The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer.

Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.

Targeted Enhancer Activation by a Subunit of the Integrator Complex.

The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation.

Direct repression of Nanog and Oct4 by OTX2 modulates the contribution of epiblast-derived cells to germline and somatic lineage.

In mammals, the pre-gastrula proximal epiblast gives rise to primordial germ cells (PGCs) or somatic precursors in response to BMP4 and WNT signaling. Entry into the germline requires activation of a naïve-like pluripotency gene regulatory network (GRN). Recent work has shown that suppression of OTX2 expression in the epiblast by BMP4 allows cells to develop a PGC fate in a precise temporal window. However, the mechanisms by which OTX2 suppresses PGC fate are unknown. Here, we show that, in mice, OTX2 prevents epiblast cells from activating the pluripotency GRN by direct repression of Oct4 and Nanog. Loss of this control during PGC differentiation in vitro causes widespread activation of the pluripotency GRN and a deregulated response to LIF, BMP4 and WNT signaling. These abnormalities, in specific cell culture conditions, result in massive germline entry at the expense of somatic mesoderm differentiation. Increased generation of PGCs also occurs in mutant embryos. We propose that the OTX2-mediated repressive control of Oct4 and Nanog is the basis of the mechanism that determines epiblast contribution to germline and somatic lineage.

Application of the Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the empiric antibiotic treatment of febrile neutropenia in oncological paediatric patients: experience from two paediatric hospitals in Northern Italy.

BACKGROUND: Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. METHODS: We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. RESULTS: We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin-tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin-tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. CONCLUSIONS: The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Comparative study showed that children faced a 78% higher risk of new-onset conditions after they had COVID-19.

AIM: Children have largely been unaffected by severe COVID-19 compared to adults, but data suggest that they may have experienced new conditions after developing the disease. We compared outcomes in children who had experienced COVID-19 and healthy controls. METHODS: A retrospective nested cohort study assessed the incidence rate of new-onset conditions after COVID-19 in children aged 0-14 years. Data were retrieved from an Italian paediatric primary care database linked to Veneto Region registries. Exposed children with a positive nasopharyngeal swab were matched 1:1 with unexposed children who had tested negative. Conditional Cox regression was fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the exposure and outcome associations after adjusting for covariates. RESULTS: We compared 1656 exposed and 1656 unexposed children from 1 February 2020 to 30 November 2021. The overall excess risk for new-onset conditions after COVID-19 was 78% higher in the exposed than unexposed children. We found significantly higher risks for some new conditions in exposed children, including mental health issues (aHR 1.8, 95% CI 1.1-3.0) and neurological problems (aHR 2.4, 95% CI 1.4-4.1). CONCLUSION: Exposed children had a 78% higher risk of developing new conditions of interest after COVID-19 than unexposed children.

Empirical Antimicrobial Therapy of Neonates with Necrotizing Enterocolitis: A Systematic Review.

OBJECTIVE: Necrotizing enterocolitis (NEC) is an inflammatory disease of the gastrointestinal tract characterized by ischemic necrosis of the intestinal mucosa, mostly affecting premature neonates. Management of NEC includes medical care and surgical approaches, with supportive care and empirical antibiotic therapy recommended to avoid any disease progression. However, there is still no clear evidence-based consensus on empiric antibiotic strategies or surgical timing. This study was aimed to review the available evidence on the effectiveness and safety of different antibiotic regimens for NEC. STUDY DESIGN: MEDLINE, EMBASE, Cochrane CENTRAL, and CINAHL databases were systematically searched through May 31, 2020. Randomized controlled trials (RCTs) and nonrandomized interventions reporting data on predefined outcomes related to NEC treatments were included. Clinical trials were assessed using the criteria and standard methods of the Cochrane risk of bias tool for randomized trials, while the risk of bias in nonrandomized studies of interventions was evaluated using the ROBINS-I tool. The certainty in evidence of each outcome's effects was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Five studies were included in this review, two RCTs and three observational studies, for a total amount of 3,161 patients. One RCT compared the outcomes of parenteral (ampicillin plus gentamicin) and oral (gentamicin) treatment with parenteral only. Three studies (one RCT and two observational) evaluated adding anaerobic coverage to different parenteral regimens. The last observational study compared two different parenteral antibiotic combinations (ampicillin and gentamicin vs. cefotaxime and vancomycin). CONCLUSION: No antimicrobial regimen has been shown to be superior to ampicillin and gentamicin in decreasing mortality and preventing clinical deterioration in NEC. The use of additional antibiotics providing anaerobic coverage, typically metronidazole, or use of other broad-spectrum regimens as first-line empiric therapy is not supported by the very limited current evidence. Well-conducted, appropriately sized comparative trials are needed to make evidence-based recommendations. KEY POINTS: · Ampicillin and gentamicin are effective in decreasing mortality and preventing clinical deterioration in NEC.. · Metronidazole could be added in patients with surgical NEC.. · No study with high-quality evidence was found..

A Systematic Review of European Clinical Practice Guidelines for Respiratory Syncytial Virus Prophylaxis.

BACKGROUND: Since the widespread adoption of palivizumab prophylaxis in Europe, there have been a number of clinical practice guidelines (CPGs) published for the prevention of respiratory syncytial virus (RSV) infection in children. The aim of this systematic review was to identify CPGs for the prevention of RSV infection across Europe. METHODS: We performed a systematic literature search and contacted European influenza and respiratory virus networks and public health institutions, to identify national CPGs for the prevention of RSV infection. The Reporting Items for practice Guidelines in Healthcare (RIGHT) Statement checklist was applied to extract data and review the quality of reporting. RESULTS: A total of 20 national CPGs were identified, all published between 2000 and 2018. The greatest discrepancy between guidelines was the recommendations for palivizumab prophylaxis for premature infants, with recommendations varying by gestational age. All guidelines recommended or considered the use of palivizumab in infants with bronchopulmonary dysplasia, 85% (n = 17) in children with congenital heart disease (CHD), and 60% (n = 12) in children with severe combined immunodeficiency. CONCLUSIONS: We recommend that agencies publishing RSV prevention guidelines adopt the RIGHT reporting requirements when updating these guidelines to improve the presentation of the evidence-base for decisions.

SARS-CoV-2 infection in people living with HIV: a systematic review.

BACKGROUND AND SETTING: Little is known about SARS-CoV-2 impact on some vulnerable subgroups, such as people living with HIV/AIDS (PLWHA). In our study we reviewed the current knowledge on SARS-CoV-2 cases in PLWHA. METHODS: A systematic review was conducted by searching the MEDLINE, EMBASE and Google Scholar databases. Studies reporting data on PLWHA affected by SARS-CoV-2 were considered for inclusion. The aim of this study was the systematic characterization of cases of SARS-CoV-2 infection among PLWHA, particularly focusing on age, clinical findings at diagnosis, radiological features, therapeutic management and clinical outcomes. RESULTS: Twenty three relevant articles were identified, which reported 164 adults with both HIV and SARS-CoV-2 infection. Of those, the large majority were males (120/142, 84.5%), often with one or more comorbidities. Fifteen cases needed intensive care treatment and 16 died. For each group, respectively three patients had underlying comorbidities. There were no studies on children. The included studies were mostly retrospective or case series/reports (19 studies). The overall risk of bias was moderate, due to the study types and characteristics. CONCLUSION: It is still unclear if HIV infection may influence SARS-CoV-2 infection and disease course, however some PLWHA and particularly males affected by ARV-related complications may be at greater risk of severe Covid-19 course.

Industrial policy for sustainable human development in the post-Covid19 era.

National and local societies all around the world are fighting the most dramatic global public health emergency of our time, which has soon become an economic, social and human crisis touching all key dimensions of our lives. Within an inevitable revamping attention on the need for government intervention to face the challenges raised by the Covid19 pandemic, industrial policy is appearing as a central piece of the puzzle. As production dynamics in every country is highly affected by the crisis, industrial policy is considered part of the response to solve dramatic economic and social problems deriving by extraordinary levels of unemployment, deprivation and poverty. In this paper, we argue that a turning point on the connection between industrial policy, sustainability and development has been reached, highlighting the need to rethink its theoretical foundations as well as its governance and implementation processes for a new role in our post-Covid 19 societies. Therefore, the research question underlying this paper deals primarily with the nexus between the debate on industrial policy and its effects in terms of human development, social cohesion and sustainability. For this reason, we attempt at closing the gap between different strands of literature, whose integrated connection leads to a new analytical framework with real-world implications on the role of industrial policy, not only as tool for productive dynamics, but also as a leverage for sustainable human development. All in all, we aim at contributing to the debate on our post-Covid19 economies and societies in two ways: firstly, by providing a new integrated analytical framework on industrial policy to steer a sustainable structural change of our economies and societies towards sustainable human development; secondly, by identifying preliminary implications on industrial policy governance and implementation, investing in the accurate and transparent design of industrial policy in the post-Covid19 era.

Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.

During wound repair, branching morphogenesis and carcinoma dissemination, cellular rearrangements are fostered by a solid-to-liquid transition, known as unjamming. The biomolecular machinery behind unjamming and its pathophysiological relevance remain, however, unclear. Here, we study unjamming in a variety of normal and tumorigenic epithelial two-dimensional (2D) and 3D collectives. Biologically, the increased level of the small GTPase RAB5A sparks unjamming by promoting non-clathrin-dependent internalization of epidermal growth factor receptor that leads to hyperactivation of the kinase ERK1/2 and phosphorylation of the actin nucleator WAVE2. This cascade triggers collective motility effects with striking biophysical consequences. Specifically, unjamming in tumour spheroids is accompanied by persistent and coordinated rotations that progressively remodel the extracellular matrix, while simultaneously fluidizing cells at the periphery. This concurrent action results in collective invasion, supporting the concept that the endo-ERK1/2 pathway is a physicochemical switch to initiate collective invasion and dissemination of otherwise jammed carcinoma.

DRP1-dependent apoptotic mitochondrial fission occurs independently of BAX, BAK and APAF1 to amplify cell death by BID and oxidative stress.

During apoptosis mitochondria undergo cristae remodeling and fragmentation, but how the latter relates to outer membrane permeabilization and downstream caspase activation is unclear. Here we show that the mitochondrial fission protein Dynamin Related Protein (Drp) 1 participates in cytochrome c release by selected intrinsic death stimuli. While Bax, Bak double deficient (DKO) and Apaf1(-/-) mouse embryonic fibroblasts (MEFs) were less susceptible to apoptosis by Bcl-2 family member BID, H(2)O(2), staurosporine and thapsigargin, Drp1(-/-) MEFs were protected only from BID and H(2)O(2). Resistance to cell death of Drp1(-/-) and DKO MEFs correlated with blunted cytochrome c release, whereas mitochondrial fragmentation occurred in all cell lines in response to all tested stimuli, indicating that other mechanisms accounted for the reduced cytochrome c release. Indeed, cristae remodeling was reduced in Drp1(-/-) cells, potentially explaining their resistance to apoptosis. Our results indicate that caspase-independent mitochondrial fission and Drp1-dependent cristae remodeling amplify apoptosis. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.

A population database analysis to estimate the varicella vaccine effectiveness in children < 14 years in a high vaccination coverage area from 2004 to 2022.

INTRODUCTION: In the Veneto Region of Italy, universal varicella vaccination (VV) started in 2007 with a two-dose schedule at 12-15 months and 5-6 years of age achieving 90 % coverage in 2019. The study aimed at evaluating the vaccine effectiveness (VE) in children using a primary-care database METHODS: This retrospective analysis used Pedianet, a comprehensive database of 73 family paediatricians in the Veneto Region. Incidence rates (IR) of varicella were evaluated in children aged <14 years enrolled since birth, between January 2004 to April 2022. Cases were classified as breakthrough if happening beyond 42 days post-VV. Complications and prescription were evaluated. Subject were followed up from 2004 or the enrollment date, until the end of assistance/study or the first or second VV dose. Kaplan-Meier curves and log-rank tests were used to compare the varicella incidence by vaccination status. Hazard ratios of varicella infection, adjusted (aHRs) for sex, vaccinal status, age group, prematurity and socioeconomic status were estimated with Cox's regression. VE for one and two VV doses was defined as 1-aHR*. RESULTS: 36,498 children, followed for 233,508 person-years from 2004 to 2022 experienced 1006 cases of varicella (13 complicated and 35 breakthrough). Younger children had a higher risk of experiencing varicella compared to children aged >7 years, irrespective of their vaccination status. Indeed, the IR increased from 5.5 to 19.5 × 1000 person-years and from 1.1 to 5.4 × 1000 person-years in unvaccinated and vaccinated children aged <12 months versus those aged 5-6 years, respectively. Varicella VE was 83.4 % and 94.7 % in those vaccinated with one and two doses. After six years, the cumulative probability of experiencing varicella was 10.7 % for unvaccinated subjects, and 2.5 % and 0.4 % for those vaccinated with one and two-doses (log-rank test, p < 0.001). CONCLUSIONS: Two-dose schedule VV is effective in drastically reduce varicella episodes. Breakthrough varicella episodes remain rare events.

Association Between Early-Life Exposure to Antibiotics and Development of Child Obesity: Population-Based Study in Italy.

BACKGROUND: Childhood obesity is a significant public health problem representing the most severe challenge in the world. Antibiotic exposure in early life has been identified as a potential factor that can disrupt the development of the gut microbiome, which may have implications for obesity. OBJECTIVE: This study aims to evaluate the risk of developing obesity among children exposed to antibiotics early in life. METHODS: An Italian retrospective pediatric population-based cohort study of children born between 2004 and 2018 was adopted using the Pedianet database. Children were required to be born at term, with normal weight, and without genetic diseases or congenital anomalies. We assessed the timing of the first antibiotic prescription from birth to 6, 12, and 24 months of life and the dose-response relationship via the number of antibiotic prescriptions recorded in the first year of life (none, 1, 2, and ≥3 prescriptions). Obesity was defined as a BMI z score >3 for children aged ≤5 years and >2 for children aged >5 years, using the World Health Organization growth references. The obese incidence rate (IR) × 100 person-years and the relative 95% CI were computed using infant sex, area of residence, preschool and school age, and area deprivation index, which are the covariates of interest. A mixed-effect Cox proportional hazards model was used to estimate the hazard ratio and 95% CI for the association between antibiotic exposure in early life and child obesity between 24 months and 14 years of age, considering the family pediatricians as a random factor. Several subgroup and sensitivity analyses were performed to assess the robustness of our results. RESULTS: Among 121,540 children identified, 54,698 were prescribed at least an antibiotic within the first year of life and 26,990 were classified as obese during follow-up with an incidence rate of 4.05 cases (95% CI 4.01-4.10) × 100 person-year. The risk of obesity remained consistent across different timings of antibiotic prescriptions at 6 months, 1 year, and 2 years (fully adjusted hazard ratio [aHR] 1.07, 95% CI 1.04-1.10; aHR 1.06, 95% CI 1.03-1.09; and aHR 1.07, 95% CI 1.04-1.10, respectively). Increasing the number of antibiotic exposures increases the risk of obesity significantly (P trend<.001). The individual-specific age analysis showed that starting antibiotic therapy very early (between 0 and 5 months) had the greatest impact (aHR 1.12, 95% CI 1.08-1.17) on childhood obesity with respect to what was observed among those who were first prescribed antibiotics after the fifth month of life. These results were consistent across subgroup and sensitivity analyses. CONCLUSIONS: The results from this large population-based study support the association between early exposure to antibiotics and an increased risk of childhood obesity. This association becomes progressively stronger with both increasing numbers of antibiotic prescriptions and younger age at the time of the first prescription.

Validation of Administrative Data and Timing of Point Prevalence Surveys for Antibiotic Monitoring.

Importance: Point prevalence surveys (PPSs) are used globally to collect data on antibiotic prescriptions. However, the optimal frequency for data collection to ensure comprehensive understanding of antibiotic use and to target and monitor stewardship interventions remains unknown. Objective: To identify the optimal frequency for collecting data on antibiotic use among the pediatric population through PPSs leveraging administrative data. Design, Setting, and Participants: This prognostic study used a cross-sectional validation approach and was conducted in pediatric outpatient and inpatient settings in the Veneto region of Italy. Antibiotics were classified according to the World Health Organization Access, Watch and Reserve criteria. Prescribing rates of access antibiotics were analyzed for pediatric inpatients with records dated between October 1, 2014, and December 31, 2022, and outpatients with records dated between January 1, 2010, and December 31, 2022. The study included children younger than 15 years with an antibiotic prescription who were admitted to the pediatric acute care unit or evaluated by a primary care pediatrician. Data analysis was performed from October 2023 to January 2024. Main Outcomes and Measures: An algorithm was developed to identify optimal time frames for conducting PPSs. This approach sought to minimize the discrepancy between quarterly and yearly PPS results, aiming to accurately estimate annual antibiotic prescribing rates in both inpatient and outpatient settings (primary outcome). External validity of the optimal PPS time frames derived from outpatient data when applied to the inpatient setting was also investigated. Validation involved assessing the effectiveness of administrative data in identifying strategic PPS periods for capturing inpatient antibiotic use patterns (secondary outcome). Results: This analysis included 106 309 children: 3124 were inpatients (1773 males [56.8%]) and 103 185 were outpatients (53 651 males [52.0%]). A total of 5099 and 474 867 antibiotic prescriptions from inpatients and outpatients were analyzed, respectively. Outpatients tended to be older than inpatients, with a median age of 3.2 (IQR, 1.3-6.3) years vs 2.6 (IQR, 0.6-6.6) years, respectively, and with a lower burden of clinical comorbidities (≥1 comorbidity: 6618 [6.4%] vs 1141 [36.5%], respectively). The algorithm successfully identified distinct time frames within the calendar year from inpatient and outpatient records optimized for PPS data collection. Rates obtained from the quarterly PPS during these identified periods exhibited greater agreement with annual antibiotic prescribing rates (inpatient: r = 0.17, P < .001; and outpatient: r = 0.42, P < .001) than those derived from the yearly PPS (inpatient: r = 0.04, P = .58; and outpatient: r = 0.05, P = .34), with a Δ reduction of up to 89.8% (where Δ represents the percentage point change in antibiotic prescribing rates). Furthermore, the optimal PPS time frames gleaned from the outpatient data demonstrated robust applicability to the inpatient setting, yielding comparable results in both scenarios. Conclusions and Relevance: This study evaluated the potential of administrative data in determining the optimal timing of PPS implementation. The quarterly PPS balanced precision and sustainability, especially when implemented during strategically selected periods across different seasons. Further studies are needed to validate the algorithm used in this study, especially in post-COVID-19 pandemic years and different settings.

Comparison between the Viral Illness Caused by SARS-CoV-2, Influenza Virus, Respiratory Syncytial Virus and Other Respiratory Viruses in Pediatrics.

Respiratory tract infections (RTIs) are the most common infectious syndromes, primarily caused by viruses. The primary objective was to compare the illness courses between historical RTIs and recent SARS-CoV-2 infections. The study cohort consisted of RTI cases evaluated at the Pediatric Emergency Departments of Padua and Bologna, discharged or admitted with microbiologically confirmed viral RTI between 1 November 2018 and 30 April 2019 (historical period) and 1 March 2020 and 30 April 2021 (recent period). We evaluated the risk of oxygen or respiratory support, hospitalization, antibiotic therapy, and complications among different viral infections. The odds ratio (OR) and the 95% confidence intervals (CIs) were estimated through mixed-effect logistic regression models, including a random intercept on the individual and hospital. We identified 767 RTIs: 359 in the historical period compared with 408 SARS-CoV-2 infections. Infections of SARS-CoV-2 had a lower risk of being admitted (OR 0.04, 95% CI 0.03-0.07), receiving respiratory support (OR 0.19, 95% CI 0.06-0.58), needing antibiotic therapy (OR 0.35, 95% CI 0.22-0.56) and developing complications (OR 0.27, 95% CI 0.14-0.51) compared to all other viral RTIs. COVID-19 in children is clinically similar to other viral RTIs but is associated with a less severe infection course. Thus, most prevention strategies implemented for SARS-CoV-2 should still be considered during RSV and Influenza epidemics.

A tripartite organelle platform links growth factor receptor signaling to mitochondrial metabolism.

One open question in the biology of growth factor receptors is how a quantitative input (i.e., ligand concentration) is decoded by the cell to produce specific response(s). Here, we show that an EGFR endocytic mechanism, non-clathrin endocytosis (NCE), which is activated only at high ligand concentrations and targets receptor to degradation, requires a tripartite organelle platform involving the plasma membrane (PM), endoplasmic reticulum (ER) and mitochondria. At these contact sites, EGFR-dependent, ER-generated Ca2+ oscillations are sensed by mitochondria, leading to increased metabolism and ATP production. Locally released ATP is required for cortical actin remodeling and EGFR-NCE vesicle fission. The same biochemical circuitry is also needed for an effector function of EGFR, i.e., collective motility. The multiorganelle signaling platform herein described mediates direct communication between EGFR signaling and mitochondrial metabolism, and is predicted to have a broad impact on cell physiology as it is activated by another growth factor receptor, HGFR/MET.

Epidemiology of pediatric psoriasis: a population-based study using two Italian data sources.

BACKGROUND: Psoriasis can be associated with certain comorbidities. This information is important for family pediatricians (FPs) and general practitioners (GPs) who have a key role in the identification and management of skin diseases. This study aimed to assess the incidence and prevalence rates of pediatrics psoriasis and its association with specific comorbidities. METHODS: A retrospective cohort study was performed in patients aged less than 18 years registered in two Italian primary care databases (Pedianet and HSD) between 2015 and 2019. Prevalence and incidence of psoriasis were estimated, and a case-control design was adopted to assess specific comorbidities in psoriasis patients. RESULTS: The annual prevalence rate of psoriasis was 0.2% in Pedianet and between 0.5% and 0.7% in HSD. The incidence rate ranged from 0.47 to 0.58 and from 1.3 to 1.77 per 1000 person-years in Pedianet and HSD, respectively. Allergic rhinitis, asthma, celiac disease, other malabsorption disease and non-infective cutaneous diseases showed a statistically significant association with psoriasis in Pedianet, while no statistically significant difference was found in HSD. CONCLUSION: Given the FP-GP transition of patients, there is a need for accurate registration of clinical correlates, enabling GPs to implement strategies to minimize the lifetime risk of psoriatic progression.

Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project.

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.

The impact of Antimicrobial Stewardship Programmes in paediatric emergency departments and primary care: a systematic review.

Background: Antibiotics remain the most prescribed medicine in children worldwide, but half of the prescriptions are unnecessary or inappropriate, leading to an increase in antibiotic resistance. This study aims to systemically review the effects of different Antimicrobial Stewardship Programmes (ASPs) on reducing the rates of both antibiotic prescriptions and changes in antimicrobial resistance, and on the economic impact in paediatric emergency departments (PED) and primary care settings. Materials and methods: Embase, MEDLINE, and Cochrane Library were systematically searched, combining Medical Subject Heading and free-text terms for 'children' and 'antimicrobial' and 'stewardship'. The search strategy involved restrictions on dates (from 1 January 2007 to 30 December 2020) but not on language. Randomized controlled trials, controlled and non-controlled before and after studies, controlled and non-controlled interrupted time series, and cohort studies were included for review. The review protocol was registered at the PROSPERO International Prospective Register of Systematic Reviews: Registration Number CRD42021270630. Results: Of the 47,158 articles that remained after removing duplicates, 59 were eligible for inclusion. Most of the studies were published after 2015 (37/59, 62.7%) and in high-income countries (51/59, 86.4%). Almost half of the studies described the implementation of an ASP in the primary care setting (28/59, 47.5%), while 15 manuscripts described the implementation of ASPs in EDs (15/59, 25.4%). More than half of the studies (43/59, 72.9%) described the implementation of multiple interventions, whereas few studies considered the implementation of a single intervention. Antibiotic prescriptions and compliance with guidelines were the most frequent outcomes (47/59, 79.7% and 20/59, 33.9%, respectively). Most of the articles reported an improvement in these outcomes after implementing an ASP. Meanwhile, only very few studies focused on health care costs (6/59, 10.2%) and antimicrobial resistance (3/59 5.1%). Conclusion: The implementation of ASPs has been proven to be feasible and valuable, even in challenging settings such as Emergency Departments and Primary care.