Development of innovative synthetic processes for the industrial production of APIs

Active Pharmaceutical Ingredients (APIs) are a fundamental class of chemicals due to their important role in the human health. APIs are protected by intellectual property (IP), allowing the owners of the newly invented drug to have a temporary but complete exclusivity in terms of use, production and commercialization. The activity of the PhD is focused on the research of efficient and alternative synthesis of APIs, for which product/process patents are no longer valid or they are about to expire. The molecules selected for the research of alternative syntheses were vildagliptin (treatment of type 2 diabetes mellitus), fexofenadine hydrochloride (therapy for allergic rhinitis) and ravidasvir hydrochloride (a novel API, not yet approved, for the treatment of chronic hepatitis C). The aim of this work is to design alternative preparations for these selected APIs, optimising all the synthetic steps by adjusting reactions conditions and maximizing the yield of the processes and finally scaling up the whole syntheses to transfer the processes to the industrial scale

Complete Metabolic Response with Recanalization of Portal Vein Tumor Thrombosis after Sunitinib in a Patient with Advanced Hepatocellular Carcinoma

The prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The outcome of these patients is particularly bleak when the disease is complicated by portal vein tumor thrombosis (PVTT), since the increased portal pressure often causes serious gastrointestinal bleedings. Before the introduction of sorafenib (SOR), a tyrosine kinase inhibitor, no effective treatment was available for patients with advanced disease. SOR is now considered the standard treatment even for patients with tumor thrombosis, although the well-known interference between tyrosine kinase inhibitors and the coagulation pathway calls for caution against their use in this setting. Here, we report the case of a 74-year-old male patient with advanced HCC and PVTT treated with sunitinib (SUN), another multikinase inhibitor. During the third cycle, our patient experienced a life-threatening hematemesis with hemorrhagic shock that required intensive care treatment and SUN discontinuation. However, he completely recovered, and the PET/CT scan performed 1 year after the adverse effect demonstrated no evidence of the tumor together with portal vein recanalization. The short course of SUN causing both tumor response and gastrointestinal bleeding warrants further studies on the effectiveness of SUN in this setting as well as on the duration of treatment with multikinase inhibitors in patients with tumor thrombosis

P-195 Effectiveness of COVID-19 vaccine in health care workers, Milan, Italy

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Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass