Determining line-crossing sequences between laser printing and black ink using digital microscopy: The influence of writing tool and toner.

One of the recurring issues in forensic document analysis is determining the chronological order of line-crossing sequences. This seemingly simple but tricky task allows forensic laboratories to demonstrate the real order of events. The aim of this work is to analyse black ink/toner intersections using the digital microscope Hirox RH-2000. Five types of pens (ballpoint, gel, rollerball, fountain and fineliner) as well as five different laser printers were used to create the samples. Forensic examiners were tasked with assessing toner fractures, the bronzing effect, and gaps. The findings were analysed to determine the importance of each characteristic for each type of pen. Results indicate that observing the bronzing effect at high magnification (700x) is crucial for establishing the sequence order of application. In this regard, the fineliner pen is considered the most challenging type of pen to analyse in a black ink/toner intersection. The method was validated through a blind test. Based on this, a flow chart has been developed to assist the Forensic Document Examiners (FDEs) in their evaluations. The flow chart emphasises the significance of combining multiple observations and enables a more objective analysis for trained FDEs.

A combined crossed molecular beam and theorerical study of the O(3P,1D) + acrylonitrile (CH2CHCN) reactions and implications for combustion and extraterrestrial environments.

Acrylonitrile (CH2CHCN) is ubiquitous in space (molecular clouds, solar-type star forming regions, and circumstellar envelopes) and is also abundant in the upper atmosphere of Titan. The reaction O(3P) + CH2CHCN can be of relevance in the chemistry of the interstellar medium because of the abundance of atomic oxygen. The oxidation of acrylonitrile is also important in combustion as the thermal decomposition of pyrrolic and pyridinic structures present in fuel-bound nitrogen generates many nitrogen-bearing compounds, including acrylonitrile. Despite its relevance, limited information exists on this reaction. We report a combined experimental and theoretical investigation of the reactions of acrylonitrile with both ground 3P and excited 1D atomic oxygen. From product angular and time-of-flight distributions in crossed molecular beam experiments with mass spectrometric detection at a collision energy, Ec, of 31.4 kJ mol-1, we have identified the primary reaction products and determined their branching fractions (BFs). Theoretical calculations of the relevant triplet and singlet potential energy surfaces (PESs) were performed to interpret the experimental results and elucidate the reaction mechanism. Adiabatic statistical calculations of product BFs for the decomposition of the main triplet and singlet intermediates have been carried out. Combining the experimental and theoretical results, we conclude that the O(3P) reaction leads to two main product channels: (i) CH2CNH (ketenimine) + CO (dominant with a BF of 0.87 ± 0.05), formed via efficient intersystem crossing from the entrance triplet PES to the underlying singlet PES, and (ii) HCOCHCN + H (minor, with a BF of 0.13 ± 0.05), occurring adiabatically on the triplet PES. Our study suggests the inclusion of this reaction as a possible destruction pathway of CH2CHCN and a possible formation route of CH2CNH in the interstellar medium. The O(1D) + CH2CHCN reaction mainly leads to the formation of CH2CNH + CO adiabatically on the singlet PES. This result can improve models related to the chemistry of interstellar ice and cometary comas, where O(1D) reactions can play a role. Overall, our results are expected to be useful for improving the models of combustion and extraterrestrial environments.

OH(2Π) + C2H4 Reaction: A Combined Crossed Molecular Beam and Theoretical Study.

The reaction between the ground-state hydroxyl radical, OH(2Π), and ethylene, C2H4, has been investigated under single-collision conditions by the crossed molecular beam scattering technique with mass-spectrometric detection and time-of-flight analysis at the collision energy of 50.4 kJ/mol. Electronic structure calculations of the underlying potential energy surface (PES) and statistical Rice-Ramsperger-Kassel-Marcus (RRKM) calculations of product branching fractions on the derived PES for the addition pathway have been performed. The theoretical results indicate a temperature-dependent competition between the anti-/syn-CH2CHOH (vinyl alcohol) + H, CH3CHO (acetaldehyde) + H, and H2CO (formaldehyde) + CH3 product channels. The yield of the H-abstraction channel could not be quantified with the employed methods. The RRKM results predict that under our experimental conditions, the anti- and syn-CH2CHOH + H product channels account for 38% (in similar amounts) of the addition mechanism yield, the H2CO + CH3 channel for ∼58%, while the CH3CHO + H channel is formed in negligible amount (<4%). The implications for combustion and astrochemical environments are discussed.

Fluorescent sensing of non-steroidal anti-inflammatory drugs naproxen and ketoprofen by dansylated squaramide-based receptors.

Bis-squaramide receptors L1-L4 bearing a dansyl moiety were synthesised and their potential applications as fluorescent probes towards non steroidal anti-inflammatory drugs naproxen and ketoprofen was investigated. A detailed photophysical characterization in CH3CN/DMSO solution (9 : 1 v/v) was conducted and demonstrated that the two macrocyclic receptors L1 and L2 show good sensitivity towards ketoprofen with an ON-OFF fluorescent response, while the two open chain receptors L3 and L4 behave similarly with the three guests considered. DFT theoretical calculations carried out on L2 and L4 as model receptors allowed to propose a possible coordination mode towards the guests. Finally, 1H-NMR spectroscopy in DMSO-d6/0.5% water solution demonstrated that the four receptors interact with the considered guests via H-bonds.

Long-Term Sequential Digital Dermoscopy of Low-Risk Patients May Not Improve Early Diagnosis of Melanoma Compared to Periodical Handheld Dermoscopy.

Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84, p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.

Reaction N(2D) + CH2CCH2 (Allene): An Experimental and Theoretical Investigation and Implications for the Photochemical Models of Titan.

We report on a combined experimental and theoretical investigation of the N(2D) + CH2CCH2 (allene) reaction of relevance in the atmospheric chemistry of Titan. Experimentally, the reaction was investigated (i) under single-collision conditions by the crossed molecular beams (CMB) scattering method with mass spectrometric detection and time-of-flight analysis at the collision energy (E c) of 33 kJ/mol to determine the primary products and the reaction micromechanism and (ii) in a continuous supersonic flow reactor to determine the rate constant as a function of temperature from 50 to 296 K. Theoretically, electronic structure calculations of the doublet C3H4N potential energy surface (PES) were performed to assist the interpretation of the experimental results and characterize the overall reaction mechanism. The reaction is found to proceed via barrierless addition of N(2D) to one of the two equivalent carbon-carbon double bonds of CH2CCH2, followed by the formation of several cyclic and linear isomeric C3H4N intermediates that can undergo unimolecular decomposition to bimolecular products with elimination of H, CH3, HCN, HNC, and CN. The kinetic experiments confirm the barrierless nature of the reaction through the measurement of rate constants close to the gas-kinetic rate at all temperatures. Statistical estimates of product branching fractions (BFs) on the theoretical PES were carried out under the conditions of the CMB experiments at room temperature and at temperatures (94 and 175 K) relevant for Titan. Up to 14 competing product channels were statistically predicted with the main ones at E c = 33 kJ/mol being formation of cyclic-CH2C(N)CH + H (BF = 87.0%) followed by CHCCHNH + H (BF = 10.5%) and CH2CCNH + H (BF = 1.4%) the other 11 possible channels being negligible (BFs ranging from 0 to 0.5%). BFs under the other conditions are essentially unchanged. Experimental dynamical information could only be obtained on the overall H-displacement channel, while other possible channels could not be confirmed within the sensitivity of the method. This is also in line with theoretical predictions as the other possible channels are predicted to be negligible, including the HCN/HNC + C2H3 (vinyl) channels (overall BF < 1%). The dynamics and product distributions are dramatically different with respect to those observed in the isomeric reaction N(2D) + CH3CCH (propyne), where at a similar E c the main product channels are CH2NH (methanimine) + C2H (BF = 41%), c-C(N)CH + CH3 (BF = 32%), and CH2CHCN (vinyl cyanide) + H (BF = 12%). Rate coefficients (the recommended value is 1.7 (±0.2) × 10-10 cm3 s-1 over the 50-300 K range) and BFs have been used in a photochemical model of Titan's atmosphere to simulate the effect of the title reaction on the species abundance (including any new products formed) as a function of the altitude.

Fragmentation of interstellar methanol by collisions with He˙+: an experimental and computational study.

Methanol is a key species in astrochemistry as its presence and reactivity provides a primary route to the synthesis of more complex interstellar organic molecules (iCOMs) that may eventually be incorporated in newly formed planetary systems. In the interstellar medium, methanol is formed by hydrogenation of CO ices on grains, and its fate upon collisions with interstellar ions should be accounted for to correctly model iCOM abundances in objects at various stages of stellar evolution. The absolute cross sections (CSs) and branching ratios (BRs) for the collisions of He˙+ ions with CH3OH are measured, as a function of the collision energy, using a Guided Ion Beam Mass Spectrometer (GIB-MS). Insights into the dissociative electron (charge) exchange mechanism have been obtained by computing the entrance and exit multidimensional Potential Energy Surfaces (PESs) and by modelling the non-adiabatic transitions using an improved Landau-Zener-Stückelberg approach. Notably, the dynamical treatment reproducing the experimental findings includes a strong orientation effect of the system formed by the small He˙+ ion and the highly polar CH3OH molecule, in the electric field gradient associated to the strongly anisotropic intermolecular interaction. This is a stereodynamical effect that plays a fundamental role in collision events occurring under a variety of conditions, with kinetic energy confined within intervals ranging from the sub-thermal to the hyper-thermal regime.

The N(2D) + CH2CHCN (Vinyl Cyanide) Reaction: A Combined Crossed Molecular Beam and Theoretical Study and Implications for the Atmosphere of Titan.

The reaction of electronically excited nitrogen atoms, N(2D), with vinyl cyanide, CH2CHCN, has been investigated under single-collision conditions by the crossed molecular beam (CMB) scattering method with mass spectrometric detection and time-of-flight (TOF) analysis at the collision energy, Ec, of 31.4 kJ/mol. Synergistic electronic structure calculations of the doublet potential energy surface (PES) have been performed to assist in the interpretation of the experimental results and characterize the overall reaction micromechanism. Statistical (Rice-Ramsperger-Kassel-Marcus, RRKM) calculations of product branching fractions (BFs) on the theoretical PES have been carried out at different values of temperature, including the one corresponding to the temperature (175 K) of Titan's stratosphere and at a total energy corresponding to the Ec of the CMB experiment. According to our theoretical calculations, the reaction is found to proceed via barrierless addition of N(2D) to the carbon-carbon double bond of CH2═CH-CN, followed by the formation of cyclic and linear intermediates that can undergo H, CN, and HCN elimination. In competition, the N(2D) addition to the CN group is also possible via a submerged barrier, leading ultimately to N2 + C3H3 formation, the most exothermic of all possible channels. Product angular and TOF distributions have been recorded for the H-displacement channels leading to the formation of a variety of possible C3H2N2 isomeric products. Experimentally, no evidence of CN, HCN, and N2 forming channels was observed. These findings were corroborated by the theory, which predicts a variety of competing product channels, following N(2D) addition to the double bond, with the main ones, at Ec = 31.4 kJ/mol, being six isomeric H forming channels: c-CH(N)CHCN + H (BF = 35.0%), c-CHNCHCN + H (BF = 28.1%), CH2NCCN + H (BF = 26.3%), c-CH2(N)CCN(cyano-azirine) + H (BF = 7.4%), trans-HNCCHCN + H (BF = 1.6%), and cis-HNCCHCN + H (BF = 1.3%), while C-C bond breaking channels leading to c-CH2(N)CH(2H-azirine) + CN and c-CH2(N)C + HCN are predicted to be negligible (0.02% and 0.2%, respectively). The highly exothermic N2 + CH2CCH (propargyl) channel is also predicted to be negligible because of the very high isomerization barrier from the initial addition intermediate to the precursor intermediate able to lead to products. The predicted product BFs are found to have, in general, a very weak energy dependence. The above cyclic and linear products containing an additional C-N bond could be potential precursors of more complex, N-rich organic molecules that contribute to the formation of the aerosols on Titan's upper atmosphere. Overall, the results are expected to have a significant impact on the gas-phase chemistry of Titan's atmosphere and should be properly included in the photochemical models.

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in BRAF V600E-Mutated Metastatic Melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.

Unsaturated Dinitriles Formation Routes in Extraterrestrial Environments: A Combined Experimental and Theoretical Investigation of the Reaction between Cyano Radicals and Cyanoethene (C2H3CN).

The reaction between cyano radicals (CN, X2Σ+) and cyanoethene (C2H3CN) has been investigated by a combined approach coupling crossed molecular beam (CMB) experiments with mass spectrometric detection and time-of-flight analysis at a collision energy of 44.6 kJ mol-1 and electronic structure calculations to determine the relevant potential energy surface. The experimental results can be interpreted by assuming the occurrence of a dominant reaction pathway leading to the two but-2-enedinitrile (1,2-dicyanothene) isomers (E- and Z-NC-CH═CH-CN) in a H-displacement channel and, to a much minor extent, to 1,1-dicyanoethene, CH2C(CN)2. In order to derive the product branching ratios under the conditions of the CMB experiments and at colder temperatures, including those relevant to Titan and to cold interstellar clouds, we have carried out RRKM statistical calculations using the relevant potential energy surface of the investigated reaction. We have also estimated the rate coefficient at very low temperatures by employing a semiempirical method for the treatment of long-range interactions. The reaction has been found to be barrierless and fast also under the low temperature conditions of cold interstellar clouds and the atmosphere of Titan. Astrophysical implications and comparison with literature data are also presented. On the basis of the present work, 1,2-dicyanothene and 1,1-dicyanothene are excellent candidates for the search of dinitriles in the interstellar medium.

Semiempirical Potential in Kinetics Calculations on the HC3N + CN Reaction.

The reaction between the cyano radical CN and cyanoacetylene molecule HC3N is of great interest in different astronomical fields, from star-forming regions to planetary atmospheres. In this work, we present a new synergistic theoretical approach for the derivation of the rate coefficient for gas phase neutral-neutral reactions. Statistic RRKM calculations on the Potential Energy Surface are coupled with a semiempirical analysis of the initial bimolecular interaction. The value of the rate coefficient for the HC3N + CN → H + NCCCCN reaction obtained with this method is compared with previous theoretical and experimental investigations, showing strengths and weaknesses of the new presented approach.

The Reaction N(2D) + CH3CCH (Methylacetylene): A Combined Crossed Molecular Beams and Theoretical Investigation and Implications for the Atmosphere of Titan.

The reaction of excited nitrogen atoms N(2D) with CH3CCH (methylacetylene) was investigated under single-collision conditions by the crossed molecular beams (CMB) scattering method with mass spectrometric detection and time-of-flight analysis at the collision energy (Ec) of 31.0 kJ/mol. Synergistic electronic structure calculations of the doublet potential energy surface (PES) were performed to assist the interpretation of the experimental results and characterize the overall reaction micromechanism. Theoretically, the reaction is found to proceed via a barrierless addition of N(2D) to the carbon-carbon triple bond of CH3CCH and an insertion of N(2D) into the CH bond of the methyl group, followed by the formation of cyclic and linear intermediates that can undergo H, CH3, and C2H elimination or isomerize to other intermediates before unimolecularly decaying to a variety of products. Kinetic calculations for addition and insertion mechanisms and statistical (Rice-Ramsperger-Kassel-Marcus) computations of product branching fractions (BFs) on the theoretical PES were performed at different values of total energy, including the one corresponding to the temperature (175 K) of Titan's stratosphere and that of the CMB experiment. Up to 14 competing product channels were statistically predicted, with the main ones, at Ec = 31.0 kJ/mol, being the formation of CH2NH (methanimine) + C2H (ethylidyne) (BF = 0.41), c-C(N)CH + CH3 (BF = 0.32), CH2CHCN (acrylonitrile) + H (BF = 0.12), and c-CH2C(N)CH + H (BF = 0.04). Of the 14 possible channels, seven correspond to H displacement channels of different exothermicity, for a total H channel BF of ∼0.25 at Ec = 31.0 kJ/mol. Experimentally, dynamical information could only be obtained about the overall H channels. In particular, the experiment corroborates the formation of acrylonitrile + H, which is the most exothermic of all 14 reaction channels and is theoretically calculated to be the dominant H-forming channel (BF = 0.12). The products containing a novel C-N bond could be potential precursors to form other nitriles (C2N2, C3N) or more complex organic species containing N atoms in planetary atmospheres, such as those of Titan and Pluto. Overall, the results are expected to have a potentially significant impact on the understanding of the gas-phase chemistry of Titan's atmosphere and the modeling of that atmosphere.

Impact of delay in follow-up due to COVID-19 pandemic on skin cancer progression: a real-life experience from an Italian hub hospital.

BACKGROUND: The COVID-19 pandemic required the setting of a national lockdown in Italy from March 9, 2020, until May 18, 2020; therefore, most of the non-COVID-19 activities were postponed. As a consequence, many follow-up visits in patients with previously excised skin cancers were delayed. The aim of this retrospective real-life case-control study is demonstrating that delay in follow-up led to an increased incidence of advanced melanoma and keratinocyte cancers on the total of surgically excised skin cancers. METHODS: The incidence of excised advanced melanoma and keratinocyte cancers in our dermato-surgery division in the period May 18 to November 18, 2020, was compared to the same time span of 2019. All data were collected from the electronic database of our department. Odds ratio with 95% confidence interval was used to assess the risk of excised advanced skin cancers in 2020 compared to 2019. RESULTS: From May to November 2019, we performed 265 surgical excisions, while during the pandemic in 2020, we completed 280 surgeries. The number of advanced skin cancers excised between May 18 and November 18, 2020, was significantly higher compared with the same period in 2019 (54 vs. 22, OR: 2.64; 95% CI: 1.56-4.47; P = 0.0003). Significant differences were also observed regarding the number of surgically removed advanced BCCs (OR 2.15; 95% CI 1.14-4.07; P = 0.0187) and advanced SCCs (OR 4.60; 95% CI 1.31-16.18; P = 0.0175). CONCLUSION: These results confirm that delay in follow-up and, consequently, postponed surgical excisions are related to an increased incidence of advanced skin tumors, resulting in poorer prognosis lifelong. Follow-up visits should be carried on even during COVID-19 pandemic, avoiding significant delays as much as possible.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and ß-caryophyllene association on human endothelial and monocytic cells.

A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal ß-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1ß and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1ß, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Fingermark visualization exploiting electrostatic detection apparatus (ESDA): The effect of the composition and age of the latent deposit.

Paper evidence usually undergoes two consecutive examinations in forensic laboratories: ESDA (electrostatic detection apparatus) to detect indented impressions and a subsequent search for fingermarks by optical, physical, and chemical techniques. The ability of ESDA in visualizing fingermarks is well known. The aim of the present study is to understand better how long fingermarks can be developed with ESDA and if the different constituents of fingermarks show a different susceptibility to being developed. Several types of marks were collected from six donors on A4 standard office copy paper and tested with ESDA up to 69 days from deposition. A clear difference between natural, eccrine, and sebaceous marks emerged, being the latter ones better developed. ESDA developed standard sebaceous marks up to 16 days from deposition, whereas natural marks were visible within a few days. Eccrine marks were mainly visualized in reverse mode, despite the quality of these marks was not as good as the sebaceous marks. The appearance of the mark (standard/reverse) seemed to be correlated with time since deposition. Data suggest that the mechanism by which ESDA visualizes the fingermarks could be related to the residue (water-soluble and/or non-water-soluble) available on the surface of the substrate and not yet absorbed by the paper. ESDA could act as a useful screening tool in fingermark visualization on porous surfaces, especially because it is a non-destructive technique. Therefore, as a general procedure, it is highly recommended to acquire potential fingermarks developed by means of ESDA before proceeding with fingermark visualization.

Paw preference in wolves (Canis lupus): A preliminary study using manipulative tasks.

Behavioural and brain lateralization is widespread among non-human vertebrates. Motor lateralization has been investigated in the domestic dog, revealing that "pawedness" in this species seems to be sex and task related; however, few if any studies considered this asymmetry in wolves (Canis lupus). The aim of this study was to investigate the paw preference of seven wolves housed at Parco Natura Viva - Italy, during the interaction with food-related (FD) and olfactory (OLF) environmental enrichment devices. Eleven sessions were done (22 session in total) per condition (FD and OLF), and data about enrichment manipulation were collected. Most of the wolves manipulated the enrichment devices using one paw rather than both paws. At the individual level, all subjects were lateralized in paw use, six were right pawed, one was left pawed (the alpha male) regardless of the enrichment condition. The fact that one paw rather than both was frequently involved in manipulation could indicate a practical advantage for each individual in being lateralized in paw use. Despite the small sample size, our results provide interesting insights about lateralization in wolves, deserving further investigations. More studies are needed considering factors such as temperament, social rank and task complexity on canid motor lateralization.

Tailored Toxicity-Driven Administration of Vismodegib in Patients With Multiple or Locally Advanced Basal Cell Carcinoma: A Pilot Analysis.

In this pilot study, we describe our experience with vismodegib in the treatment of basal cell carcinoma (BCC) and evaluate the feasibility of a tailored toxicity-driven administration of vismodegib in patients with multiple or locally advanced BCC. We retrospectively analyzed the clinical charts of 17 consecutive patients with BCC who were treated with vismodegib. Therapy was started at the usual dosage of 150 mg per day per person, continuously; a rescheduled dosage of 150 mg per day for 4 weeks with a subsequent stop of 2 weeks was allowed during the treatment according to the standard practice of our institution. During treatment, 14 patients with responsive disease presented an adverse event (100% cramps and 20% dysgeusia), therefore, requiring a change in the treatment plan. Overall, in eight out of 17 patients (47% of the overall population), it was possible to re-schedule the treatment by postponing therapy for 2 weeks every 4 weeks. These patients were all still alive at the time of the present analysis and were showing complete response. Adverse events resolved during the first interruption of therapy. The intermittent vismodegib schedule assessed in this pilot series could be beneficial in improving duration of treatment, allowing to maintain a long-term treatment response, even in an elderly and fragile population. Based on these preliminary findings, dedicated studies may be planned to further evaluate an intermittent schedule of vismodegib administration.