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To date there has been limited head-to-head evaluation of immune responses to different types of COVID-19 vaccines. A real-world population-based longitudinal study was designed with the aim to define the magnitude and duration of immunity induced by each of four different COVID-19 vaccines available in Italy at the time of this study. Overall, 2497 individuals were enrolled at time of their first vaccination (T0). Vaccine-specific antibody responses induced over time by Comirnaty, Spikevax, Vaxzevria, Janssen Ad26.COV2.S and heterologous vaccination were compared up to six months after immunization. On a subset of Comirnaty vaccinees, serology data were correlated with the ability to neutralize a reference SARS-CoV-2 B strain, as well as Delta AY.4 and Omicron BA.1. The frequency of SARS-CoV-2-specific CD4+ T cells, CD8+ T cells, and memory B cells induced by the four different vaccines was assessed six months after the immunization. We found that mRNA vaccines are stronger inducer of anti-Spike IgG and B-memory cell responses. Humoral immune responses are lower in frail elderly subjects. Neutralization of the Delta AY.4 and Omicron BA.1 variants is severely impaired, especially in older individuals. Most vaccinees display a vaccine-specific T-cell memory six months after the vaccination. By describing the immunological response during the first phase of COVID-19 vaccination campaign in different cohorts and considering several aspects of the immunological response, this study allowed to collect key information that could facilitate the implementation of effective prevention and control measures against SARS-CoV-2.

New-generation drug-eluting stents (DES) strongly reduce restenosis and repeat revascu- larization compared with bare-metal stents (BMS) for percutaneous coronary interven- tion. There is residual uncertainty as to whether other prognostically relevant outcomes are affected by DES versus BMS concerning initial presentation (chronic coronary syn- drome [CCS] vs acute coronary syndrome [ACS]). We performed an individual patient data meta-analysis of randomized trials comparing new-generation DES versus BMS (CRD42017060520). The primary outcome was the composite of cardiac death or myocar- dial infarction (MI). Outcomes were examined at maximum follow-up and with a 1-year landmark. Risk estimates are expressed as hazard ratio (HR) with 95% confidence inter- val (CI). A total of 22,319 patients were included across 14 trials; 7,691 patients (34.5%) with CCS and 14,628 patients (65.5%) with ACS. We found evidence that new-generation DES versus BMS consistently reduced the risk of cardiac death or MI in both patients with CCS (HR 0.83, 95% CI 0.70 to 0.98, p

Introduction Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. Methods We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. Results Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. Conclusions In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

Background Noonan syndrome (NS) is a clinically and genetically heterogeneous disorder. Since its clinical phenotype is often mild and difficult to differentiate from other syndromes, its diagnosis can be challenging and its prevalence in the pediatric population is most certainly underestimated. The difficulty in identifying Noonan syndrome is also increased by the fact that genetic tests are currently not able to detect an underlying mutation in around 10% of the cases. Methods This is a retrospective, observational study conducted at the Institute for Maternal and Child “Burlo Garofolo” in Trieste, Italy. We recruited all the patients with clinical and/or genetic diagnosis of NS who were evaluated at the Department of Pediatrics between October 2015 and October 2020. Statistical analyses were performed with IBM SPSS Statistics software. The association between discrete variables has been evaluated through chi-squared test, indicating statistically significant p with Pearson test or Fischer test for variables less than 5. Results We recruited a total of 35 patients affected by Noonan syndrome. In 24 patients (75%) we identified an underlying genetic substrate: 17 patients had a mutation on PTPN11 (61%), 2 in SOS1, KRAS and SHOC2 (7% each) and only 1 in RAF1 (4%). 25% of the subjects did not receive a genetic confirm. As for the phenotype of the syndrome, our study identified the presence of some clinical features which were previously unrelated or poorly related to NS. For example, renal and central nervous system abnormalities were found at a higher rate compared to the current literature. On the contrary, some features that are considered very suggestive of NS (such as lymphatic abnormalities and the classical facial features) were not frequently found in our population. Conclusions In our analysis, we focused on the main phenotypic features of NS, identifying various clinical manifestation that were not associated with this genetic condition before. This could be helpful in raising the knowledge of NS’s clinical spectrum, facilitating its diagnosis.

Objective: To analyze the association between physical fitness, cognitive function, and depressive symptoms among older adults in long-term care facilities (LTCFs). Methods: Seventy-six institutionalized male and female elderly individuals (65 years and older) living in LTCFs participated of this study. Physical fitness (aerobic capacity and strength), cognitive functions (global cognition, short-term and working and semantic memories, and executive function), and depressive symptoms were assessed. Linear regression and contingency analyses were performed. Significance was accepted at p-values ≤ 0.05. Results: Aerobic capacity predicted 32% of variance in global cognition (p < 0.01) and 25% of variance in semantic fluency/executive function (p < 0.01). Low levels of upper limb strength, lower limb strength, and aerobic capacity were associated with semantic fluency/executive function (OR = 1.38, p = 0.01, OR = 1.26, p = 0.03, and OR = 1.07, p = 0.01, respectively) and depressive symptoms (OR = 1.06, p < 0.01). Conclusion: Poor physical fitness is associated with cognition and depressive symptoms in institutionalized older adults. Low levels of strength and aerobic fitness increase the odds of presenting with impaired semantic fluency and executive function, possibly denoting an increased risk of developing dementia.

Objectives Several studies suggested that CD30 expression is a favorable prognostic marker in transformed mycosis fungoides (tMF). However, evidence in this field is still unclear. This systematic review and meta-analysis aimed to evaluate the prognostic significance of CD30 in tMF. Methods Electronic databases were searched from their inception to June 2020 for all studies assessing the prognostic value of CD30 in tMF. Pooled hazard ratio (HR) for death was calculated; a P value less than .05 was considered significant. Inconsistency index (I2) was used to assess statistical heterogeneity among studies. Results Seven studies with 323 patients were included. CD30 expression in tMF was significantly associated with a decreased hazard of death both on univariate (HR, 0.459; 95% confidence interval [CI], 0.319-0.660; P < .001) and multivariate analysis (HR, 0.503; 95% CI, 0.345-0.734; P < .001), and the statistical heterogeneity among studies was null in all analyses (I2 = 0%). Conclusions tMF cases with CD30 expression in large cells have a hazard of death two times lower than CD30-negative cases.

Gene therapy is a technique that aims at the delivery of nucleic acids to cells, to obtain a therapeutic effect. In situ gene therapy consists of the administration of the gene product to a specific site. It possesses several advantages, such as the reduction in potential side effects, the need for a lower vector dose, and, as a consequence, reduced costs, compared to intravenous administration. Different vectors, administration routes and doses involving in situ gene transfer have been tested both in animal models and humans, with in situ gene therapy drugs already approved in the market. In this review, we present applications of in situ gene therapy for different diseases, ranging from monogenic to multifactorial diseases, focusing mainly on therapies designed for the intra-articular and intraocular compartments, as well as gene therapies for the central nervous system (CNS) and for tumors. Gene therapy finally seems to blossom as a viable therapeutic approach. The growth in the number of clinical protocols shown here is evident, and the positive outcomes observed in several clinical trials indicate that more products based on in situ gene therapy should reach the market in the next years.

The COVID-19 pandemic has limited in-lab cognitive testing. While at-home alternatives exist (testing over the phone), differences in test design and delivery complicate direct comparison of most in-lab and at-home tests. Here we describe the design, infrastructure, and implementation of the California Cognitive Assessment Battery (CCAB), a cognitive test battery and administration system. Using automated remote administration over cellular networks, identical computerized cognitive tests can be administered at-home or in the lab.The CCAB comprises 30+ computerized cognitive tests. Test delivery is automated through text, text-to-speech, and graphical instructions; test scoring is also automated, using automatic speech recognition for verbal responses. The test delivery infrastructure consists of two components: the test kit (MS Surface Pro tablet computer with mouse, headset, and cellular dongle) , and a web-browser application "CCAB Examiner," used by the test administrator to control test delivery, view real-time progress and scores, and monitor/chat with the participant via AV feeds. The system is coordinated by a cloud-based server which also delivers the CCAB Examiner application to any browser. Once connected, the "CCAB Test Station" application and CCAB Examiner communicate over a commercial Communication as a Service (CAAS) provider, which transmits AV streams and a text messaging protocol. CCAB Test Station is designed to isolate control, communications, and testing functions for maximal fault tolerance. For example, test administration continues automatically even if Examiner and Test Station lose connection. Test data is uploaded to the server during sessions and re-synced when the test kit returns.442 participants underwent three 90-minute CCAB test sessions on successive days (72 total tests per participant). More than 98% of participants finished all three sessions, and99% of tests were completed. Cellular connection failures occurred occasionally, but98% resulted only in the loss of A/V feeds for the examiner, while tests continued automatically and examiners were able to monitor real-time performance data.The CCAB permits identical tests to be administered at home or in the laboratory, while cellular-network based remote administration allows for nationwide access for all socioeconomic groups, even for people in remote areas without Wi-Fi, or those with limited technical expertise.

Recent reports have investigated the use of automatic speech recognition (ASR) to analyze and score verbal responses in cognitive tests. ASR scoring is objective, permits the efficient computerized administration of verbal tests, and generates timestamps that enable the detailed temporal analysis of responses. However, ASR transcription accuracy varies by engine, task, and participant, and ASR can incorrectly score responses from participants with atypical speech patterns. Here we describe the speech-transcription pipeline of the California Cognitive Assessment Battery (CCAB), which incorporates consensus ASR (CASR) to produce more accurate transcripts than possible with any single ASR engine. We also developed a Transcript Review Tool (TRT) which facilitates the manual correction of mis-transcribed words in problem subjects.Figure 1 shows the CCAB speech transcription pipeline. Realtime ASR transcriptions are obtained along with the transcriptions of the digital recordings of responses using six cloud-based ASR engines (e.g., Google, etc.). Individual transcripts are then combined to produce a "consensus" transcript, and a transcription confidence measure based primarily on the agreement between ASR engines (Figure 2). If needed, "consensus" transcripts can be manually corrected using the Transcript Review Tool which enables the review of all words or just those words below a predefined CASR confidence threshold (Figure 3).ASR transcriptions were obtained from 442 healthy adults (mean age = 65.1 ±14.4) who each underwent three days of cognitive testing that included 25 verbal tests. In all, approximately 276 hours of speech were transcribed. Preliminary analyses show that CASR transcription accuracy surpassed 99% for tests with limited response sets (e.g., digit span, verbal list learning, face-name binding, etc.) and exceeded 95% for discursive speech tests (e.g., picture description and logical memory).CASR transcription is more accurate than that of any single ASR engine. When combined with the TRT, "consensus" ASR can produce error-free, timestamped transcripts that enable the detailed analysis of verbal responses from older individuals at risk of cognitive decline.

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Neuroimaging is a key tool in the diagnostic process of various clinical conditions, especially in pediatric endocrinology. Thanks to continuous and remarkable technological developments, magnetic resonance imaging can precisely characterize numerous structural brain anomalies, including the pituitary gland and hypothalamus. Sometimes the use of radiological exams might become excessive and even disproportionate to the patients’ medical needs, especially regarding the incidental findings, the so-called “incidentalomas”. This unclarity is due to the absence of well-defined pediatric guidelines for managing and following these radiological findings. We review and summarize some indications on how to, and even if to, monitor these anomalies over time to avoid unnecessary, expensive, and time-consuming investigations and to encourage a more appropriate follow-up of brain MRI anomalies in the pediatric population with endocrinological conditions.

The rapid development of nanomedicine has created a high demand for silver, copper and copper oxide nanoparticles. Due to their high reactivity and potent antimicrobial activity, silver and copper-based nanomaterials have been playing an important role in the search for new alternatives for the treatment of several issues of concern, such as pathologies caused by bacteria and viruses. Viral diseases are a significant and constant threat to public health. The most recent example is the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this context, the object of the present review is to highlight recent progress in the biomedical uses of these metal nanoparticles for the treatment and prevention of human viral infections. We discuss the antiviral activity of AgNPs and Cu-based NPs, including their actions against SARS-CoV-2. We also discuss the toxicity, biodistribution and excretion of AgNPs and CuNPs, along with their uses in medical devices or on inert surfaces to avoid viral dissemination by fomites. The challenges and limitations of the biomedical use of these nanoparticles are presented.

BACKGROUND: Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking. METHODS: To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male patients with CKD (stages 2–5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO(2) rebreathing technique was used to measure peak O(2) consumption (VO(2peak)) and peak cardiac output simultaneously, and to calculate peak peripheral O(2) extraction (C[a-v]O(2)), the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors. RESULTS: Compared with healthy controls, in patients with CKD, the VO(2peak) was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO(2peak) in healthy controls and patients with heart failure, whereas C(a-v)O(2) played a more significant role in determining VO(2peak) in CKD (β=0.68, P

Background Stress and negative emotions may impact on appetite, inducing some individuals to eat less and others to eat more. This behavior has been implicated in the onset of bodyweight problems and eating disorders in childhood. The aim of our study is to evaluate factors potentially associated with emotional eating in children. Methods The present cross-sectional study derives from a survey conducted in 2021 on 8–9 years old children attending 11 primary schools. A questionnaire was administered that contained multiple-choice items relating to the children and their mothers, and touching on all the factors thought to be associated with emotional eating as behavioral traits or adherence to Mediterranean diet. A multivariable logistic regression was performed to test the association. Results Emotional undereating was positively associated with emotional symptoms (OR 1.72; 95% CI 1.11–2.67); emotional overeating was positively associated with both emotional symptoms (OR 2.01; 95% CI 1.29–3.13) and hyperactivity (OR 2.80; 95% CI 1.59–4.92), and inversely associated with peer problems (OR 0.50; 95% CI 0.25–0.99). Emotional undereating was also positively associated with the number of siblings (OR 1.50; 95% CI 1.03–2.18), and inversely associated with a good adherence to the Mediterranean diet (OR 0.25; 95% CI 0.08–0.84). Conclusions The study found children’s emotional eating associated with both dietary patterns and behavioral traits (in particular emotional symptoms, hyperactivity and peer problems). It could be useful to improve parents’ awareness so that they can anticipate and pay more attention to this issue. Adherence to the Mediterranean diet should also be reinforced, by means of health promotion interventions at school, for example.

In the last two decades, thanks to the data that have been obtained from the Human Genome Project and the development of next-generation sequencing (NGS) technologies, research in oncology has produced extremely important results in understanding the genomic landscape of pediatric cancers, which are the main cause of death during childhood. NGS has provided significant advances in medicine by detecting germline and somatic driver variants that determine the development and progression of many types of cancers, allowing a distinction between hereditary and non-hereditary cancers, characterizing resistance mechanisms that are also related to alterations of the epigenetic apparatus, and quantifying the mutational burden of tumor cells. A combined approach of next-generation technologies allows us to investigate the numerous molecular features of the cancer cell and the effects of the environment on it, discovering and following the path of personalized therapy to defeat an “ancient” disease that has had victories and defeats. In this paper, we provide an overview of the results that have been obtained in the last decade from genomic studies that were carried out on pediatric cancer and their contribution to the more accurate and faster diagnosis in the stratification of patients and the development of new precision therapies.

Background Collyrium administration is a common procedure in the neonatal ward, both in preterm and at term babies. Various molecules are used to induce mydriasis and cycloplegia: among them, phenylephrine and tropicamide are the most popular, and their administration is generally considered safe. Case presentation A 35 + 2 weeks-old, 2510 g, well-appearing male newborn required an ophthalmologic evaluation after a doubtful red reflex test. A collyrium with 1% phenylephrine and 0.95% tropicamide was administered prior to the consult, one drop per eye. Two minutes after the administration, the baby developed a severe apnea that required tactile stimulation. Moreover, the area around his eyes became visibly pale. Three minutes later, the baby became severely bradycardic (59 bpm), but remained in good general condition, so that resuscitation maneuvers were not required. Bradycardia lasted for almost three hours and then gradually resolved. Conclusions Cardiopulmonary manifestations, such as bradycardia and even cardiopulmonary arrest, are severe complications that can happen after phenylephrine collyrium administration in preterm newborns. However, they have been described in babies below 1500 g or with concurrent respiratory manifestations. Our patient, on the other hand, was late preterm, and never required a ventilatory support prior to the collyrium administration. Practitioners who deal with premature babies, even if late preterm, must be aware of these possible complications and administer phenylephrine collyrium carefully, where cardiopulmonary resuscitation equipment and personnel are available.

Background Dentofacial features are related to increased bullying episodes in young people. The aim of this study was to assess the association between gingival bleeding and reports of verbal bullying among adolescents. Methods This is a cross-sectional study conducted with a representative sample of 608 12-year-old adolescents from southern Brazil. The occurrence of verbal bullying was verified through adolescents' self-report. Oral health measurements included the presence of gingival bleeding, dental fracture, dental fluorosis, and dental caries experience. Gingival bleeding was assessed through adolescent self-perception by the following question: "Did you notice any bleeding in your gums?" Demographic, socioeconomic, and psychosocial variables were also evaluated. Poisson regression models with robust variance were used to evaluate the influence of gingival bleeding on the occurrence of verbal bullying. Results are presented as prevalence ratio (PR) and 95% confidence interval (95% CI). Results Out of 608 adolescents evaluated, 577 answered bullying questions. The prevalence of self-reported verbal bullying was 12.8%. Adolescents who presented gingival bleeding had an 80% higher prevalence of verbal bullying than their counterparts (PR 1.80; 95% CI 1.01 -3.19). Dental shame, speech difficulties and influence of dental condition on studies also impacted the higher prevalence of bullying. Conclusion Our results suggest that the presence of gingival bleeding negatively impacts the social life of adolescents, causing more episodes of verbal bullying. These findings encourage public health policies aimed at reducing oral health inequities, thus reflecting on the well-being and quality of life of this target population.

Human cardiac β myosin undergoes the crossbridge cycle as part of the force-generating mechanism of cardiac muscle. The recovery stroke is considered one of the key steps of the kinetic cycle as it is the conformational rearrangement required to position the active site residues for hydrolysis of ATP and interaction with actin. We explored the free-energy surface of the transition and investigated the effect of the genetic cardiomyopathy causing mutations R453C, I457T, and I467T on this step using metadynamics. This work extends previous studies on Dictyostelium myosin II with engineered mutations. Here, like previously, we generated an unbiased thermodynamic ensemble of reactive trajectories for the chemical step using transition path sampling. Our methodologies were able to predict the changes to the dynamics of the recovery stroke as well as predict the pathway of breakdown of ATP to ADP and HPO(4)(2−) with the stabilization of the metaphosphate intermediate. We also observed clear differences between the Dictyostelium myosin II and human cardiac β myosin for ATP hydrolysis as well as predict the effect of the mutation I467T on the chemical step.

Among health care professionals, dentists are more prone to infection due to their direct contact with blood and saliva. This study highlights the level of compliance with infection control measures among dental students; and linked this to their knowledge and attitudes regarding infection control measures and proper vaccinations. The study is a multi-centre analytical cross-sectional survey. The sample size was 969 clinical years' students from governmental and private dental colleges in Sudan and Saudi Arabia. A pre-coded, pre-tested, and anonymous questionnaire consisted of seven categories of knowledge, attitude, awareness, and practices, including 40 questions, was answered. The study has linked knowledge, attitude, and practice in dental clinics with possible COVID-19 transmission in dental clinics. The results showed that the use of some Personal Protective Equipment was low in Sudan and moderate in Saudi Arabia (statistically significant, p < 0.001). Moderate percentage of Hepatitis B vaccination status, with low percentage of Post HBV serology, was reported (p < 0.001). The percentages of major causes of percutaneous and/or eye exposure/injury, for examples, were as follows: anesthesia (33.3-62.7%, p 0.006) and suture needle (17.5-39.4%, p 0.037). In conclusion, dental students in the present study had good knowledge and positive attitudes regarding infection control in general, but showed moderate compliance with the recommended infection control guidelines.

Objectives We examined the association between travellers’ characteristics, compliance with pre-travel recommendations and health problems. Methods Volunteer travellers were enrolled and data collected using a questionnaire between 30–60 days after returning home. We analyzed the associations through bivariate and multivariate models. Results Of the 468 enrolled travelers, 68% consumed raw food and 81% food containing milk and/or eggs. 32% consumed street vendor food and 30% drinks containing ice. 24% used the recommended mechanical prophylaxis measures. 46% got sick during and/or after travel (gastrointestinal symptoms most frequently). Factors predisposing to health problems were female gender, youth/middle age, intermediate travel duration and profession. The American continent and staying in hostels and tents were significantly associated with febrile illness. Street vendor food was significantly associated with skin reactions. Conclusions Adherence to behavioral recommendations remains low. Travellers must be informed of health risks during and after travel.

Metformin reduces the incidence of placental-mediated disease (PMD) in pregnancies with and without diabetes, but the mechanism through which it exerts these effects is not yet fully understood. We performed a systematic review and meta-analysis to examine the effect of metformin on biomarkers implicated in the pathogenesis of PMD. We searched Medline, Embase and the Cochrane Library for studies of metformin and biomarkers of PMD in pregnancy. Meta-analysis was undertaken where comparable data were obtained from two or more studies. 12 studies were included in the final review. Meta-analysis of 2 studies including 323 pregnant women showed significantly reduced CRP levels following treatment with metformin compared to placebo [mean difference = −1.72, 95% CI (−2.97; −0.48); p = 0.007]. Metformin exposure was also associated with decreased levels of the inflammatory cytokines TNFα, IL-1a, IL-1b and IL-6 in serum, placenta and omental tissue taken from pregnant women. Metformin significantly decreased the release of anti-angiogenic factors sFlt-1 and sEng from ex-vivo placental and umbilical vein tissue, and increased maternal serum levels of non-phosphorylated IGFBP-1. Overall, our findings show that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation. Metformin therefore has exciting potential as a therapeutic, as well as preventative, agent in the treatment of PMD, which warrants further investigation.

Mycosis fungoides (MF) represents the most common type of cutaneous lymphoma. In the majority of patients, the disease has a slow evolution and a protracted course; however, a subset of patients shows poor oncologic outcomes. Unfortunately, there are no reliable prognostic markers for MF, and the currently available treatments are only effective in a minority of patients. This study aimed to evaluate the expression and clinical significance of PARP-1 and CAF-1/p60 in MF. Sixty-four MF representatives of the different stages of disease were assessed by immunohistochemistry for PARP-1 and CAF-1/p60. The association of PARP-1 and CAF-1/p60 with the MF stage and outcome was assessed by using Fisher’s exact test and Kaplan-Meier survival analysis with the Log-rank test; a p value II (p = 0.034) but not with the risk of death (p = 0.237). CAF-1/p60 was overexpressed in 26.8% of MF and was significantly associated with decreased overall survival (p p = 1). A significant association was found between PARP-1 overexpression and CAF-1/p60 overexpression (p = 0.0025). Simultaneous overexpression of PARP-1 and CAF-1/p60 was significantly associated with decreased overall survival (p χ2 = 14.916 vs 21.729, respectively). In MF, PARP-1 is overexpressed in advanced stages, while CAF-1/p60 is overexpressed in the cases with shorter overall survival, appearing as a significant prognostic marker. A role for PARP-1 inhibitors and anti-CAF-1/p60 targeted therapy may be reasonably hypothesized in MF.

Aims The objective of this study was to evaluate the antibacterial effect of sophorolipids in combination with palmarosa essential oil and to develop a cosmetic formulation against acne-causing bacteria. Methods and Results The antibacterial activity of sophorolipids, palmarosa oil and their combined effect was evaluated by broth microdilution and checkerboard methods. Antioxidant activity was determined by the DPPH method. The results showed that the compounds presented antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. The combination of sophorolipid and palmarosa oil resulted in synergistic and additive interaction reducing the concentration needed for the effectiveness against S. aureus and S. epidermidis, to 98.4% and 50%, respectively. The compounds interaction showed an additive effect for antioxidant activity. The cosmetic formulation without any chemical preservative presents antibacterial activity against S. aureus, S. epidermidis and Cutibacterium acnes. The pH values and organoleptic characteristics of formulations remained stable under all conditions tested. Conclusions The association of sophorolipids and palmarosa oil resulted in a self-preserving cosmetic formulation with great stability, and effective antioxidant and antibacterial activities against acne-causing micro-organisms. Significance and Impact of the Study This study showed the development of an effective multifunctional cosmetic formulation with natural preservatives to treat acne vulgaris and other skin infections.

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis.

In this work, we present a microfluidic amperometric immunosensor for cancer biomarker claudin7 (CLD7) determination in circulating extracellular vesicles (EVs) as well as its validation in colorectal cancer (CC) patients. The device is based on synthetized nanosized MIL-125-NH

Durable T cell responses to SARS-CoV-2 antigens after infection or vaccination improve immune-mediated viral clearance. To date, population-based surveys of COVID-19 adaptive immunity have focused on testing for IgG antibodies that bind spike protein and/or neutralize the virus. Deployment of existing methods for measuring T cell immunity could provide a more complete profile of immune status, informing public health policies and interventions.

High-Grade Gliomas (HGG) are among the deadliest malignant tumors of central nervous system (CNS) in pediatrics. Despite aggressive multimodal treatment - including surgical resection, radiotherapy and chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches. Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric proteins, known as chimeric antigen receptors (CARs), targeting selected tumor-associated antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the antigens common to adult glioblastoma – such as interleukin-13 receptor alpha 2 (IL-13α2), human epidermal growth factor receptor 2 (HER-2) and erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2). CAR-T therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target antigen expression and the difficulty of accessing the tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells – like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T therapies overcoming these hurdles.

Owing to an increasing number of infections in adults

Deterioration of physical and functional capacities is often seen in nursing homes. The present study aimed at assessing the effectiveness of an individually tailored physical exercise intervention on mobility and functional decline in nursing home residents in a 1-year follow-up period. Information on gender, age, education, profession and cognitive status was collected at baseline and at 6 and 12 months of the intervention. The decline in functional capacity and mobility was assessed using the Barthel index. Some 221 participants were included. Results from the multivariate logistic regression showed how residents who never participated in physical activities had a five-fold higher risk of mobility decline compared with residents who did engage for the whole follow-up time. A lower effect was seen in residents who participated for only 6 months. Although dementia appeared to be a significant predictor of decline, a substantial stabilisation in mobility capacity was noted in patients with both mild and severe dementia performing exercise. The findings suggest that preventing or slowing physical decline in nursing home residents is an achievable goal, and even those with a higher degree of cognitive decline may benefit from a tailored physical activity plan.

The antimicrobial activity of the metabolites produced by Fusarium oxysporum PR-33 in submerged culture was evaluated against Gram-positive and Gram-negative bacteria and yeasts. Metabolites were determined by HPLC-DAD-MS/MS. An extract was obtained following the removal of mycelium by centrifugation and lyophilisation of the supernatant. The compounds in this extract demonstrated broad-spectrum antimicrobial action, with rates of inhibition between 60 and 80%, depending on the species and extract tested. The major compounds of the extracts were identified as fusarinolic acid and its isomer [56.9% flask extract (FE)] and 59.2% bioreactor extract (BE), dehydrofusaric acid (35.7% FE and 31.6% BE), and fusaric acid (6.5% FE and 1.1% BE). Fusaric acid has been shown to be responsible for antimicrobial activity. The cytotoxicity of the extracts was evaluated in culture of HEK-293 and SH-SY5Y animal cells and toxicity of these extracts was verified even in the lowest tested concentrations. Therefore, our results indicate that the compounds identified exhibit potential as antimicrobial agents.

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m

Background: Mucopolysaccharidosis type II (Hunter syndrome, or MPS II) is an X-linked lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which leads to the accumulation of glycosaminoglycans (GAGs) in a variety of tissues, resulting in a multisystemic disease that can also impair the central nervous system (CNS). Objective: This review focuses on providing the latest information and expert opinion about the therapies available and under development for MPS II. Methods: We have comprehensively revised the latest studies about hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT - intravenous, intrathecal, intracerebroventricular, and intravenous with fusion proteins), small molecules, gene therapy/genome editing, and supportive management. Results and Discussion: Intravenous ERT is a well-established specific therapy, which ameliorates the somatic features but not the CNS manifestations. Intrathecal or intracerebroventricular ERT and intravenous ERT with fusion proteins, presently under development, seem to be able to reduce the levels of GAGs in the CNS and have the potential of reducing the impact of the neurological burden of the disease. Gene therapy and/or genome editing have shown promising results in preclinical studies, bringing hope for a “one-time therapy” soon. Results with HSCT in MPS II are controversial, and small molecules could potentially address some disease manifestations. In addition to the specific therapeutic options, supportive care plays a major role in the management of these patients. Conclusion: At this time, the treatment of individuals with MPS II is mainly based on intravenous ERT, whereas HSCT can be a potential alternative in specific cases. In the coming years, several new therapy options that target the neurological phenotype of MPS II should be available.

Myosin regulates muscle function through a complex cycle of conformational rearrangements coupled with the hydrolysis of adenosine triphosphate (ATP). The recovery stroke reorganizes the myosin active site to hydrolyze ATP and cross bridge with the thin filament to produce muscle contraction. Engineered mutations K84M and R704E in Dictyostelium myosin have been designed to specifically inhibit the recovery stroke and have been shown to indirectly affect the ATPase activity of myosin. We investigated these mutagenic perturbations to the recovery stroke and generated thermodynamically correct and unbiased trajectories for native ATP hydrolysis with computationally enhanced sampling methods. Our methodology was able to resolve experimentally observed changes to kinetic and equilibrium dynamics for the recovery stroke with the correct prediction in the severity of these changes. For ATP hydrolysis, the sequential nature along with the stabilization of a metaphosphate intermediate was observed in agreement with previous studies. However, we observed glutamate 459 being utilized as a proton abstractor to prime the attacking water instead of a lytic water, a phenomenon not well categorized in myosin but has in other ATPases. Both rare event methodologies can be extended to human myosin to investigate isoformic differences from Dictyostelium and scan cardiomyopathic mutations to see differential perturbations to kinetics of other conformational changes in myosin such as the power stroke.

Background Pacifier use is a major cause of anterior open bite (AOB), which negatively impacts the quality of life of children affected. Aim To assess the direct and indirect pathways related to pacifier sucking habit and AOB in preschool children. Design This 2-year cohort study evaluated a random sample of preschool children (2-5 years of age) from Southern Brazil. Caregivers answered a questionnaire addressing socio-economic and behavioural characteristics. Anterior open bite was recorded following the criteria recommended by Foster and Hamilton. Structural equation model was performed to assess the direct and indirect pathways among variables at baseline (T1) to predict the AOB at follow-up (T2). Results Regarding the AOB, 407 children were evaluated at T1 and 187 at T2. The prevalence of AOB was 32.9% at baseline and 16.0% at follow-up. The presence of AOB at follow-up was directly affected by the change in pacifier sucking habit from T1 to T2. Considering the indirect paths, the AOB at T1 influenced the AOB in T2 via a change of pacifier sucking habit. Conclusion These findings suggest that the non-habit of sucking pacifiers is a fundamental strategy for the prevention of AOB as well as the promotion of health in childhood.

The ongoing pandemic caused by a novel coronavirus, SARS‐CoV‐2, affects thousands of people every day worldwide. Hence, drugs and vaccines effective against all variants of SARS‐CoV‐2 are crucial today. Viral genome mutations are commonly existent which may impact the encoded proteins, possibly resulting to varied effectivity of detection tools and disease treatment. Thus, this study surveyed the SARS‐CoV‐2 genome and proteome and evaluated its mutation characteristics. Phylogenetic analyses of SARS‐CoV‐2 genes and proteins show three major clades and one minor clade (P6810S; ORF1ab). The overall frequency and densities of mutations in the genes and proteins of SARS‐CoV‐2 were observed Nucleocapsid exhibited the highest mutation density among the structural proteins while the Spike D614G was the most common, occurring mostly in genomes outside China and USA. ORF8 protein had the highest mutation density across all geographical areas. Moreover, mutation hotspots neighboring and at the catalytic site of RNA‐dependent‐RNA‐polymerase were found that might challenge the binding and effectivity of remdesivir. Mutation coldspots may present as conserved diagnostic and therapeutic targets were found in ORF7b, ORF9b and ORF14. These findings suggest that the virion's genotype and phenotype in a specific population should be considered in developing diagnostic tools, and treatment options. This article is protected by copyright. All rights reserved.

Objective Evaluate the impact of the availability of public dental care service on the increment of dental caries in children. Methods This is a 2-year cohort study that followed preschool children from southern Brazil. Dental caries was measured at baseline and follow-up evaluation, considering the number of surfaces with untreated dental caries. Demographic and socioeconomic characteristics as well as the use and availability of dental services were assessed. Multilevel Poisson regression analysis through a hierarchical approach and considering a random effect for repeated measures was used to explore the influence of exploratory variables in the increase in the outcome. Results A total of 419 cases were evaluated at follow-up (91.3% cohort retention rate). The increase in the untreated dental caries was associated with living in places where there is no regular presence of dentists in the public health system. In addition, the increment of dental caries was influenced by age, household income, and dental attendance. Conclusion The results suggest that the availability of dentists in the public health system have an impact the increment of dental caries among children. The integration of the dentist in the primary healthcare can contribute to decrease the barriers that lead to children's oral health.

Background Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder characterized by cardiovascular manifestations, especially aortic dilatations and arterial tortuosity, craniofacial and skeletal features, joint laxity or contractures, skin abnormalities, hypotonia and motor delay. Its diagnosis is established by the identification of a pathogenic variant in TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 or TGFB3 genes. In newborns and toddlers, vascular complications such as aneurism rupture, aortic dissection, and intracerebral incidents, can occur already in the weeks of life. To avoid these events, it is crucial to precociously identify this condition and to start an apunderwent a surgical procedurepropriate treatment which, depending on the severity of the vascular involvement, might be medical or surgical. Case presentation We report two cases of Loeys-Dietz syndrome precociously diagnosed. The first describes a male, born at 38 + 1 weeks of gestation, with hypotonia, joint hypermobility, arachnodactyly, and fingers joint contractures, as well as senile appearance and facial dysmorphisms. In the suspect of a connective tissue disorder, an echocardiography was performed and revealed an aortic root dilatation of 13 mm (Z score + 3). A trio based Whole Exome Sequencing found a novel de novo variant in the TGFBR2 gene. Despite the onset of a low-dose angiotensin receptor blocker therapy, the aneurysm progressed. The second case describes a female, born at 41 + 3 weeks of gestation. During the neonatal examination a cleft palate was noticed, as well as minor dysmorphisms. Since the family history was suspicious for connective tissue disorders, a genetic panel was performed and identified a pathogenetic variant in TGFB3 gene. In this case, the echocardiography revealed no abnormalities. Conclusions In addition to our cases, we identified 14 subjects with neonatal LDS in the medical literature. All of them had aortic involvement. Skeletal and face abnormalities, including eyes and palate malformations, were also highly frequent. Overall, 10 subjects required medical therapy to avoid aneurysm progression, and 8 patients underwent surgical procedures. Benefits of an early diagnosis of LDS are various and imply a potential modification of the natural history of the disease with early interventions on its complications.

Previous studies associated high-level exposure to ultraviolet radiation with a greater risk of cutaneous malignant melanoma (CMM). This study focuses on the changing incidence of CMM over time (from 1990 to 2017) in the Veneto region of Northeast Italy, and its Alpine area (the province of Belluno). The clinicopathological profile of CMM by residence is also considered. A joinpoint regression analysis was performed to identify significant changes in the yearly incidence of CMM by sex and age. For each trend, the average annual percent change (AAPC) was also calculated. In the 2017 CMM cohort, the study includes a descriptive analysis of the disease’s categorical clinicopathological variables. In the population investigated, the incidence of CMM has increased significantly over the last 30 years. The AAPC in the incidence of CMM was significantly higher among Alpine residents aged 0–49 than for the rest of the region’s population (males: 6.9 versus 2.4; females 7.7 versus 2.7, respectively). Among the Alpine residents, the AAPC was 3.35 times greater for females aged 0–49 than for people aged 50+. The clinicopathological profile of CMM was significantly associated with the place of residence. Over three decades, the Veneto population has observed a significant increase in the incidence of CMM, and its AAPC. Both trends have been markedly more pronounced among Alpine residents, particularly younger females. While epidemiology and clinicopathological profiles support the role of UV radiation in CMM, the young age of this CMM-affected female population points to other possible host-related etiological factors. These findings also confirm the importance of primary and secondary prevention strategies.

(1) Background: aging is associated with complex and dynamic changes leading to multimorbidity and, therefore, polypharmacy. A periodic medication review (MR) in frail older people leads to optimizing medication use. The aims of the study were to perform a comparative analysis of the impact of place of residence (own home versus nursing home) in a cohort of older patients on the characteristics of the baseline therapeutic plan and characteristics of the therapeutic plan after an MR; (2) Methods: Study with paired pre- and post-MR data based on person-centred prescription, with a follow-up assessment at three months. Patients who lived either in their own home or in a nursing home were recruited. We selected patients of 65 years or more with multimorbidity whose General Practitioner identified difficulties with the prescription management and the need for an MR. Each patient’s treatment was analysed by applying the Patient-Centred Prescription (PCP) model; (3) Results: 428 patients. 90% presented at least one inappropriate prescription (IP) in both settings. In nursing homes, a higher number of implemented optimization proposals was detected (81.6% versus 65.7% (p < 0.001)). After the MR, nursing-home patients had a greater decrease in their mean number of medications, polypharmacy prevalence, therapeutic complexity, and monthly drug expenditure (p < 0.001); (4) Conclusions: PCP model detected a high number of IP in both settings. However, after an individualized MR, nursing-home patients presented a greater decrease in some pharmacological parameters related to adverse events, such as polypharmacy and therapeutic complexity, compared to those living at home. Nursing homes may be regarded as a highly suitable scenario to carry out a periodic MR, due to its high prevalence of frail people and its feasibility to apply the recommendations of an MR. Prospective studies with a robust design should be performed to demonstrate this quasi-experimental study along with a longitudinal follow-up on clinical outcomes.