode a protein incapable of exerting a repressive effect on flowering. Here we characterize a closely related MADS-box transcription factor, MADS AFFECTING FLOWERING2 (MAF2), which has independently evolved TD-AS. At low temperatures the most abundant MAF2 splice variant encodes a protein that interacts with SVP to repress flowering. At increased temperature the relative abundance of splice isoforms shifts in favour of an intron-retaining variant that introduces a premature termination codon. We show that this isoform encodes a protein that cannot interact with SVP or repress flowering. At lower temperatures MAF2 and SVP repress flowering in parallel with FLM and SVP, providing an additional input to sense ambient temperature for the control of flowering.

The molecular mechanisms by which floral homeotic genes act as major developmental switches to specify the identity of floral organs are still largely unknown. Floral homeotic genes encode transcription factors of the MADS-box family, which are supposed to assemble in a combinatorial fashion into organ-specific multimeric protein complexes. Major mediators of protein interactions are MADS-domain proteins of the SEPALLATA subfamily, which play a crucial role in the development of all types of floral organs. In order to characterize the roles of the SEPALLATA3 transcription factor complexes at the molecular level, we analyzed genome-wide the direct targets of SEPALLATA3. We used chromatin immunoprecipitation followed by ultrahigh-throughput sequencing or hybridization to whole-genome tiling arrays to obtain genome-wide DNA-binding patterns of SEPALLATA3. The results demonstrate that SEPALLATA3 binds to thousands of sites in the genome. Most potential target sites that were strongly bound in wild-type inflorescences are also bound in the floral homeotic agamous mutant, which displays only the perianth organs, sepals, and petals. Characterization of the target genes shows that SEPALLATA3 integrates and modulates different growth-related and hormonal pathways in a combinatorial fashion with other MADS-box proteins and possibly with non-MADS transcription factors. In particular, the results suggest multiple links between SEPALLATA3 and auxin signaling pathways. Our gene expression analyses link the genomic binding site data with the phenotype of plants expressing a dominant repressor version of SEPALLATA3, suggesting that it modulates auxin response to facilitate floral organ outgrowth and morphogenesis. Furthermore, the binding of the SEPALLATA3 protein to cis-regulatory elements of other MADS-box genes and expression analyses reveal that this protein is a key component in the regulatory transcriptional network underlying the formation of floral organs.

Dermatological conditions account for a significant proportion of Emergency Department (ED) visits but are often misclassified at triage and managed without timely specialist input. A Dermatology Fast Track (DFT) pathway was implemented to improve diagnostic accuracy, optimize resource use, and enhance integration between ED and dermatology services. We conducted a retrospective study of patients referred through the DFT between April 2023 and October 2024. Demographics, triage codes, diagnoses, comorbidities, prior healthcare utilization, treatments, and follow-up were analyzed. Concordance between ED and dermatology-assigned triage codes was assessed using Cohen's kappa, and temporal trends in referrals were explored. Of 621 patients referred, 554 were included (mean age of 47.7 years and balanced sex distribution). Most were triaged green (75.6%) or white (23.1%), and 99.5% were discharged home. Infectious dermatoses (21.1%) and eczema (17.7%) were most frequent, with age-specific variations. Combined topical and systemic therapy was prescribed in 66.1% of cases, and 30.9% were referred for follow-up. Concordance between ED and dermatology triage codes was limited (58.7% agreement; Cohen's kappa 0.25), with frequent down-grading of priority by dermatologists. Seasonal peaks were observed, with higher demand during summer months. The DFT pathway streamlines ED care, ensuring timely management of acute dermatological conditions and reducing overcrowding. Seasonal demand fluctuations and discrepancies in triage highlight the need for targeted staff training, structured follow-up, and resource planning. Overall, the DFT is an effective model for enhancing ED efficiency, diagnostic accuracy, and patient care; however, as outcomes were assessed only in the DFT cohort and the study was conducted in a single center using Italy's color-coded triage system, the generalizability of these findings may be limited. Multicenter studies are needed to confirm its broader applicability.

While state sequence analysis (SSA) has been long used in social sciences, its use in pharmacoepidemiology is still in its infancy. Indeed, this technique is relatively easy to use, and its intrinsic visual nature may help investigators to untangle the latent information within prescription data, facilitating the individuation of specific patterns and possible inappropriate use of medications. In this paper, we provide an educational primer of the most important learning concepts and methods of SSA, including measurement of dissimilarities between sequences, the application of clustering methods to identify sequence patterns, the use of complexity measures for sequence patterns, the graphical visualization of sequences, and the use of SSA in predictive models. As a worked example, we present an application of SSA to opioid prescription patterns in patients with non-cancer pain, using real-world data from Italy. We show how SSA allows the identification of patterns in prescriptions in these data that might not be evident using standard statistical approaches and how these patterns are associated with future discontinuation of opioid therapy.

Introduction Computer-Aided Lung Informatics for Pathology Evaluation and Ratings (CALIPER) software has already been widely used in the evaluation of interstitial lung diseases (ILD) but has not yet been tested in patients affected by COVID-19. Our aim was to use it to describe the relationship between Coronavirus Disease 2019 (COVID-19) outcome and the CALIPER-detected pulmonary vascular-related structures (VRS). Materials and methods We performed a multicentric retrospective study enrolling 570 COVID-19 patients who performed a chest CT in emergency settings in two different institutions. Fifty-three age- and sex-matched healthy controls were also identified. Chest CTs were analyzed with CALIPER identifying the percentage of VRS over the total lung parenchyma. Patients were followed for up to 72 days recording mortality and required intensity of care. Results There was a statistically significant difference in VRS between COVID-19-positive patients and controls (median (iqr) 4.05 (3.74) and 1.57 (0.40) respectively, p  = 0.0001). VRS showed an increasing trend with the severity of care, p  < 0.0001. The univariate Cox regression model showed that VRS increase is a risk factor for mortality (HR 1.17, p  < 0.0001). The multivariate analysis demonstrated that VRS is an independent explanatory factor of mortality along with age (HR 1.13, p  < 0.0001). Conclusion Our study suggests that VRS increases with the required intensity of care, and it is an independent explanatory factor for mortality. Key Points • The percentage of vascular-related structure volume (VRS) in the lung is significatively increased in COVID-19 patients. • VRS showed an increasing trend with the required intensity of care, test for trend p< 0.0001. • Univariate and multivariate Cox models showed that VRS is a significant and independent explanatory factor of mortality.

The molecular mechanisms underlying the developmental processes that shape living organisms provide a basis to understand the evolution of biological complexity. Gene duplication allows biological functions to become separated, leading to increased complexity through subfunctionalization. Recently, the relative contributions to morphological evolution of changes to the regulatory and/or coding regions of duplicated genes have been the subject of debate. Duplication generated multiple copies of the MADS-box transcription factor genes that play essential roles in specifying organ identity in the flower, making this evolutionary novelty a good model to investigate the nature of the changes necessary to drive subfunctionalization. Here, we show that naturally occurring variation at a single amino acid in a MADS-box transcription factor switches its ability to specify male and female reproductive organs by altering its repertoire of protein–protein interactions. However, these different developmental fates are only manifest because of an underlying variation in the expression pattern of interacting proteins. This shows that the morphological outcomes of changes to protein sequence and gene expression must be interpreted in the context of the wider regulatory network. It also suggests an explanation for the surprisingly widespread duplications of some of the floral transcription factors.

ObjectiveTo find a definition of chronic disease based on literature review and to estimate the population-based prevalence rate of chronicity in a province in Northern Italy.DesignRetrospective observational study based on administrative databases.Data sources/settingArchives of the National Health Service that contain demographic and administrative information linked with the archives of ticket exemptions (2000–2019), the hospital discharge and drug prescriptions (2016–2019).ParticipantsSubjects who lived in Vercelli Local Health Authority, a Northern Italian province (Piedmont region), and were alive in December 2019.Main outcome measuresPrevalence of subjects with at least one chronic disease identified by administrative sources and stratification of population according to the number of comorbidities. The pathologies considered were: chronic ischaemic heart disease, congestive heart failure, cardiac arrhythmias, hypertension, stroke, neoplasm, asthma, chronic obstructive pulmonary disease, diabetes, thyroid disorders, osteoporosis, rheumatoid arthritis, chronic kidney disease, dementia, autism spectrum disorder, depression, schizophrenia, hepatitis, HIV and substance use disorders.ResultsOur target population was about 164 344 subjects. The overall prevalence of subjects with at least one chronic condition was 21.43% (n=35 212): 19 541 were female and 15 671 were male with a raw prevalence of 22.96% and 19.77%, respectively. The overall prevalence increases with age until 85 years old, then a decrease is observed. Moreover, 16.39% had only one pathology, 4.30% two diseases and 0.74% had a more complex clinical condition (more than three diseases).ConclusionsDespite the difficulty of having a unique definition of chronic disease, the prevalence obtained was coherent with the estimates reported by other national surveillance systems such as Passi and Passi d’Argento. Underestimates were observed when international comparisons were done; however, when we used less stringent definitions of chronic diseases, similar results were obtained.

Background: There is limited available data about the natural history and clinical characteristics of patients affected by high-grade vaginal intraepithelial neoplasia (or vaginal intraepithelial neoplasia 2/3 or vaginal high-grade squamous intraepithelial lesion, HSIL). The aim of the study was to review clinical characteristics and treatment outcomes of a large cohort of patients with vaginal HSIL. Methods: A retrospective analysis was performed for patients with histologically confirmed VaIN 2/3 treated at two Italian referral centers from 2003 to 2022. Demographics, referring cytology, associated cervical and vulvar HSIL treatment modalities, follow-up visits, and vaccination status were recorded. The primary outcome was risk of recurrence; the secondary outcome was risk of progression to invasive carcinoma after treatment. Results: 323 women were included in the analysis: 69.7% (225) had VaIN2, and 30.3% (98) had VaIN3. Mean age at diagnosis was 55.43 years (range 24–93 years). 20.4% had a previous hysterectomy, mainly for cervical intraepithelial neoplasia (CIN)/invasive squamous carcinoma (64.6%). In total, 55.2% underwent ablative therapy, and 44.8% underwent excisional treatment. Over a mean follow-up of 62.43 months, 22.0% of patients recurred as vaginal HSIL. At univariate analysis older age, VaIN grade 3, previous hysterectomy, associated cervical lesions, associated vulvar HSIL, and excisional treatment were significantly associated with increased risk of recurrence. At multivariate analysis, only hysterectomy and excisional treatment maintained significance. Five patients progressed to invasive vaginal carcinoma, with a median time to invasion of 87.1 months. Conclusions: The risk of recurrence of vaginal HSIL is higher in patients treated with excisional methods and/or those who have undergone hysterectomy for both benign and preinvasive lesions. Long-term follow-up is essential to monitor clinical outcomes and prevent disease progression.

Background Recently, many studies have investigated the role of migration on mental health. Nonetheless, only few focused on the consequences of childhood trauma, hopelessness, and resilience on migrants’ psychopathology, including psychiatric disorders and symptoms. Method 119 migrants were recruited between May 2017 and April 2018, among those applying for assessment to the Mental Health Operational Unit of the National Institute for Health, Migration and Poverty (NIHMP) in Rome, Italy. Assessment included the following: Zung Self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS), Connor-Davidson Resilience Scale (CD-RISC), Childhood Trauma Questionnaire (CTQ), Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), Beck Hopelessness Scale (BHS), Beck’s Suicide Intent Scale (SIS), Brief Aggression Questionnaire (BAQ), Deliberate Self-Harm Inventory (DSHI). Results 53.39% of migrants scored above the PCL-5 cut-off score (mean score was 39.45). SDS scores below the cutoff suggested the presence of depression in 42.37%, while According to SAS scores anxiety levels were low in 38.98% of migrants. During childhood, physical abuse and neglect were reported respectively by 56.78 and 69.49% of migrants. Conclusion We found that Post Traumatic Stress Disorders play the role of mediators for the relation between the childhood traumatic experiences and aggressiveness, anxious and depressive symptomatology, while hopelessness is a mediator between the childhood traumatic experiences and the development of depression in adulthood. Hopelessness seems to influence the strength of the relation between childhood traumatic experiences and the individual’s current intensity of suicidal attitudes, plans, and behaviors. Further developments and future perspectives of the research project are to address key gaps in the field of resilience by means of a longitudinal evaluation study in migrants, including a native population control group, acceding to NIHMP.

Members of the plant type I MADS domain subfamily have been reported to be involved in reproductive development in Arabidopsis (Arabidopsis thaliana). However, from the 61 type I genes in the Arabidopsis genome, only PHERES1, AGAMOUS-LIKE80 (AGL80), DIANA, AGL62, and AGL23 have been functionally characterized, which revealed important roles for these genes during female gametophyte and early seed development. The functions of the other genes are still unknown, despite the fact that the available single T-DNA insertion mutants have been largely investigated. The lack of mutant phenotypes is likely due to a considerable number of recent intrachromosomal duplications in the type I subfamily, resulting in nonfunctional genes in addition to a high level of redundancy. To enable a breakthrough in type I MADS box gene characterization, a framework needs to be established that allows the prediction of the functionality and redundancy of the type I genes. Here, we present a complete atlas of their expression patterns during female gametophyte and seed development in Arabidopsis, deduced from reporter lines containing translational fusions of the genes to green fluorescent protein and β-glucuronidase. All the expressed genes were revealed to be active in the female gametophyte or developing seed, indicating that the entire type I subfamily is involved in reproductive development in Arabidopsis. Interestingly, expression was predominantly observed in the central cell, antipodal cells, and chalazal endosperm. The combination of our expression results with phylogenetic and protein interaction data allows a better identification of putative redundantly acting genes and provides a useful tool for the functional characterization of the type I MADS box genes in Arabidopsis.