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Standard enthalpies, entropies, and heat capacities are calculated for 16,813 halocarbons using an automated high-fidelity thermochemistry workflow. This workflow generates conformers at density functional tight binding (DFTB) level, optimizes geometries, calculates harmonic frequencies, and performs 1D hindered rotor scans at DFT level, and computes electronic energies at G4 level. The computed enthalpies of formation for 400 molecules show good agreement with literature references, but the majority of the calculated species have no reference in the literature. Thus, this work presents the most accurate thermochemistry for many halocarbons to date. This new data set is used to train an extensive ensemble of group additivity values and hydrogen bond increment groups within the Reaction Mechanism Generator (RMG) framework. On average, the new group values estimate standard enthalpies for halogenated hydrocarbons within 3 kcal/mol of their G4 values. A significant contribution towards automated mechanism generation of halocarbon combustion, this research provides thermochemical data for thousands of novel halogenated species and presents a self-consistent set of halogen group additivity values.

This paper describes the zoological specimens collected by Giuseppe Raddi during the Franco-Tuscan expedition to Egypt (1828–1829) held in the collection of the Museo di Storia Naturale dell’Università di Pisa. Twenty-two specimens exist, including four amphibians preserved in alcohol, and 18 taxidermy specimens (16 birds, 2 mammals). Among these is a specimen of the taxonomically controversial Canis lupaster (African wolf) and one of the first specimen of Oenanthe xanthoprymna (Kurdish wheatear) held in European museums.

In order to draw a trajectory of use and utility of the conventional technique such as ozone therapy going through its historical trajectory and its effectiveness, mainly with regard to the treatment of painful and chronic inflammatory processes. The technique called “ozone therapy” is recommended for the use of ozone gas (5%) and oxygen (95%), being used to treat injuries, especially wounds and having been described in scientific articles as an alternative to suffering pain, inflammation, infection and wound healing. Scientific publications evidence or benefit ozone, it as an important option in the treatment or association of treatment of patients with chronic diseases. Such as example in the other techniques under supervision and validation, there are recommendations from new studies that establish the safety of the use of ozone in health and aesthetic procedures. Therefore, this study aims to present a literature review that includes relevant information on the ozone therapy technique, investing in information about the processes and methods used in various diseases, and especially in the treatment of chronic painful and inflammation. After applying the article selection, selecting 39 articles published in the years 2019 and 2020, describing the use of ozone therapy to treat pain and inflammation in various pathologies. The results that ozone therapy is presented as a therapeutic option, minimally invasive and inexpensive, can be used in conjunction with other therapeutic measures to enhance the beneficial results of resources and can be integrated into Alternative and Complementary Practices.

Introduction In the last years, genetic testing for inherited cardiac conditions (ICCs) is expanded and evolved at an incredible rate. This tool may inform treatment options and lifestyle choices to avoid arrhythmia triggers. Furthermore, identifying the genetic underpinning of the disorder improves risk assessment for asymptomatic or pre-symptomatic family members. However, despite the large numbers of disease-causative genes identified in the last years, only 60% of the patients with a clinical diagnosis of ICCs carry a pathogenic or likely pathogenic variant. The remaining 40% of the cases have an inconclusive or ambiguous test caused by negative results or mainly by the identification of one or more variants of unknown significance (VUS). In this case, the test results are uninformative and clinically irrelevant, increasing uncertainty about medical management. Purpose We investigated whether a periodic re-evaluation of the detected VUS, using the American College of Medical Genetics and Genomics (ACMG) criteria, may impact the clinical setting of patients with suspected ICC and their family members. Methods We reevaluated 306 consecutive probands with suspected ICC undergoing genetic testing by next-generation sequencing using the Illumina TruSight Cardio Sequencing panel, from 2017 to 2021. Results Thirty-five percent of patients carried at least one variant in a gene associated with the phenotype. Of these, 94 had been previously classified as VUS and were not considered clinically actionable. After an average time of 36 months, they were reevaluated and 26.6% of the VUS were reclassified. In particular, 1 was downgraded to Benign and 24 were upgraded to Likely Pathogenic (16) or Pathogenic (8). According to the different phenotypes, the reclassification rate was 45.8% in Hypertrophic cardiomyopathy, 33.3% in Dilated cardiomyopathy, 27.3% in Arrhythmogenic cardiomyopathy, 12.5% in Brugada syndrome, and 50% in Long QT syndrome patients. This reclassification process allowed to recategorize 24 probands as clinically and molecularly diagnosed and to extend the genetic screening to their at-risk family members. Conclusions Given the extent of the clinical impact that genetic testing can have, these findings suggest that a periodic reevaluation of genetic test results, particularly VUS, should be a mandatory step in the ICC diagnostic workflow. Funding Acknowledgement Type of funding sources: None.

Background Personalised medicine (PM) has the potential to transform health systems and make them more sustainable, by making the population healthier and allocating resources efficiently. European Union and China have become world leaders in the field of PM, increasing collaborations worldwide. In this context, the EU Commission in 2020 launched the IC2PerMed (Integrating China in the International Consortium for Personalised Medicine) project to provide key solutions to enable the convergence of European and Chinese stakeholders toward a common approach in PM. Methods From a mapping exercise of policies and programs in PM in EU and China, we identified 20 priority items for shaping sustainable healthcare. Such items were submitted to several Chinese and European experts in PM involved in a 3-round Delphi survey. Experts were asked to review the items’ content and rate their validity and relevance on a 5-point Likert scale. Priorities reaching a Content Validity Index of more than 79% were included, between 70 and 79% were revised, and less than 70% were excluded. Results Of 20 priorities submitted, 9 reached consensus. The priorities hinge on the resources allocation, defining in advance priority investment, and identifying new payment models for public reimbursement, health technology impact, and assessment importance, while integrating end-user perceptions into the whole innovation process. In addition, the pivotal role of multidisciplinary and cross-sectorial collaborations emerged. Ethical, legal, and social implications and the related costs should be always considered in policymaking, evaluation, and management of technological innovation. Conclusions Integrating resources and setting a clear agenda for the implementation of PM would lead to a faster and more efficient translation into clinical practice. Developing policies valuing all the stakeholders’ contributions would implement PM adoption. Key messages • Healthcare systems sustainability is a priority and PM could make the population healthier and help allocate resources more efficiently, hence reducing the overall costs of healthcare. • The inter-sectoral collaborations in healthcare are fundamental to achieving the best standard of care. All stakeholders and policymakers should engage to foster sustainability.

Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%) ; 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p &lt ; 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count &gt ; 500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.

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Periodic repetition of right heart catheterization (RHC) in pulmonary arterial hypertension (PAH) can be challenging. We evaluated the correlation between RHC and cardiopulmonary exercise test (CPET) aiming at CPET use as a potential noninvasive tool for hemodynamic burden evaluation. One hundred and forty-four retrospective PAH patients who had performed CPET and RHC within 2 months were enrolled. The following analyses were performed: (a) CPET parameters in hemodynamic variables tertiles; (b) position of hemodynamic parameters in the peak end-tidal carbon dioxide pressure (P

The reduction of detector dead time represents an enabling factor in several photon counting applications. In this work, we investigate the free-running operation of reach-through single-photon avalanche diodes (SPADs) at ultra-low dead times. By employing a fast active quenching circuit with direct bonding to the detector, we are able to achieve a 10 ns dead time with a thick SPAD by Excelitas, still maintaining extremely low afterpulsing probabilities (below 1.5%).

Background Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. Methods Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). Results There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. Conclusions Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Pembrolizumab is a humanized monoclonal antibody that targets PD-1. In the Phase III trial KEYNOTE-045, pembrolizumab was associated with a significant overall survival benefit when compared with docetaxel, paclitaxel and vinflunine in second line metastatic urothelial carcinoma (UC). Additionally, in the first line, early results from an interim analysis of the Phase II trial Keynote-052 study indicated that pembrolizumab is efficacious for cisplatin-ineligible patients. Based on data from these trials, pembrolizumab was the most recent among the five checkpoint inhibitors tested in UC to be approved by the US FDA in May 2017. It was granted regular approval for patients with advanced-stage UC who progress after receiving platinum-based chemotherapy and accelerated approval in the first line for patients who are ineligible to receive cisplatin.

Background Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed. Objectives To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non–lymph node distant metastasis. Design, Setting, and Participants Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana-Farber Cancer Institute between 2009 and 2014. Outcome Measurements and Statistical Analysis Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model. Results and Limitations A total of 102 patients were identified, 57 of whom had non–lymph node distant metastases at relapse; 45 received chemotherapy. Median follow-up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first-line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin Conclusions Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin-based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings. Patient Summary Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival.

Background The incidence of gemcitabine-induced hemolytic uremic syndrome has already been described in adults. Several approaches have been employed in the treatment of gemcitabine-induced hemolytic uremic syndrome with different outcomes. One of the most promising agents is eculizumab, which is a monoclonal antibody directed against C5 complement protein. Case presentation We reported the case of a 3-year-old white boy with medulloblastoma who underwent high-dose chemotherapy and craniospinal irradiation. Afterwards he started maintenance chemotherapy with gemcitabine and oxaliplatin. After five courses he presented a progressive clinical worsening, which resulted in a systemic thrombotic microangiopathy. Initially he was treated with rituximab without clinical improvement. Therefore he started therapy with repeated cycles of eculizumab. After seven infusions he showed a gradual improvement and finally a complete remission of gemcitabine-induced hemolytic uremic syndrome. Conclusions Eculizumab prevents serious complement-mediated vascular damage for chemotherapy-induced thrombotic microangiopathy in pediatric cases.

In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m2. Consolidated knowledges are present only with the dose of 5 g/m2 in acute lymphoblastic leukemia. We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m2, to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m2 = 30 kg). The median age was 4.5 months (range 0–9). The median weight was 5.63 kg (range 3.12–9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227–790). The median systemic MTX clearance was 4.14 L/h/m2 (range 1.98–9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14–100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m2 can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion). Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.

BACKGROUND: Pediatric high-grade gliomas (HGGs) are comprised primarily of anaplastic astrocytomas (AA, WHO-grade III) and glioblastomas (GBM, WHO-grade IV). Despite advances in treatment for other childhood tumors, their outcomes are comparable to adults, with 5-year survival rates less than 20%. Primary treatment includes surgery, followed by radiotherapy and chemotherapy with temozolomide. Consolidated studies demonstrated that adjuvant treatment remains important for improving outcome. MATERIAL AND METHODS: We considered 19 HGG patients admitted to the Neuro-Oncology Unit in Florence between September 2008 and January 2018. Patients were enrolled in a temozolomide-vinorelbine chemotherapy protocol developed on the basis of EORTC-COG experiences. The children were subjected to resection and to radiotherapy with concomitant chemotherapy (6 weeks) with vinorelbine (20 mg/sqm i.v weekly), temozolomide (75 mg/sqm i.o daily). The adjuvant phase consisted in 12 months of treatment with exclusive chemotherapy with vinorelbine 30 mg/sqm i.v. days 1, 14 every 28, temozolomide 150 mg/sqm i.o. days 1–5 every 28. RESULTS: The median age of 19 treated patients was 10 years (range 6–25). Six patients (31,6%) had GBM and thirteen patients (68,4%) had an AA. According the localization, 16 tumors (84,2%) were sovratentorial and 3 (15,8%) infratentorial tumors. Radical surgery was performed in seven patients. The median of follow-up was 50 months. At time of analysis, 12 patients were still alive and more than 50% of the patients have not yet relapsed. Five patients (26,3%) had a disease progression during the adjuvant phase. One patient died after radiotherapy. The patients who received the highest dose of radiotherapy (59–60 Gy vs 54 Gy) showed better survival (not reached vs 38,8 months). Patients who experienced disease progression during the maintenance treatment had a significant worst survival (11,3 months vs NR p< 0.0001). CONCLUSION: Adjuvant chemotherapy is crucial for a better outcome of malignant gliomas. In pediatric HGGs, the combination of vinorelbine to temozolomide seems to be safely, without significant adverse events. At 50 months of follow-up (beyond the median OS described in the literature) more than 50% of patients have not yet experienced recurrence. Our analysis confirms that disease progression during the treatment represents a negative prognostic factor for survival. This may identify a subgroup of patients with a marked chemoresistance.

Background Among all osteoporotic fractures the painful vertebral fractures (PVF) are the minority and their management is challenging for the clinician because the evidences about the best approach are conflicting and of low quality. Moreover there are no guidelines or consensus of experts. A real life picture of the management of the PVF is lacking in the literature. Objectives The primary end point of the study is to describe the pharmacological and or non-pharmacological management of PVF through the record of use of individual classes, associations and sequences of drugs or procedures. Secondary end point is the outcome of treatment in term of pain, disabilities and quality of life. Methods We present the iterim analysis results of a multicentric cross-sectional observational study. 400 interviews will be collected consecutively about pain, disability, pharmacological, spinal orthoses and orthopaedic surgery after the diagnosis of PFV in postmenopausal women treated by orthopaedics, endocrinologists, geriatricians, physiatrists, neurosurgeons and E.R. pysicians. Pain and disability were quantified by NRS scale and by QUALEFFO-41. Data collected from the first 100 patients have been analysed. Results One hundred postmenopausal women aged 73.1±7.49 y.o (age of menopause 48.6±3.9 years, L1-L4 T-score −2.75±0.92, Total hip T-score −2.35±0.98) with a new or first PFV were recorded. About 49% of them had a previous vertebral fracture and 22% a previous non-vertebral fragility fracture, 27% was not on osteoporosis treatment. The interviews were collected 135±114 days from diagnosis of PV,174±141 days from onset of pain. 92.3%±12% of subjects were treated for pain relief for a mean time of 98±12 days. Only 1.6% of cohort underwent to percutaneous vertebroplasty while 84.6%±17.1% had spinal orthoses. Pharmacological treatment for pain was prescibed to 98.2+7.1% of subjects: acetaminophen (42%), tapentadol (24%), opioids (24%), NSAID (6%) and codeine with acetaminophen (4%). In 95% of patients with spinal orthoses drugs for pain were assumed. In about 40% of cases NSAID was switched to acetaminophen, in 18% opioid and tapentadol switched to NSAID or acetaminophen. Only a few titration of opioids/tapentadol were reported. Not adequate pain relief (NRS scale 6.2±3.1; QUALEFFO-41 pain score 70±14.2) and impairment quality of life (mean total QUALEFFO-41 score 65.1±20.1) were reported. Conclusions With the limits of the study design and low number of cases, preliminary data seem to confirm an inadequate pain relief in PVF. The emerging critical issues crossing all cathegories of physicians are the lag of diagnosis, the inappropiate use of acetaminophen, the missing tritation of opioids or tapentadol. A definition of optimal management of acute vertebral fracture is missing due to conflicting and scarce evidences in this field predisposing to chronic pain and disability. Disclosure of Interest None declared

In the Mediterranean Sea, many species of Cystoseira, which are important habitat-forming species on shallow rocky bottoms, have gone missing from many coastal areas, impairing essential ecosystem services. Cystoseira crinita forests thrive in very shallow waters from sheltered environments and are currently regressing in several European shores. In the actual scenario of ocean warming it is essential to determine the vulnerability of these populations to thermal stress in order to design future conservation actions. Since the response of this macroalgae to thermal stress may be site-specific, here we compared the thermal tolerance of populations dwelling in the coldest and warmest areas of the Mediterranean Sea. We show that C. crinita populations from warmer areas (Eastern Mediterranean) had a temperature tolerance threshold 2ºC higher than Northwestern Mediterranean populations. There is a strong correlation between the observed differential phenotypic responses and the local temperature regimes experienced by each population. This is the first evidence for the role of thermal history in shaping the thermotolerance responses marine habitat-forming macroalgae under contrasting temperature environments. Financial support from EU2020 (R+I) under grant agreement No 689518 (MERCES) and MINECO (CGL2016-76341-R).

In this article the authors propose a specific myofunctional therapy protocol for children with Down syndrome. For these patients, who usually present with atypical swallowing problems, mouth breathing and lip incompetence, the use of a myofunctional therapy protocol with specific exercises has been shown to improve orofacial and nasal functions. In addition to the functional results, such as the correction of the atypical swallowing, restoration of lip competence, breathing improvement and reduction of nasal rhinorrhea, there were also aesthetic results. This protocol can be useful to improve the quality of life of these patients.

Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12–14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently. Immune-checkpoint inhibitors targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant anti-tumor activity, tolerable safety profiles and durable, long-term responses in clinical trials. Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs under investigation that will redefine the standard of care for bladder cancer. CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are the first Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in bladder cancer for platinum-pretreated patients based on phase II data. On March 16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that survival was significantly longer in patients treated with pembrolizumab when compared with the standard second-line chemotherapy. Research into biomarkers such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load and gene signature expression will be crucial to determining why some patients respond to immunotherapy and others do not. This review article describes the advances in immunotherapy since the development of BCG, presents results from clinical trials investigating immune-checkpoint inhibitors and discusses biomarkers and prognostic factors associated with response to these new drugs.

BACKGROUND The diagnosis of a child’s brain tumor is a terrible situation for every member of the family. Numerous are the case of separations and divorces in Italy after a diagnosis of a child’s cancer. In particular, it happens with parents of children affected with brain tumor, being the most frequent solid tumor and the first cause of a tumor child’s death. The crisis related to the discovery of a tumor consists of four phases: shock, reaction, processing and re-orientation. It can happen that the diagnosis, experienced as a traumatic experience, can unite the family members as well as separate them. If there is already a process of family disintegration, a trauma can be a cause for breakup. The aim of our study was to investigate the possible correlation between brain tumor diagnosis in children and parental separations/divorces. MATERIAL AND METHODS We considered 427 patients afferent from 2012 to 2018 to the Neuro-Oncology Unit of the Meyer Children’s Hospital. Brain tumors are the 55–60% of all the tumors of our hospital, with an extra-regionality greater than 65%. The data analysis was conducted through information obtained directly from the families during follow-up visits or by telephone interviews. RESULTS Consistent with literature data in our series, the most frequent brain tumors were low-grade gliomas medulloblastomas, high-grade gliomas, ependymomas, midline diffuse gliomas, craniopharyngiomas, germ cell tumors and other rare pediatric tumors. The population was divided in 16 females and 18 males from different Italian regions: 65% from Central Italy, 23% from the South and Islands, 12% from the North. Data analysis showed 34 cases of separation and/or divorce, equal to 7% of our whole population, during treatment and more frequently at the end of treatment or after death. The median age of the 34 patients at the diagnosis of brain tumor was 9.5 years (range 1–19 years), with a higher percentage of cases of separations (41%) for parents of patients aged 10 years-14 years; 7 were the cases of separation and/or divorce when the diagnosis of brain tumor was made around 12–48 months after the child birth. CONCLUSION The diagnosis of a child’s brain tumor can generate stress in the family leading to different reactions, such as conflicts between parents or a real family crisis. The results of our study suggest a possible correlation between the diagnosis of a child’s brain tumor and the cases of separation and/or divorce. High risk medulloblastomas and high-grade gliomas that are likely to have a shorter path due to the unfavorable prognosis of the disease, appear to be the pathologies more often related to situations of family disputes. However, further investigations are necessary to verify the trend emerged from our study respect to the normal population.

Malignant meningioma has a bad prognosis. Surgery and radiotherapy are the most effective therapeutic options, without an established role for chemotherapy. We report a case of 2-year-old male child with diagnosis of postoperative relapse of a malignant meningioma. Considering the rapid progression, the young age and the lack of effective therapeutic alternatives, the patient underwent multidisciplinary anticancer treatment with a protocol made for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol), with positive outcome. This case represents a successful management of an anaplastic meningioma with a multimodal treatment, including chemotherapy, in a pediatric patient.

BACKGROUND: Somatic TP53 mutations have been reported to occur in almost every type of cancer. They are common alterations in brain tumors. Nevertheless, germline mutations of TP53 gene are linked to Li-Fraumeni syndrome (LFS), a tumor susceptibility condition, characterized by an increased risk of developing early synchronous or metachronous malignancies. TP53 germline mutations have also been reported in individuals with no family history or with a family history not fulfilling LFS characteristics. MATERIAL AND METHODS: We retrospectively considered 7 patients with brain tumors followed at the Neuro-Oncology Unit between September 2008 and January 2018. The median age at diagnosis was 13,7 years (range 1–31); Six patients were male and one female. Five patients developed metachronous tumors. Two LFS patients had only a primary anaplastic astrocytoma. Five (71,4%) patients had primary brain tumor (3 anaplastic astrocytoma, 1 ependymoma, 1 medulloepithelioma). Molecular analysis of TP53 gene was performed in all patients. Family’s cancer history was investigated. RESULTS: Six patients (85,7%) had a germline TP53 mutation all contained between exons 4 and 7. Only one patient with metachronous tumors (leukemia and ependymoma) and without a family’s cancer history did not show a TP53 mutation. Two patients (28,6%) were negative for family’s cancer history but positive for germline TP53 mutation, ones with history of primary medulloepithelioma and osteosarcoma. The second patient had two brain tumors (anaplastic astrocytoma and PNET). The second tumors developed after two years from the first diagnosis. One LFS patient positive for germline TP53 mutation died for an anaplastic astrocytoma. The other four patients (57,1%) resulted positive both for germline TP53 mutation and for family’s cancer history. The median time between the first and second diagnosis was 7,2 years. CONCLUSION: Germline TP53 mutation predisposes to develop synchronous or methachronous tumors even after many years. Our study evidenced that germline TP53 mutation is also frequent in brain tumor patients without cancer family’s history. Therefore they must necessarily be constantly monitored with a correct follow-up and the decisions to be made to avoid unnecessary therapy when they have a poor outcome.

BACKGROUND: Congenital malignant brain tumors are extremely rare characterized by a poor prognosis. This could be due to a massive size of these tumors when they are diagnosed, the surgical difficulties and the lack of consolidated therapeutic approaches. Being radiotherapy not recommend for very young patients, the most favorable outcome is correlated to the gross total resection. We evaluated genetic characteristics, response rate, progression-free survival (PFS), and overall survival (OS) of high-dose chemotherapy and autologous stem cell transplant (ASCT) after surgery of infants with congenital brain malignancy. MATERIAL AND METHODS: Ten infant aged less than 12 months were included in this study. The median age at diagnosis was 56 days (range: 1–279 days; mean: 80,9 days). All patients were subjected to a regimen of induction chemotherapy, two high-dose chemotherapy courses and autologous stem cell transplant after surgery. Furthermore, we analyzed the Copy Number Variants (CNVs) profile using SNP/CGH array approach in all patients. We also performed a sequence analysis of the coding regions for investigating the clinical relevance of germline INI1 gene mutation in atypical teratoid/rhabdoid tumors (AT/RT) patients. RESULTS: Pathological diagnosis was available in all cases: 4 anaplastic astrocytomas, 2 glioblastoma multiforme, 2 supratentorial primitive neuroectodermal tumors and 2 AT/RT. In our study only two patients were subjected to maximal surgery. A tumor debulking with macroscopic residual was performed in the other patients. At 1–5 years from diagnosis, the PFS was 80% and 58% and the OS was 90%, 69%, respectively. Two germline INI1 mutations were found in both patients with AT/RT. One patients with AT/RT had a c.618G>A (p.Trp206*) mutation in exon 5 of INI1 gene. The genetic analysis of other patient showed c.175C>T mutation in exon 2 of INI1 in heterozygosis in tumor’s DNA. The two patients with AT/RT died early, whereas the other congenital patients showed an 5-years OS of 85%. We found a statistical correlation with OS and PFS with the presence of mutation (p: 0,0009; p: 0,01) and the histology (p:0.007 and p:0.0590). CONCLUSION: Intensive postoperative chemotherapy and ASCT represents the most effective therapeutic approach for congenital brain tumors with a high response rate. The determination of germline INI1 mutation in AT/RT could be a decisive prognostic marker for the palliative choice.

Background Data on the epidemiology of bacteremias and invasive fungal diseases (IFD) in children with acute myeloid leukemia (AML) are scarce. Design and Methods In a multi-center, retrospective study, we analyzed proportion, rate per 1,000 person-days at risk, and cumulative risk of bacteremias and IFD in children with AML. Results Between January 1998 and December 2005, 240 children were treated for AML at 8 Italian Centers, for a total of 521 treatment courses and 63,232 person-days at risk. Bacteremia was observed in 32% of treatment courses and IFD was seen in 10% (P

This paper discusses about design and analysis of double stator slotted rotor (DSSR) BLDC motor for electric bicycle application. Usually single stator (SS) BLDC motor is used in an electric bicycle. This type of motor has low performance and need to be charged regularly. The objective of this research is to design and analysis DSSR motor that have high torque. At starts, design specification for the electric bicycle is calculated. Next, design process for DSSR is carried out by using the desired parameter. Lastly, analysis for double stator slotted rotor is simulated using FEM. Result for average back emf, average inductance, inner stator flux density, outer stator flux density, average torque and estimate torque constant is obtained. Result for average torque from FEM archieve the requirement of motor torque for DSSR design where the maximum average torque is 16.2 Nm. This research will give benefit to mankind and society in term of environment protection and energy consumption.

In the present work the corrosion susceptibility of ion nitrided AISI 316L stainless steel was investigated for two different nitriding times and compared with the corrosion susceptibility of the untreated material. Plasma nitriding for short times (30 min) produced the “S” phase or expanded austenite (γN), with a thickness of ∼ 5 μm and a micro-hardness of 1300–1400 HV0.025 (6.5 times higher than the untreated material). Plasma nitriding for long times (6 h) resulted in the precipitation of iron and chromium nitrides. To evaluate the corrosion resistance of both untreated and nitrided samples, anodic potentiodynamic polarization curves and immersion tests were performed in 1 M NaCl at room temperature. It was found that the corrosion resistance depends on the nitriding time. Samples nitrided for half an hour developed a much better corrosion resistance – close to that observed in the untreated samples – than those nitrided for 6 h. Samples nitrided for half an hour showed high roughness probably due to the presence of sliding bands developed in the expanded austenite phase. These sliding bands provide appropriate sites for the developing of the corrosion process. This would explain the results obtained in the corrosion tests. Samples ion nitrided for 6 h showed a severe and massive surface damage due to corrosion. Ion nitriding of AISI 316L stainless steel for short periods of time (30 min in the present case) may be an interesting surface treatment process that efficiently improves the surface hardness of the steel with some reduction in its corrosion resistance.

This paper examines ring size patterns of natural product macrocycles. Evidence is presented that natural macrocycles containing 14-, 16-, and 18-membered rings are of frequent occurrence based on a data mining study. The results raise a question about the limited diversity of macrocycle ring sizes and the nature of the constraints that may cause them. The data suggest that the preference bears no relationship to the odd-even frequency in natural fatty acids. The trends reported here, along with those reported previously (Wessjohann et al. (2005) Mol Divers 9:171), may be generalized to better understand the possible structure preferences of natural macrocycles.

This paper discusses on the improvement of power density of hollow rotor compared to conventional spoke type Permanent Magnet Generator (PMG). The objective of this research is to propose a rotor structure that could improve the power density by maximizing the flux linkage of the machine. In this research the Finite Element Analysis (FEA) is used to simulate the characteristics of the hollow rotor spoke type PMG at various speed. The result shows that the hollow-rotor topology has higher back electromagnetive force and output voltage compared to conventional spoke type PMG. In addition, the hollow-rotor spoke type motor has higher output power compared to conventional spoke type PMG. In summary, this paper provides an overview of the performance of the hollow-rotor spoke type topology that contributes high power density.

A 2 year-old child with motor deficits and headache was referred to our Hospital with an history of speech difficulties and walking difficulties. A brain MRI scan evidenced a giant tumor of the right hemisphere with diffuse contrast enhancement, hydrocephalus and mass effect. After diagnosis, he immediately underwent neurosurgery and a massive debulking of the lesion was performed. The histological diagnosis was anaplastic meningioma (WHO-grade III). Despite radical surgery, after one-month evidence of disease progression was documented by MRI (relapse on surgical margins) and lumbar puncture (neoplastic cells in liquor sample). Rapid progression, young age and absence of successful therapeutic alternatives determined the decision to start chemotherapy with a protocol for soft tissue sarcomas (EpSSG NRSSTS 2005 protocol). The treatment was started in December 2011 and ended in April 2012, and consisted in 3 cycles of Ifosfamide (3 g/m2/day for 3 days) plus Doxorubucin (37.5 mg/m2/day for 2 days) every 21 days. The cycles were followed by Ifosfamide (3 g/m2/day for 3 days ) concomitant with radiotherapy (54 Gy on tumor primary site). A last cycle of Ifosfamide plus Doxorubicin was after performed. In the last 2 cycles, Doxorubicin dose was reduced of 50% to avoid toxicity. End therapy evaluation showed stable disease at brain MRI and absence of tumor cells in liquor sample. Nonetheless, considering risk of disease progression and of late chemotherapy side effects, a strict follow-up was started. After 3 years from diagnosis the patient showed good clinical conditions, with no evidence of disease progression. Anaplastic meningioma is the most undifferentiated, invasive and aggressive type of meningioma (approximately 1-4%). Surgery and radiotherapy are the most effective therapeutic options, while chemotherapy is usually useless. This case represents a successful management of an anaplastic meningioma with chemotherapy in a pediatric patient.

We propose a mechanism that bilateral symmetry yields an entropic advantage for enzyme recognition. We suggest that bilateral symmetry may be a guiding principle used by nature to produce some particularly effective receptor–ligand interactions. An essential result is that bilateral symmetry is common among enzyme inhibitors, which coupled with an enhanced bond energy that connects dimer molecules compared to a reduced bond energy profile for higher oligomers provides a clue to explain the abundance of bilaterally symmetrical molecules found in Nature.

A literature survey and theoretical calculations have been applied to explore bilateral symmetry in natural product systems. Molecular bilateral symmetry is defined to include C(2) (sigma plane or axis), C(s)(), and C(2)(v)() point groups in molecules. Natural products that possess chirality in the form of C(2)-axes or sigma planes of symmetry are present in higher proportions (69%) compared to molecules bearing achiral C(s)() or C(2)(v)() point groups (14% and 16%, respectively). Density functional theoretical and semiempirical calculations indicate that the dimers 3,3'-dibromo-5,5'-[N-(2-(3-bromo-4-hydroxyphenyl)ethyl)-2-hydroxyiminoacetamide]biphenyl-2,2'-diol (1), (S,S)-1,2-bis(2-amino-3H-imidazol-4-yl)-(R,R)-3,4-bis(1H-pyrrole-2-amido)cyclobutane (2), 2-oxo-dimethyl-1,3-bis(3,4-dibromobenzene-1,2-diol) (11), 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (12), and bis(5-isopropyl-8-methylazulene)methane (13) evolve more energy per connecting bond than the corresponding trimers or tetramers would. This we propose is a guiding parameter that may adjust molecule growth. The corresponding trimers, tetramers, or higher oligomers of 1, 2, and 11-13 appear to represent "missing" compounds in nature. Natural products 1, 2, and 11-13, having 3-fold and higher levels of symmetry, would founder on the lack of a facile method of synthesis and on the prohibitively high-energy costs caused by steric crowding at their core.

Diencephalic Syndrome (DS) is a rare but potentially lethal condition, which may complicate the clinical course of infants with hypothalamic/chiasmatic tumors, usually low-grade gliomas, either pilocytic (WHO-grade I) or pilomyxoid (WHO-grade II) astrocytomas. The mean survival of DS patients who do not receive any treatment after diagnosis, is usually less than 12 months. Yet, effective therapy is hampered by the tumor location preventing its complete resection, and by significant neurocognitive and endocrinological sequelae associated with potentially curative radiotherapy. The aim of our study was to induce an objective tumor response and to obtain a rapid weight recovery, using ten three-day courses of reduced dose cisplatin-etoposide. Between 2004 and 2009, 8 pediatric patients with DS due to a hypothalamic tumor and a median age at diagnosis of 6.5 months (range: 4-60 months) received 10 monthly courses of cisplatin (25 mg/m2/d on days 1 to 3) and etoposide (100 mg/m2/d on days 1 to 3). All patients had a rapid weight recovery and a tumor response in 6 (75%;partial response in four and minimal response in two), while the remaining two had a stable disease at completion of treatment. Mean time to weight recovery was 6 months (range, 5 - 7 months) for pilomyxoid astrocytoma patients, and 3.3 months (range, 3 - 4 months) for those with pilocytic astrocytoma. DS patients who received nutritional support (enteral or parenteral nutrition) had a mean time of weight recovery of 5 months (range: 3 - 7 months), while children who were able to assume high energy diet by oral route had a mean time of weight recovery of 8.66 months (range 3 - 19 months). After a follow-up time ranging from 22 to 89 months (median, 38 months), all patients are alive. In conclusion, a chemotherapy program with ten three-day courses of reduced dose cisplatin-etoposide, according to a LGG type schedule, seems appropriate and effective in far most cases of DS, with lower ototoxicity and myelosuppression compared with other LGG regimens.

With the increased brilliance of state-of-the-art Synchrotron radiation sources and the advent of Free Electron Lasers enabling revolutionary science with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon counting capability with low probability of false positives, and (multi)-megapixels. PERCIVAL (``Pixelated Energy Resolving CMOS Imager, Versatile and Large'') is currently being developed by a collaboration of DESY, RAL, Elettra and DLS to address this need for the soft X-ray regime. PERCIVAL is a monolithic active pixel sensor (MAPS), i.e. based on CMOS technology. It will be back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to its preliminary specifications, the roughly 10 × 10 cm2, 3520 × 3710 pixel monolithic sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within its 27 μm pixels to measure (e.g. at 500 eV) 1 to ~ 105 simultaneously-arriving photons. Currently, small-scale front-illuminated prototype systems (160 × 210 pixels) are undergoing detailed testing with visible-light as well as X-ray photons.