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This chapter is devoted to the presentation of the most popular approaches employed to design mitigation measures. Initially, the mitigation measures necessary for a safe excavation and a permanent cavity stabilization are considered. Subsequently, the observational method, a design procedure aimed at optimizing the management of the unavoidable geological and geotechnical uncertainties affecting both tunnel design and construction, is presented. Finally, the long-term tunnel performance under accidental loads is discussed.

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting human populations, yet CL remains largely ignored in drug discovery programs. CL causes disfiguring skin lesions and often relapses after "clinical cure" using existing therapeutics. To expand the pool of anti-CL lead candidates, we implemented an integrated screening platform comprising three progressive Leishmania parasite life cycle forms. We identified tretazicar (CB1954, 5-(aziridin-1-yl)-2,4-dinitrobenzamide) as a potent inhibitor of Leishmania parasite viability across multiple Leishmania species, which translated into complete and prolonged in vivo suppression of CL lesion formation in BALB/c mice when used as a monotherapy and which was superior to liposomal amphotericin B. In addition, oral twice a day administration of tretazicar healed the majority of existing Leishmania major (L. major) cutaneous lesions. In drug combination studies, there was a strong potentiation when subtherapeutic doses of liposomal amphotericin B and tretazicar were simultaneously administered. This drug combination decreased L. major lesion size in mice earlier than individual monotherapy drug treatments and maintained all animals lesion free for up to 64 days after treatment cessation. In contrast, administration of subtherapeutic doses of tretazicar or amphotericin B as monotherapies resulted in no or partial lesion cures, respectively. We propose that tretazicar should be explored as a component of a systemic CL combination therapy and potentially for other diseases where amphotericin B is a first line therapy.

Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission...

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

The Brenner Base Tunnel (BBT) is being built to connect Italy with Austria. The southern access connects Ponte Gardena with Fortezza by two railway tunnels named Gardena and Scaleres. A 3D groundwater flow model, extended through an area of about 200 km2, has been built using MODFLOW code to evaluate the water inflow. The model thickness is 1200 m, divided into 8 layers varying from 100 m to 400 m. The model has been solved in transient conditions, allowing the water inflow both during 6 excavation stages reproducing the design excavation time schedule and during the subsequent equilibrium phase to be evaluated. Based on the geological and geotechnical model, the excavation methods have been defined; the results of the evaluation of water inflow and of the possible impact on the hydrogeological resources have been taken into account by defining risk mitigation measures to ensure hydraulic ante-operam conditions.

Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are under way to develop therapies that target essential biological processes in S. aureus. Antimicrobial photodynamic therapy is an effective alternative to antibiotics; therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photosensitizers. A near infrared photosensitizer was conjugated to human monoclonal antibodies (MAbs) that target the S. aureus iron-regulated surface determinant (Isd) heme acquisition proteins. In addition, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial photodynamic treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd MAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.

The aim of this analysis was to assess the quality of reporting of randomized controlled trials (RCTs) relating to pain management in rotator cuff (RC) tears. This review evaluated the quality of the studies in the literature regarding this topic through the use of some factors and trends. The online databases used to search all RCTs on the topic of RC surgery were Medline, Scopus, CINAHL, EMBASE, and CENTRAL. This research was completed in September 2020. To assess the quality of reports, the Consolidated Standards of Reporting Trials (CONSORT) and the modified Coleman methodology score (MCMS) were used. From the research, 262 articles emerged. Finally, 79 studies were included in this historical analysis. There were no statistically significant changes in MCMS across trials that included or did not include a CONSORT diagram (p = 0.10). A statistically significant difference in MCMS was discovered between papers produced prior to 2009 and publications produced after 2015 (p = 0.03). There was no association between the number of checklist items for each article and the Coleman score. During the years there has been a significant increase in both quantity and quality of RCTs relating to pain in RC tears.

[Image: see text] Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the development of chemotherapeutic agents against kinetoplastid diseases and malaria.

We recently reported a series of compounds for a solubility-driven optimization campaign of antitrypanosomal compounds. Extending a parasite-hopping approach to the series, a subset of compounds from this library has been cross-screened for activity against the metazoan flatworm parasite, Schistosoma mansoni. This study reports the identification and preliminary development of several potently bioactive compounds against adult schistosomes, one or more of which represent promising leads for further assessment and optimization.

Objectives Drugs for Neglected Diseases initiative (DNDi) has identified three chemical lead series, the nitroimidazoles, benzoxaboroles and aminopyrazoles, as innovative treatments for visceral leishmaniasis. The leads discovered using phenotypic screening, were optimised following disease- and compound-specific criteria. Several leads of each series were progressed and preclinical drug candidates have been nominated. Here we evaluate the efficacy of the lead compounds of each of these three chemical classes in in vitro and in vivo models of cutaneous leishmaniasis. Methods The in vitro activity of fifty-five compounds was evaluated against the intracellular amastigotes of L. major, L. aethiopica, L. amazonensis, L. panamensis, L. mexicana and L. tropica. The drugs demonstrating potent activity (EC50, Graphical abstract Image 1

Background and Objectives: Unicompartmental knee arthroplasty (UKA) is a valid alternative to total knee arthroplasties (TKAs) in selected cases. After surgery, patients’ experience and satisfaction were traditionally evaluated by pre- and postsurgical scores and Patient-Reported Outcome Measures (PROMs). Otherwise, a statistically significant change does not necessarily correlate to a clinically meaningful improvement when measured using PROMs. To evaluate the real effect of a specific treatment and understand the difference between groups in a clinical trial, it is necessary to use a meaningful quantum of change on the score assessed. The minimal clinically important difference (MCID) and the Patient Acceptable Symptom State (PASS) can provide this meaningful change. This paper aimed to calculate the MCID and the PASS of the Forgotten Joint Score (FJS-12) after UKA. Materials and Methods: A total of 40 patients with a mean age 72.5 ± 6.4 years undergoing UKA were assessed preoperatively and six months postsurgery using the FJS-12 and the Oxford Knee Score (OKS). The baseline and 6-month postoperative scores were compared using the Wilcoxon signed ranks test. The correlation was calculated with Spearman’s rho. Both distribution-based approaches and anchor approaches were used to estimate MCID for the FJS-12. The 75th percentile and the Receiver operating characteristic (ROC) curve methods were used to calculate the PASS of FJS-12. Results: MCID estimates for normalized FJS-12 for UKA ranged from 5.68 to 19.82. The threshold of the FJS-12 with ROC method was 72.92 (AUC = 0.76). The cut-off value computed with the 75th percentile approach was 92.71. Conclusions: The MCID and PASS represent valid tools to assess the real perception of clinical improvement in patients who underwent UKA. The MCID value of FJS-12 was 12.5 for patients who underwent UKA. The value of the PASS for the FJS-12 in patients who underwent UKA was 72.92.

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting human populations, yet CL remains largely ignored in drug discovery programs. CL causes disfiguring skin lesions and often relapses after "clinical cure" using existing therapeutics. To expand the pool of anti-CL lead candidates, we implemented an integrated screening platform comprising three progressive

Enzymes in toothpastes can support host immune responses, and thus maintain oral health. This study aimed to investigate gingival health and the plaque-reducing effects of enzyme-containing toothpastes. A laboratory study tested the antimicrobial potential of different enzyme-containing toothpaste formulations. Two promising formulations (enzyme-containing toothpastes with glucose oxidase and D-glucose with (C+) and without Citrox (C&minus, ) Citrox) were investigated in a clinical crossover trial (two slurries: sodium lauryl sulfate-containing (SLS), a toothpaste without SLS (reference), and water). Subjects (n = 20) abstained from toothbrushing for four days and rinsed with a toothpaste slurry. Bleeding on probing (BOP) and plaque indices (PI) were measured. A mixed linear model was used to statistically compare the slurries with respect to BOP and PI change. The in vitro bacterial growth-inhibiting evaluation showed the best results for SLS, followed by C+ and C&minus, The change in BOP and PI exhibited statistically significant differences to water rinsing (BOP, PI changes in % points (difference of the baseline and post-rinse values: water = 8.8%, 90.0%, C+ = &minus, 1.4%, 80.4%, SLS = 1.5%, 72.1%, reference = 0.8%, 77.5%, C&minus, = &minus, 1.8%, 75.1%). All slurries exhibited anti-gingivitis and anti-plaque effects, resulting in a prophylactic benefit for limited-access regions during brushing.

Unicompartmental Knee Arthroplasty (UKA) recorded an increased incidence of around 30% per year in the United States. Patient’s experience and satisfaction after surgery were traditionally assessed by pre, and post-surgical scores and Patient-Reported Outcome Measures (PROMs) scales. Traditional scales as Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and Oxford Knee Score (OKS) reported high ceiling effect. Patients treated by UKA usually perform well; therefore, it is necessary to have a PROMs’ scale with a low ceiling effect as the Forgotten Joint Score-12 (FJS-12). PROMs have to be validated in the local language to be used. This study aims to perform a psychometric validation of the Italian version of FJS-12 for UKA for the first time. Between January 2019 and October 2019, 44 patients were included. Each patient completed both the FJS-12 Italian version and the WOMAC Italian version in preoperative follow-up, after 2-week and 1-month, 3-month, and 6-month postoperative follow-up. Cronbach’s α, intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimal detectable change (MDC) were calculated to evaluate the reliability. The Pearson coefficient was used to assess validity. The Effect Size (ES) was used to test the responsiveness. A range of Cronbach’s α between 0.90 and 0.95 indicated good internal consistency for the FJS-12. The test–retest reliability was acceptable (i.e., the ICC was higher than 0.7) at each follow-up. The Pearson correlation coefficient between the FJS-12 and WOMAC was − 0.11 (n.s.) at preoperative follow-up, r = 0.47 (P = 0.001) at 1 month, r = 0.57 (P

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.

A kinase-targeting cell-based high-throughput screen (HTS) against Trypanosoma brucei was recently reported, and this screening set included the Published Kinase Inhibitor Set (PKIS). From the PKIS was identified 53 compounds with pEC(50) >= 6. Utilizing the published data available for the PKIS, a statistical analysis of these active antiparasitic compounds was performed, allowing identification of a set of human kinases having inhibitors that show a high likelihood for blocking T. brucei cellular proliferation in vitro. This observation was confirmed by testing other established inhibitors of these human kinases and by mining past screening campaigns at GlaxoSmithKline. Overall, although the parasite targets of action are not known, inhibitors of this set of human kinases displayed an enhanced hit rate relative to a random kinase-targeting HTS campaign, suggesting that repurposing efforts should focus primarily on inhibitors of these specific human kinases. We therefore term this statistical analysis-driven approach "preferred lead repurposing"., We acknowledge funding from The Tres Cantos Open Lab Foundation (TC-007) and the National Institutes of Health (R01AI082577, R01AI114685).

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.

Background and objectives: Our research aimed to evaluate the quality of reporting of randomized controlled trials (RCTs) linked to rotator cuff (RC) tears. The present study analyzed factors connected to the quality of the RCTs and trends in the quality of reporting through time. Materials and Methods: The online databases used to search all RCTs on the topic of RC surgery completed until March 2020 were PubMed and Ovid (MEDLINE). The quality of reporting was evaluated using the modified Coleman methodology score (MCMS) and the consolidated standards of reporting trials (CONSORT). Results: The online search found 957 articles. Finally, 183 studies were included in the quantitative synthesis. A total of 97 (53%) of 183 studies had a level of evidence I and 86 (47%) of 183 studies had a level of evidence II, according to the Oxford Center of Evidence Based Medicine (EBM). A statistically significant difference in MCMS between articles written before 2010 and articles written after 2010 was found. Articles written after 2010 had, on average, the highest Coleman score. The average number of CONSORT checklist items for each article across all analyzed RCTs was 21.67. The 37 studies completed up to 2010 averaged a number of checklist items of 19.97 and the studies completed between 2011 and 2019 averaged a number of checklist items of 22.10. A statistically significant difference in the number of checklist items between articles written before 2010 and articles written after 2010 was found. Articles written after 2010 had on average more checklist items. However, low correlation (0.26) between the number of checklist items for each article and the respective Coleman score was found. On the other hand, articles with the CONSORT diagram had a significantly high Coleman score. Conclusions: An improvement in the quantity and quality of RCTs relating to RC surgery over the analyzed period was found.

[Image: see text] Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC(50)s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIβ). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIIIβ. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIIIβ with an IC(50) of 2.0 ± 0.30 nM. Together the results demonstrate that Pf PI4KIIIβ is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.

Both the two-dimensional harmonic oscillator and the Newton potential allow particular solutions for the orbits which are ellipses with center of attraction in the center, in the first case, and in one focus, in the second. The same complex map which allows to go from Kepler’s to Hooke’s orbits, and back, is used to transform the Lenz vector, defined for the Kepler orbit, into two conserved quantities for the harmonic motion. Upon quantization, the resulting operators, together with the angular momentum L z , are found to correspond to the generators of the SU(2) internal symmetry of the two-dimensional quantum oscillator and the connection to the Schwinger model of angular momentum is made apparent. We give a self-contained new look on this topic.

The two single track railway tunnels of Ponte Gardena along Fortezza-Verona High Speed line (North of Italy) are designed to be excavated by EPB-TBM. Its alignment runs on the left bank of the Isarco River. Combined interpretation of geological and geotechnical data led to crucial information during the design process, allowing a deeper knowledge on the geomorphological complexity of the area. These studies together with the contribution of the satellite radar monitoring technique permitted to define the borders of a large-scale landslide through thick debris deposits overlying a fractured rock basement. The railway alignment was optimized to prevent any influence of the tunnel construction on the landslide. Based on the new track layout, design solutions were carried out to solve the interaction issues related to the underpassing of an existing main road and to mitigate effects produced by the tunnel excavation. Specific numerical analyses were conducted to evaluate the effectiveness of the selected design choices.

Previously, ivermectin (1–10 mg/kg) was shown to inhibit liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (IC50 = 10.42 μM) and hypnozoites (IC50 = 29.24 μM) in primary macaque hepatocytes when administered in high-dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for seven consecutive days was evaluated for prophylaxis or radical cure of Plasmodium cynomolgi liver-stages in Rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for seven days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.