Challenges and opportunities in pediatric residency: an analysis of the increasing number of residents in Italy.

BACKGROUND: Pediatric residency in Italy has undergone significant changes in recent years, with a notable increase in the number of pediatric residents. Exploring the implications of this increase, highlighting disparities in training opportunities, and discussing the broader socio-economic impacts on pediatric healthcare, represent a crucial consideration for the healthcare system in the future. MAIN BODY: The Italian National Association of Pediatric Residents ("Osservatorio Nazionale Specializzandi in Pediatria", ONSP) conducted an extensive survey among pediatric residents to assess the current state of pediatric residency. Key findings indicate that 50% of respondents believe the number of residents is excessive for the available training opportunities, leading to concerns about the quality of education and hands-on experience. Despite the increased number of residents, the workload has increased, but up to one-third of residents feel that the autonomy provided by their programs is insufficient. Significant disparities in training quality were found across different regions, with notable shortages in neonatology and pediatric emergency departments. Research opportunities are also limited, with only 17% of residents finding the time allocated to research satisfactory, especially in central and southern Italy. CONCLUSION: The increase in pediatric residents presents both challenges and opportunities. Addressing these challenges through strategic reforms, such as implementing standardized national curricula, investing in training resources and mobility programs, and enhancing research opportunities, is crucial for the future of pediatric residency in Italy. Ensuring high-quality training for all residents is an ethical and practical obligation that will significantly impact pediatric healthcare.

Water and Electrolyte Content in Hypertension in the Skin (WHYSKI) in Primary Aldosteronism.

BACKGROUND: Primary aldosteronism (PA), the most common curable salt-dependent form of arterial hypertension, features renal K+ loss and enhanced Na+ reabsorption. We investigated whether the electrolyte, water, and TonEBP (tonicity-responsive enhancer binding protein)/NFAT5 (nuclear factor of activated T cells 5) content is altered in the skin of patients with PA and corrected by surgical cure. METHODS: We obtained skin biopsies from 80 subjects: 49 consecutive patients with PA, optimally treated with a mineralocorticoid receptor antagonist; 6 essential hypertensives; and 25 normotensive controls. We measured Na+, K+, water content with atomic absorption spectroscopy after ashing, and NFAT5 mRNA with digital droplet polymerase chain reaction. The patients with PA were retested after adrenalectomy. RESULTS: We discovered a higher dry weight of the skin biopsy specimen at surgery than at follow-up (P<0.001) and a direct correlation with electrolyte and water content (all P<0.01), indicating the need for dry weight adjustment of electrolyte and water data. Surgical cure of PA markedly increased skin dry weight-adjusted K+ (from 1.14±0.1 to 2.81±0.27 µg/mg; P<0.001) and water content (from 2.92±1.4 to 3.85±0.23 mg/mg; P<0.001), but left dry weight-adjusted skin Na+ content unaffected. In patients with PA, NFAT5 mRNA was higher (P=0.031) than in normotensive controls and decreased after surgery (P=0.035). CONCLUSIONS: Despite mineralocorticoid receptor antagonist treatment ensuring normokalemia, the patients with PA had a skin cell K+ depletion that was corrected by adrenalectomy. The activated NFAT5/TonEBP pathway during mineralocorticoid receptor antagonist administration suggests enhanced skin Na+ lymphatic drainage and can explain the lack of overt skin Na+ accumulation in patients with PA. Its deactivation after surgical cure can account for the lack of skin Na+ decrease postadrenalectomy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06090617.

Biomaterials for extrusion-based bioprinting and biomedical applications.

Amongst the range of bioprinting technologies currently available, bioprinting by material extrusion is gaining increasing popularity due to accessibility, low cost, and the absence of energy sources, such as lasers, which may significantly damage the cells. New applications of extrusion-based bioprinting are systematically emerging in the biomedical field in relation to tissue and organ fabrication. Extrusion-based bioprinting presents a series of specific challenges in relation to achievable resolutions, accuracy and speed. Resolution and accuracy in particular are of paramount importance for the realization of microstructures (for example, vascularization) within tissues and organs. Another major theme of research is cell survival and functional preservation, as extruded bioinks have cells subjected to considerable shear stresses as they travel through the extrusion apparatus. Here, an overview of the main available extrusion-based printing technologies and related families of bioprinting materials (bioinks) is provided. The main challenges related to achieving resolution and accuracy whilst assuring cell viability and function are discussed in relation to specific application contexts in the field of tissue and organ fabrication.

Clinical Management of Primary Aldosteronism: An Update.

Despite carrying an excess risk of cardiovascular events, primary aldosteronism (PA) is a commonly overlooked secondary form of arterial hypertension. An increased awareness of its high prevalence and broader screening strategies are urgently needed to improve its detection rate and allow early diagnosis and targeted treatment. For patients with unilateral PA, these measures can correct hyperaldosteronism and ensure cure of hypertension, even when resistant to drug treatment, thus preventing adverse cardiovascular events. Among these, atrial fibrillation is the most common, but left ventricular hypertrophy, stroke, chronic kidney disease, and myocardial infarction also occur more often than in patients with hypertension and no PA. Young patients, who have higher chances of being cured long term, and high-risk patients, such as those with stage III or resistant hypertension, are those who will benefit most from an early diagnosis of PA. Therefore, the implementation of strategies to detect PA by a simplified diagnostic algorithm is necessary. In the patients who seek for surgical cure, adrenal vein sampling is key for the identification of unilateral PA and the achievement of optimal outcomes. Unfortunately, being technically demanding and poorly available, adrenal vein sampling represents the bottleneck in the workup of PA. Considering the novel knowledge generated in the past 5 years in many studies, particularly in the AVIS-2 study (Adrenal Vein Sampling International Study-2), based on 4 decades of experience at our center and on the last guidelines, we herein provide an update on the management of PA with recommendations for drug treatment and strategies to avoid adrenal vein sampling wherever it is poorly, or not, available.

Multiscale Approach for Tuning Communication among Chemical Oscillators Confined in Biomimetic Microcompartments.

ConspectusInspired by the biological world, new cross-border disciplines and technologies have emerged. Relevant examples include systems chemistry, which offers a bottom-up approach toward chemical complexity, and bio/chemical information and communication technology (bio/chemical ICT), which explores the conditions for propagating signals among individual microreactors separated by selectively permeable membranes. To fabricate specific arrays of microreactors, microfluidics has been demonstrated as an excellent method. In particular, droplet-based microfluidics is a powerful tool for encapsulating biological entities and chemical reagents in artificial microenvironments, mostly water-in-oil microdroplets. In these systems, the interfaces are liquid-liquid, and their physicochemical properties are key factors for tuning the coupling between molecular diffusion. Simple and double emulsions, where aqueous domains are in equilibrium with oil domains through boundary layers of amphiphilic molecules, are organized assemblies with high interfacial-area-to-volume ratios. These membranes can be engineered to obtain different surface charges, single- or multilayer stacking, and a variable degree of defects in molecular packing. Emulsions find application in many fields, including the food industry, pharmaceutics, and cosmetics. Furthermore, micro- and nanoemulsions can be used to model the propagation of chemical species through long distances, which is not only vital for cell signaling but also significant in molecular computing. Here we present in-depth research on the faceted world of solutions confined in restricted environments. In particular, we focused on the multiscale aspects of structure and dynamics from molecular to micro and macro levels. The Belousov-Zhabotinsky chemical reaction, known for its robustness and well-documented oscillatory behavior, was selected to represent a generic signal emitter/receiver confined within microenvironments separated by liquid-liquid interfaces. In this pulse generator, the temporal and spatial progressions are governed by periodic fluctuations in the concentration of chemical species, which act as activatory or inhibitory messengers over long distances. When organized into "colonies" or arrays, these micro-oscillators exhibit emergent dynamical behaviors at the population level. These behaviors can be finely tuned by manipulating the geometrical distribution of the oscillators and the properties of the interfaces at the nanoscale. By carefully selecting the membrane composition, it is possible to drive the system toward either in-phase, antiphase, or mixed synchronization regimes among individual oscillators, depending on messenger molecules. This relatively simple lab-scale model replicates some of the communication strategies commonly found in biological systems, particularly those based on the passive diffusion of chemical and electrical signals. It can help shed light on fundamental life processes and inspire new implementations in molecular computing and smart materials.

'Essential' arterial hypertension: time for a paradigm change.

The exclusion of causes of hypertension is not systematically exploited in clinical practice. Therefore, essential hypertension is consistently presented as the most prevalent 'cause'. The paradox of a condition with unknown causes being described as a common cause of hypertension translates into a diagnosis of essential hypertension in most patients, which precludes the detection of a curable cause of hypertension. The aim of this review is to investigate how the notion of essential hypertension has developed and whether scientific evidence still support the notion of its high prevalence by examining the most recent studies. These studies provided solid scientific evidence that, when systematically sought for, secondary hypertension is quite common and that secondary hypertension is highly prevalent. The increased awareness should lead to a systematic search for, with the goal of curing or achieving a better control of high blood pressure, and ultimately improving patients' quality of life.

Neuroimmunomodulatory effect of Nitric Oxide on chronic wound healing after photodynamic therapy.

Neuroimmunomodulation is the capacity of the nervous system to regulate immune processes. The existence of neurotransmitter receptors in immune cells enables this phenomenon to take place. Neuronal mediators possess the capacity to direct and control several occurrences during the wound healing process. Nitric oxide (NO) functions as a neuromodulator, playing a crucial role in the regulation of vascular tone and blood pressure with antimicrobial properties. Photodynamic therapy has been shown to augment the function of immune cells involved in the healing process of venous leg ulcers. Nitric oxide can be secreted into the extracellular environment by these cells. In lesions treated with PDT, the synthesis of iNOs (the enzyme that releases NO) increased, as demonstrated by the experimental results. Therefore the significance of PDT in enhancing the clinical condition of the lesion is thus highlighted.

Bioprospecting for plant resilience to climate change: mycorrhizal symbionts of European and American beachgrass (Ammophila arenaria and Ammophila breviligulata) from maritime sand dunes.

Climate change and global warming have contributed to increase terrestrial drought, causing negative impacts on agricultural production. Drought stress may be addressed using novel agronomic practices and beneficial soil microorganisms, such as arbuscular mycorrhizal fungi (AMF), able to enhance plant use efficiency of soil resources and water and increase plant antioxidant defence systems. Specific traits functional to plant resilience improvement in dry conditions could have developed in AMF growing in association with xerophytic plants in maritime sand dunes, a drought-stressed and low-fertility environment. The most studied of such plants are European beachgrass (Ammophila arenaria Link), native to Europe and the Mediterranean basin, and American beachgrass (Ammophila breviligulata Fern.), found in North America. Given the critical role of AMF for the survival of these beachgrasses, knowledge of the composition of AMF communities colonizing their roots and rhizospheres and their distribution worldwide is fundamental for the location and isolation of native AMF as potential candidates to be tested for promoting crop growth and resilience under climate change. This review provides quantitative and qualitative data on the occurrence of AMF communities of A. arenaria and A. breviligulata growing in European, Mediterranean basin and North American maritime sand dunes, as detected by morphological studies, trap culture isolation and molecular methods, and reports on their symbiotic performance. Moreover, the review indicates the dominant AMF species associated with the two Ammophila species and the common species to be further studied to assess possible specific traits increasing their host plants resilience toward drought stress under climate change.

Mild hydrolysis of chemically stable valerolactams by a biocatalytic ATP-dependent system fueled by metaphosphate.

Medium-sized 5- and 6-membered ring lactams are molecules with remarkable stability, in contrast to smaller ß-lactams. As monomers, they grant access to nylon-4 and nylon-5, which are alternative polyamides to widespread caprolactam-based nylon-6. Chemical hydrolysis of monocyclic γ- and δ-lactams to the corresponding amino acids requires harsh reaction conditions and up to now, no mild (enzymatic) protocol has been reported. Herein, the biocatalytic potential of a pair of heterologously expressed bacterial ATP-dependent oxoprolinases - OplA and OplB - was exploited. Strong activity in the presence of excess of ATP was monitored on δ-valerolactam and derivatives thereof, while trace activity was detected on γ-butyrolactam. An ATP recycling system based on cheap Graham's salt (sodium metaphosphate) and a polyphosphate kinase allowed the use of catalytic amounts of ATP, leading to up to full conversion of 10 mM δ-valerolactam at 30 °C in aqueous medium. Further improvements were obtained by co-expressing OplA and OplB using the pETDuet1 vector, a strategy which enhanced the soluble expression yield and the protein stability. Finally, a range of phosphodonors was investigated in place of ATP. With acetyl phosphate and carbamoyl phosphate, turnover numbers up to 176 were reached, providing hints on a possible mechanism, which was studied by 31P-NMR.

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

Specific anion effects on urease activity: A Hofmeister study.

The effects of a range of electrolytes on the hydrolysis of urea by the enzyme urease is explored. The autocatalytic behavior of urease in unbuffered solutions and its pH clock reactions are studied. The concentration dependence of the experimental variables is analyzed in terms of specific ion-enzyme interactions and hydration. The results offer insights into the molecular mechanisms of the enzyme, and on the nature of its interactions with the electrolytes. We found that urease can tolerate mild electrolytes in its environment, while it is strongly inhibited by both strong kosmotropic and strong chaotropic anions. This study may cast light on an alternative therapy for Helicobacter pylori infections and contribute to the design of innovative materials and provide new approaches for the modulation of the enzymatic activity.

Radiographic evaluation of marginal bone levels around implants supporting splinted fixed bridges: A retrospective study on 412 implants.

OBJECTIVES: The effect of the implant position within the prosthesis on bone remodeling is scarcely documented so far. Thus, the aim of the present study was to investigate whether central implants may suffer higher peri-implant marginal bone levels (MBL) compared to laterals in case of fixed splinted bridges supported by ≥ three implants. MATERIALS AND METHODS: Partially edentulous subjects rehabilitated with at least one fixed bridge supported by ≥ three dental implants were enrolled. MBL was assessed radiographically by means of intraoral radiographs acquired with phosphor plates and imported in a dedicated software. MBL was calculated as the distance between the implant platform level and the most coronal visible bone-to-implant contact. A three-level linear mixed effects model was used for investigating the fixed effect of patient-, prosthesis-, and implant-level variables on the MBL. RESULTS: Overall, 90 patients rehabilitated with 130 splinted fixed bridges supported by 412 implants were included. The median follow-up was 136 months. The mean peri-implant MBL resulted statistically significantly higher at central implants if compared to lateral implants (p < .01). The estimated MBL averages for central and external implants were 1.68 and 1.18 mm, respectively. The prosthesis-level variables suggested that a cement-retained bridge was prone to a significant 0.82 mm higher MBL than a screw-retained one. Implant surface showed an association with MBL changes, although less pronounced than implant retention. CONCLUSIONS: In case of ≥3 adjacent implants supporting splinted bridges, central implants were more predisposed to MBL compared to laterals. At the prosthesis level, implants supporting cement-retained bridges were statistically more susceptible to MBL compared to screw-retained ones. Surface characteristics can also influence MBL stability at the implant level.

The effect of a protective layer on the optical behavior of retro-reflective paintings for building envelopes.

Retro-reflective (RR) materials, applied to building envelopes, constitute an option to tackle Urban Heat Island phenomenon, thanks to their capability to reflect the sunlight predominantly towards the solar incidence direction. RR coatings are obtained with the deposition of glass beads on traditional diffusive materials. During their lifetime, outdoor aging and soiling affect their optical behavior. In addition, without a proper protection, some glass beads could detach from the paint and disperse in the environment. Hence, a necessity arises for the application of a safeguarding stratum on RR materials to avert the separation of glass beads in RR coatings following the aging process. In this paper, five RR samples were produced, employing a highly reflective paint as foundation, RR glass beads and a protective layer. A diffusive sample, without glass beads, was made for comparison. Samples underwent spectrophotometric and angular distribution analyses. The effect of the protective layer on the optical behavior was assessed comparing the results with those obtained for the same RR materials without the protective layer. RR samples with a protective layer exhibit a higher reflectance with respect to the same RR sample without a protective layer. In the near-infrared (NIR) region, a lower reflectance occurs for all RR samples with a protective layer. A less concentrated angular distribution of the reflected light was observed for all RR samples with the addition of a protective layer.

Water and Electrolyte Content in Salt-Dependent HYpertension in the SKIn (WHYSKI): Effect of Surgical Cure of Primary Aldosteronism.

 INTRODUCTION: This study will test the hypothesis that primary aldosteronism (PA) involves alterations in Na+, K+, and water content in the skin that are corrected by adrenalectomy. AIM AND METHODS: In skin biopsies, we will measure the content of Na+, K+, water, by physical-chemical methods and the osmotic-stress-responsive transcription factor Tonicity-responsive Enhancer Binding Protein (TonEBP, NFAT5) mRNA copy number by droplet digital PCR, in sex-balanced cohorts of 18 -75-year-old consecutive consenting patients with unilateral and bilateral PA, primary (essential) hypertension, and normotension. Before surgery, the patients with unilateral PA will receive the mineralocorticoid receptor antagonist (MRA) canrenone at doses that correct hypokalemia and high blood pressure values. They will be reassessed in an identical way one month after surgical cure, while off MRA. PA patients not selected for adrenalectomy will similarly be assessed at diagnosis and follow-up while on stable MRA treatment. Since a pilot study showed a direct correlation of dry weight (DW) with skin electrolytes and water content and significant differences of biopsy DW between surgery and follow-up, meaningful comparison of the skin cations and water content and TonEBP mRNA copy number, between specimen obtained at different time points, will require DW- and total mRNA-adjustment, respectively. CONCLUSION: This study will provide novel information on the skin Na+, K+ and water content in PA, the paradigm of salt-dependent hypertension, and novel knowledge on the effect of surgical cure of hyperaldosteronism. The TonEBP-mediated regulation of Na+, K+ and water content in the skin will also be unveiled. TRAIL REGISTRY: Trial Registration number: NCT06090617. Date of Registration: 2023-10-19.

Multiscale Frozen Density Embedding/Molecular Mechanics Approach for Simulating Magnetic Response Properties of Solvated Systems.

We present a three-layer hybrid quantum mechanical/quantum embedding/molecular mechanics approach for calculating nuclear magnetic resonance (NMR) shieldings and J-couplings of molecular systems in solution. The model is based on the frozen density embedding (FDE) and polarizable fluctuating charges (FQ) and fluctuating dipoles (FQFµ) force fields and permits the accurate ab initio description of short-range nonelectrostatic interactions by means of the FDE shell and cost-effective treatment of long-range electrostatic interactions through the polarizable force field FQ(Fµ). Our approach's accuracy and potential are demonstrated by studying NMR spectra of Brooker's merocyanine in aqueous and nonaqueous solutions.

Synthesis of Zeolitic Imidazolate Framework-8 Using Glycerol Carbonate.

In this study, we show that glycerol carbonate (GlyC), a bio-based derivative of glycerol, can be used as a suitable green solvent for the synthesis of metal-organic frameworks (MOFs). In particular, a zinc-based zeolitic imidazolate framework-8 (ZIF-8) was synthesized by exploring several different experimental conditions (in terms of temperature, reaction time, and reactants' concentrations) to find that the yield of the reaction and the quality of the products, measured in terms of crystallinity, surface area, and porosity, were in line with those obtained in the most commonly (non-green) used solvents. GlyC was also found to be reusable for several cycles, maintaining the same original quality as a solvent for the synthesis. Finally, some indicators for the assessment of the greenness of a process (E-factor and PMI) revealed a milder environmental impact of GlyC with respect to other solvents.

Endocrine disruptors and arterial hypertension: A developing story.

Endocrine disrupting Chemicals (EDCs) are substances that interfere with hormones by several mechanisms including receptor activation or antagonism, changes in gene and protein expression, modification of signal transduction, and/or epigenetic modifications in hormone-producing cells. A survey conducted by the European Union in a Northern Italian region led to the discovery of a large environmental contamination of drinking water by perfluoroalkyl substances (PFAS). As the exposed population showed a high prevalence of arterial hypertension and cardiovascular disease, we decided to investigate if PFAS could enhance the biosynthesis of aldosterone. To this aim, we exposed human adrenocortical carcinoma HAC15 cells to PFAS and found that PFAS markedly increased aldosterone synthase (CYP11B2) gene expression and aldosterone secretion. Moreover, we found that they promoted reactive oxygen species (ROS) production in mitochondria, the organelles where aldosterone biosynthesis takes place. PFAS also enhanced the effects of the aldosterone secretagogue angiotensin II (Ang II) on CYP11B2 gene expression and aldosterone secretion. We also found that not only PFAS but also polychlorinated biphenyl 126 (PCB126), a chemical compound belonging to a different category of EDCs, can increase CYP11B2 gene expression and aldosterone secretion in adrenocortical cells. This novel information needs to be considered in the context of a widespread exposure to the most common EDC, that is excess Na+ intake, whose detrimental effects on human health occur in the setting of aldosterone production exceeding the physiological needs and lead to high blood pressure, congestion, and cardiovascular and renal damage.

Psychiatric symptoms in Long-COVID patients: a systematic review.

Objective: People who have been infected by COVID-19 showing persistent symptoms after 4 weeks from recovery are thought to suffer from Long-COVID syndrome (LC). There is uncertainty on the clinical manifestations of LC. We undertook a systematic review to summarize the available evidence about the main psychiatric manifestations of LC. Method: PubMed (Medline), Scopus, CINHAL, PsycINFO, and EMBASE were searched until May 2022. Studies reporting estimation of emerging psychiatric symptoms and/or psychiatric diagnoses among adult people with LC were included. Pooled prevalence for each psychiatric condition was calculated in absence of control groups to compare with. Results: Thirty-three reports were included in the final selection, corresponding to 282,711 participants with LC. After 4 weeks from COVID-19 infection recovery, participants reported the following psychiatric symptoms: depression, anxiety, post-traumatic symptoms (PTS), cognitive and sleeping disturbances (i.e., insomnia or hypersomnia). The most common psychiatric manifestation resulted to be sleep disturbances, followed by depression, PTS, anxiety, and cognitive impairment (i.e., attention and memory deficits). However, some estimates were affected by important outlier effect played by one study. If study weight was not considered, the most reported condition was anxiety. Conclusions: LC may have non-specific psychiatric manifestations. More research is needed to better define LC and to differentiate it from other post-infectious or post-hospitalization syndromes. Systematic review registration: PROSPERO (CRD42022299408).

Non-autonomous zinc-methylimidazole oscillator and the formation of layered precipitation structures in a hydrogel.

Oscillations are one of the intrinsic features of many animate and inanimate systems. The oscillations manifest in the temporal periodic change of one or several physical quantities describing the systems. In chemistry and biology, this physical quantity is the concentration of the chemical species. In most chemical oscillatory systems operating in batch or open reactors, the oscillations persist because of the sophisticated chemical reaction networks incorporating autocatalysis and negative feedback. However, similar oscillations can be generated by periodically changing the environment providing non-autonomous oscillatory systems. Here we present a new strategy for designing a non-autonomous chemical oscillatory system for the zinc-methylimidazole. The oscillations manifested in the periodic change of the turbidity utilizing the precipitation reaction between the zinc ions and 2-methylimidazole (2-met) followed by a partial dissolution of the formed precipitate due to a synergetic effect governed by the ratio of the 2-met in the system. Extending our idea spatiotemporally, we also show that these precipitation and dissolution phenomena can be utilized to create layered precipitation structures in a solid agarose hydrogel.