Ambient ionization mass spectrometry applied to new psychoactive substance analysis.

In the past decade a plethora of drugs with similar effects to controlled psychoactive drugs, like cannabis, amfetamine (amphetamine), or lysergic acid diethylamide, have been synthesized. These drugs can collectively be classified under the term new psychoactive substances (NPS) and are used for recreational purposes. The novelty of the substances, alongside the rapid rate of emergence and structural variability, makes their detection as well as their legal control highly challenging, increasing the demand for rapid and easy-to-use analytical techniques for their detection and identification. Therefore, interest in ambient ionization mass spectrometry applied to NPS has grown in recent years, which is largely because it is relatively fast and simple to use and has a low operating cost. This review aims to provide a critique of the suitability of current ambient ionization techniques for the analysis of NPS in the forensic and clinical toxicology fields. Consideration is given to analytical performance and ease of implementation, including ionization efficiency, selectivity, sensitivity, quantification, analyte chemistry, molecular coverage, validation, and practicality.

Validation of the Quality Analysis of Medical Artificial Intelligence (QAMAI) tool: a new tool to assess the quality of health information provided by AI platforms.

BACKGROUND: The widespread diffusion of Artificial Intelligence (AI) platforms is revolutionizing how health-related information is disseminated, thereby highlighting the need for tools to evaluate the quality of such information. This study aimed to propose and validate the Quality Assessment of Medical Artificial Intelligence (QAMAI), a tool specifically designed to assess the quality of health information provided by AI platforms. METHODS: The QAMAI tool has been developed by a panel of experts following guidelines for the development of new questionnaires. A total of 30 responses from ChatGPT4, addressing patient queries, theoretical questions, and clinical head and neck surgery scenarios were assessed by 27 reviewers from 25 academic centers worldwide. Construct validity, internal consistency, inter-rater and test-retest reliability were assessed to validate the tool. RESULTS: The validation was conducted on the basis of 792 assessments for the 30 responses given by ChatGPT4. The results of the exploratory factor analysis revealed a unidimensional structure of the QAMAI with a single factor comprising all the items that explained 51.1% of the variance with factor loadings ranging from 0.449 to 0.856. Overall internal consistency was high (Cronbach's alpha = 0.837). The Interclass Correlation Coefficient was 0.983 (95% CI 0.973-0.991; F (29,542) = 68.3; p < 0.001), indicating excellent reliability. Test-retest reliability analysis revealed a moderate-to-strong correlation with a Pearson's coefficient of 0.876 (95% CI 0.859-0.891; p < 0.001). CONCLUSIONS: The QAMAI tool demonstrated significant reliability and validity in assessing the quality of health information provided by AI platforms. Such a tool might become particularly important/useful for physicians as patients increasingly seek medical information on AI platforms.

The synthesis and properties of mitochondrial targeted iron chelators.

Iron levels in mitochondria are critically important for the normal functioning of the organelle. Abnormal levels of iron and the associated formation of toxic oxygen radicals have been linked to a wide range of diseases and consequently it is important to be able to both monitor and control levels of the mitochondrial labile iron pool. To this end a series of iron chelators which are targeted to mitochondria have been designed. This overview describes the synthesis of some of these molecules and their application in monitoring mitochondrial labile iron pools and in selectively removing excess iron from mitochondria.

Recent progress in the imaging of c-Met aberrant cancers with positron emission tomography.

Tyrosine-protein kinase Met-also known as c-Met or HGFR-is a membrane receptor protein with associated tyrosine kinase activity physiologically stimulated by its natural ligand, the hepatocyte growth factor (HGF), and is involved in different ways in cancer progression and tumourigenesis. Targeting c-Met with pharmaceuticals has been preclinically proved to have significant benefits for cancer treatment. Recently, evaluating the protein status during and before c-Met targeted therapy has been shown of relevant importance by different studies, demonstrating that there is a correlation between the status (e.g., aberrant activation and overexpression) of the HGFR with therapy response and clinical prognosis. Currently, clinical imaging based on positron emission tomography (PET) appears as one of the most promising tools for the in vivo real-time scanning of irregular alterations of the tyrosine-protein kinase Met and for the diagnosis of c-Met related cancers. In this study, we review the recent progress in the imaging of c-Met aberrant cancers with PET. Particular attention is directed on the development of PET probes with a range of different sizes (HGF, antibodies, anticalines, peptides, and small molecules), and radiolabeled with different radionuclides. The goal of this review is to report all the preclinical imaging studies based on PET imaging reported until now for in vivo diagnosis of c-Met in oncology to support the design of novel and more effective PET probes for in vivo evaluation of c-Met.

Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine.

Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 µm). 201Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked in vivo as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of 201Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. H4pypa, H5decapa, H4neunpa-NH2, and H4noneunpa are multidentate N- and O-donor chelators that have previously been shown to have high affinity for 111In, 177Lu, and 89Zr. Herein, we report the synthesis and serum stability of [nat/201Tl]Tl3+ complexes with H4pypa, H5decapa, H4neunpa-NH2, and H4noneunpa. All ligands quickly and efficiently formed complexes with [201Tl]Tl3+ that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [natTl]Tl-pypa was further characterized using nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS), and X-ray crystallography, showing evidence of the proton-dependent presence of a nine-coordinate complex and an eight-coordinate complex with a pendant carboxylic acid group. A prostate-specific membrane antigen (PSMA)-targeting bioconjugate of H4pypa was synthesized and radiolabeled. The uptake of [201Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated in vitro and showed evidence of bioreductive release of 201Tl and cellular uptake characteristic of unchelated [201Tl]TlCl. SPECT/CT imaging was used to probe the in vivo biodistribution and stability of [201Tl]Tl-pypa-PSMA. In healthy animals, [201Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated 201Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [201Tl]Tl-pypa-PSMA in DU145 PSMA-positive tumors was higher than that in DU145 PSMA-negative tumors but insufficient for useful tumor targeting. We conclude that H4pypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl3+ chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl3+ and subsequent release of Tl+. However, this is the first report describing the incorporation of [201Tl]Tl3+ into a chelator-peptide bioconjugate and represents a significant advance in the field of 201Tl-based radiopharmaceuticals. The design of the next generation of chelators must include features to mitigate this susceptibility to bioreduction, which does not arise for other trivalent heavy radiometals.

Minimally Invasive "Trocar-Free" Approach for Rear Mandibular Fractures Management.

ABSTRACT: The request of minimally invasive surgery is progressively expanding the indications of endoscopically assisted intraoral access for mandibular traumas. The aim of our study is to assess how much the use of the angled drill may affect the outcome of patients treated for rear mandibular fracture. In our retrospective case-control trial we enrolled 36 patients with mandibular rear fractures treated through endoscopically assisted intraoral access. Eighteen patients were treated by using an angled drill ''trocar free,'' and 18 treated by linear drills placed through trocars. Surgical times, hospitalization times (HT), and major complications rate were compared between the 2 groups. Group 1 showed a significant reduction in HT (1.72 versus 2.22 days, P = 0.024) and an increase in the surgical times (3.0 versus 2.53 hours, P = 0.019). Significant reduction of total amount of complication was seen in group 1 versus group 2 ( P = 0.007). The ''trocar free'' approach allowed by angled drills, in our hands, greatly reduces the invasiveness of the surgery resulting in a significant reduction in HT and smaller share of vascular-nervous sequelae. Our results suggest the ''trocar free'' approach as a valuable choice when indicated for the treatment of rear mandibular fractures.

Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives.

Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA. We hypothesized that substituting the zinc-coordinating urea group for a thiourea group, thus incorporating a sulfur atom, could facilitate stronger binding to zinc(II) within the active site, and thus improve affinity for GCP(II)/PSMA. A structurally analogous urea and thiourea pair (HO-Glu-C(O)-Glu-OH - compound 5 and HO-Glu-C(S)-Glu-OH - compound 6) were synthesized and the inhibitory concentration (IC50) of each compound measured with a cell-based assay, allowing us to refute the hypothesis: the thiourea analogue showed 100-fold weaker binding to PSMA than the urea analogue.

The Use of Dermal Substitutes for Donor Site Closure After Radial Forearm Free Flap Harvesting.

OBJECTIVE: The aim of our study was to analyze the aesthetic and functional outcome in the radial forearm free flap donor site using a simple split thickness skin grafting (STSG) closure compared with the use of dermal scaffold supporting the STSG closure. METHODS: The study analyzed 18 patients, divided in 2 groups based on the donor site closure modality. In STSG group, a simple STSG was used to cover the defect. In the DS + STSG group, the defect was covered by the use of dermal substitute (MatriDerm) supporting the STSG. Groups were compared on the following outcome variable: scar status; hand function; circumferences at most proximal and most distal point of the graft. All patients were followed up 1, 6, and 12 months post-operative. RESULTS: Nine patients from STSG group showed a difference in circumference between the operated and contralateral limbs respectively of 2.9 mm proximal and 1.2 mm distal; in the 9 patients of DS + STGS group the difference was respectively of 1.2 mm proximal and 1.3 mm distal. Welch unequal variances t-test demonstrated statistical significance of the values with P < 0.004 (P < 0.5). The average VSS was 1.82 ±â€Š0.2 for STSG group and 1.75 ±â€Š0.2 for DS + STGS group. The DASH score was 21.8% in STSG group and 19.4% in DS + STGS group. CONCLUSION: Our study shows that patients treated with Matriderm + STSG obtained a better result both in esthetic and functional outcomes.

The Role of a Deep Neuromuscular Block in the Treatment of Mandibular Subcondylar Fractures.

ABSTRACT: Mandibular fractures are the third most frequents maxillo-facial fractures. Most frequent site is the subcondylar region. Different approaches to reach subcondylar region, have been described. In the study was evaluated the advantages of neuromuscular block during endoscopic surgery for subcondylar fractures. Twenty-five patients affected by subcondylar fractures were enrolled in this study and divided in 2 groups; group A: patients who received an intraoperative booster of curare during surgical procedure and group B patients who underwent surgery treated without the intraoperative booster of curare. All patients were treated successfully by endoscope-assisted transoral approach. The analysis of time required for surgery showed a reduction in group A comparing to group B. The mean time for surgery for the patients in group B with displacement between 0° and 45° was 170 minutes, and for 45° to 90° was 230 minutes. In group A, the mean time was 117.5 minutes for patients with condylar displacement between 0° and 45°, and 147.5 minutes for the other group. In conclusion, deep neuromuscular block seems to improve the surgical conditions in patients undergoing subcondylar endoscopic assisted surgery, further study needs to assess this surgical technique in order to better define this surgical protocol.

In Vitro Phase I Metabolic Profiling of the Synthetic Cannabinoids AM-694, 5F-NNEI, FUB-APINACA, MFUBINAC, and AMB-FUBINACA.

Synthetic cannabinoids (SCs) constitute one of the most rapidly expanding class of new psychoactive substances. SCs pose a health threat to the individual and to the public due to their central (psychoactive) and peripheral effects. Their pharmacology and toxicology are poorly understood, and the substances can be unexpectedly toxic and harmful. The metabolism of SCs is also relevant in clinical and forensic toxicology as SCs are excreted in urine mostly as their metabolites. Thus, SC metabolites are widely used as markers for identifying SC intake. Herein, we used human liver microsome systems to study the in vitro phase I metabolic profiling of five SCs, namely AM-694, 5F-NNEI, FUB-APINACA, MFUBINAC, and AMB-FUBINACA. The metabolites were detected and structurally elucidated by liquid chromatography-high resolution mass spectrometry. The main metabolic pathway of AM-694 (benzoyl-indole SC) is oxidative defluorination; 5F-NNEI (naphthyl-indole carboxamide SC) follows amide hydrolysis and monohydroxylation at the naphthyl moiety. However, indazole carboxamide substituted with an adamantyl group, such as FUB-APINACA, is likely to produce (isomeric) hydroxylation of the adamantyl group as the main metabolite species. For the substrates that contain ester bonds in their structure, like MFUBINAC and AMB-FUBINACA, the ester hydrolysis metabolite is predominant.

Detection of mephedrone and its metabolites in fingerprints from a controlled human administration study by liquid chromatography-tandem mass spectrometry and paper spray-mass spectrometry.

The use of synthetic stimulants, including designer cathinones, remains a significant concern worldwide. Thus, the detection and identification of synthetic cathinones in biological matrices is of paramount importance for clinical and forensic laboratories. In this study, distribution of mephedrone and its metabolites was investigated in fingerprints. Following a controlled human mephedrone administration (100 mg nasally insufflated), two mass spectrometry-based methods for fingerprint analysis have been evaluated. The samples deposited on triangular pieces of chromatography paper were directly analysed under ambient conditions by paper spray-mass spectrometry (PS-MS) while those deposited on glass cover slips were extracted and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method was 5-6 times more sensitive than PS-MS but required sample preparation and longer analysis time. Mephedrone was detected in 62% and in 38% of all post-administration samples analysed by LC-MS/MS and PS-MS, respectively. Nor-mephedrone was the only metabolite detected in 3.8% of all samples analysed by LC-MS/MS. A large inter- and intra-subject variation was observed for mephedrone which may be due to several factors, such as the applied finger pressure, angle and duration of contact with the deposition surface and inability to control the 'amount' of collected fingerprint deposits. Until these limitations are addressed, we suggest that the sole use of fingerprints can be a useful diagnostic tool in qualitative rather than quantitative analysis, and requires a confirmatory analysis in a different biological matrix.

Hydroxypyridinone Journey into Metal Chelation.

Hydroxypyridinones (HOPOs) form outstanding building blocks for the development of a variety of agents in the field of metal chelation. The pyridinone ring is easily synthesized and readily converted into tetradentate, hexadentate, and octadentate chelators. There is considerable potential for the control of the stereochemistry of the resulting metal complex and hence the properties of these multidentate molecules. Their ability to rapidly bind hard metals in aqueous media has facilitated the development of efficient applications in both biological and medical contexts. In this Review, an in-depth analysis of the synthetic methodologies for HOPO-based ligands is presented, as well as the many aspects to achieve optimal biological activity. Recent advances and current challenges for the future application of HOPO structures are outlined. The present flourishing development of drug candidates and diagnostic agents based on this chemical scaffold opens access to many new applications in analytical, environmental, and clinical science.

Dentoalveolar Fractures: New Orthodontic Protocol Proposal and Pilot Study.

The goal of fracture treatment that includes the dentoalveolar process is to obtain the anatomic bone healing and the pre-injury occlusion restoration with functional and aesthetic recovery, avoiding dental or periodontal lesions. Fractures activates, in the damaged tissue, the Regional Acceleratory Phenomenon, a physiological healing process that can also be activated during orthodontic overloads. Orthodontic treatment in the traumatized area could exploit this phenomenon in order to sustain the cellular activity.The aim of this study is to propose a treatment protocol for dentoalveolar fractures based on the use of orthodontics in order to sustain the physiological healing process known as Regional Acceleratory Phenomenon.The authors present 2 cases of an 18 year old woman and 23 year old man affected by dentoalveolar fracture. The operative protocol the authors applied foresaw three steps of treatment: orthodontic brackets application, surgery, orthodontic treatment.The patients showed complete healing at the 3 months follow-up and were treated up to 18 months for further orthodontic treatment.The operative protocol proposed by the Authors appears to be a rational choice since it allows a single orthodontic device to be an "active splinting system", with fast application time, good acceptance by the patient, low complications rate; moreover, it produces any planned dental movements for further orthodontic treatments.

Guidelines and Recommendations for Patient Management, Surgical Activities, and Safety in the Maxillofacial Unit and Head and Neck Department During COVID-19 Pandemic.

The recent pandemic has led to an unprecedented overload of sanitary systems around the world. Despite that a maxillofacial department is not a frontline specialty in the treatment of coronavirus disease 2019 infections, our department has found itself faced with numerous problems in keeping the care system active and efficient while ensuring safety for patients and healthcare professionals. Massive redistribution of health personnel was needed to improve prevention and personal safety measures. The education and training system has been kept active, giving residents a decisive role in managing the state of emergency response. This article outlines new guidelines for infection prevention: from clinical control, treatment processes, clinical management, protection, and disinfection of healthcare professionals.

Solid-Phase Synthesis and In-Silico Analysis of Iron-Binding Catecholato Chelators.

Siderophores are iron-complexing compounds synthesized by bacteria and fungi. They are low molecular weight compounds (500-1500 Daltons) possessing high affinity for iron(III). Since 1970 a large number of siderophores have been characterized, the majority using hydroxamate or catecholate as functional groups. The biosynthesis of siderophores is typically regulated by the iron levels of the environment where the organism is located. Because of their exclusive affinity and specificity for iron(III), natural siderophores and their synthetic derivatives have been exploited in the treatment of human iron-overload diseases, as both diagnostic and therapeutic agents. Here, solid-phase approach for the preparation of hexadentate, peptide-based tricatecholato containing peptides is described. The versatility of the synthetic method allows for the design of a common scaffolding structure whereby diverse ligands can be conjugated. With so many possibilities, a computational approach has been developed which will facilitate the identification of those peptides which are capable of providing a high affinity iron(III) binding site. This study reports an integrated computational/synthetic approach towards a rational development of peptide-based siderophores.

3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation.

Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 µM, with a high level of agreement with the predicted values.

iVS analysis to evaluate the impact of scaffold diversity in the binding to cellular targets relevant in cancer.

This study reports the application of inverse virtual screening (iVS) methodologies to identify cellular proteins as suitable targets for a library of heterocyclic small-molecules, with potential pharmacological implications. Standard synthetic procedures allow facile generation of these ligands showing a high degree of core scaffold diversity. Specifically, we have computationally investigated the binding efficacy of the new series for target proteins which are involved in cancer pathogenesis. As a result, nine macromolecules demonstrated efficient binding interactions for the molecular dataset, in comparison to the co-crystallised ligand for each target. Moreover, the iVS analysis led us to confirm that 27 analogues have high affinity for one or more examined cellular proteins. The additional evaluation of ADME and drug score for selected hits also highlights their capability as drug candidates, demonstrating valuable leads for further structure optimisation and biological studies.

Surgical Management of Large Odontogenic Cysts of the Mandible.

INTRODUCTION: Odontogenic cysts are defined as those cysts that arise from odontogenic epithelium and occur in the tooth-bearing regions of the jaws. Cystectomy, marsupialization, or decompression of odontogenic cyst are the most common treatments proposed for this pathology. The aim of this study is to retrospectively evaluate the result of decompression based on the volumetric reduction of the cystic cavity and new bone formation by cone beam computerized tomography (CBCT). METHODS: The 16 patients affected by a large odontogenic mandibular cyst were enrolled in the study. All the patients underwent a surgical decompression of the cyst followed by the enucleation after a follow-up ranging from 6 to 9 months according to the volume's reduction and new bone formation. All the patients were evaluated with a CBCT before and after the surgical decompression to measure and analyze the percentage of reduction of the cystic volume before proceeding with the enucleation. RESULTS: The decompression of the cyst showed a reduction of the cystic volume ranging from 38.2% to 54.4% proportionally to the treatment duration. The highest percentage of volume reduction observed was 54.4% in 1 patient followed-up for 9 months, before the surgical enucleation. CONCLUSION: In our experience, the decompression seems to be the most suitable technique for the primary treatment of large odontogenic cyst of the jaws followed by the enucleation after 6 to 9 months. The CBCT is an objective method to evaluate the cystic volume reduction after the decompression and helps the surgeon with the surgical planning.

Self-Made Rapid Prototyping Technique for Orbital Floor Reconstruction: Showcases for Technical Description.

BACKGROUND: Restoring the orbital cavity integrity in orbital floor defects is a challenging issue due to the anatomical complexity of the floor's surface. This is a showcase for technical description of a novel "in house" rapid prototyping protocol aimed to customize implant for orbital floor reconstruction. METHODS: The authors present 4 cases to show our Computer-aided-design and Computer-aided-manufacturing digital workflow. The system was based on a 3D-printed press that; through a virtually designed mold, was used to conform a patient specific titanium mesh for orbital floor reconstruction. RESULTS: The merging procedure analysis by iPlan Cranial 3.0 (Brainlab, Munich, Germany) highlighted a 0.71 ±â€Š0.23 mm (P <0.05) discrepancy in a point-to-point superimposition between the digital planned reconstruction and the real in vivo result. CONCLUSIONS: The authors expect that this technique will reduce operative time and cost however further study and larger series may better define the applicability in everyday surgical practice.

Postoperative Management of Zygomatic Arch Fractures: In-House Rapid Prototyping System for the Manufacture of Protective Facial Shields.

Zygomatic fractures account for 10% to 15% of all facial fractures. The surgical management of isolated zygomatic arch fractures usually requires open reduction treatment without fixation through an intraoral access. Therefore, the main problem in the non-fixed treatment of zygomatic arch fractures is related to the difficulty in obtaining a stable reduction for a period long enough to guarantee the physiological bone healing process. We propose an innovative "in-house" rapid prototyping (RP) protocol for the 3D-zygoma mask manufacture of a patient-specific protective device to apply after zygomatic arch fracture reduction. Our study includes 16 consecutive patients who underwent surgical open reduction for an isolated zygoma fracture without fixation between January 2017 and February 2018. The patients received regular postoperative checks at weeks 1 and 2. Before the device was removed, a multiple choice questionnaire was administered to measure the degree of wearability of the mask. The estimated cost of the production is around &OV0556;5 per case and the construction time is around 90 minutes. Based on the encouraging results, obtained in our experience, we hope that other studies can be conducted to confirm our procedure and improve its functionality in the field of facial trauma.