Search Results (21)

Objective: To analyze the composition of the oral microbiome in periodontal pocket lesions and on the tongue dorsum of patients with Helicobacter pylori-associated gastric disease. Materials and Methods: Patients diagnosed with gastric disease and H. pylori (HP+) were evaluated in comparison to a control group of H. pylori-negative patients without gastric disease (HP−). Periodontal and oral health clinical parameters (PPD, BoP, PSE, plaque score and modified DMFT) were assessed for each patient. Microbiological samples were collected from the deepest periodontal pockets and tongue dorsum, followed by DNA extraction, 16S rRNA PCR amplification, and Next-Generation-Sequencing (NGS) analyses. Results: Sixty-seven patients (27F; 40M, aged 35–85 years) were enrolled. Of these, 52 were HP+ and 15 were HP−. HP+ patients exhibited a significantly higher presence of decayed teeth (p < 0.05) and slightly fewer missing teeth (p > 0.05). The plaque score was significantly higher in HP+ patients (p < 0.05), while PPD and BoP showed no significant differences (p > 0.05). NGS analysis revealed no presence of H. pylori in any samples of both periodontal and tongue sites. HP+ patients showed a distinct microbial composition, including higher prevalence of Capnocytophaga, Fusobacterium, and Peptostreptococcus genera in both locations (pockets and tongue dorsum). Conclusions: The study demonstrated that HP+ patients exhibit distinct oral microbial profiles compared to HP− patients, especially in areas with deeper periodontal pockets. H. pylori was not detected in the oral microbiomes of either group. Full article

In this study, we evaluated in situ click chemistry as a platform for discovering boronic acid-based β-lactamase inhibitors (BLIs). Unlike conventional drug discovery approaches requiring multi-step synthesis, protection strategies, and extensive screening, the in situ method can allow for the generation and identification of potent β-lactamase inhibitors in a rapid, economic, and efficient way. Using KPC-2 (class A carbapenemase) and AmpC (class C cephalosporinase) as templates, we demonstrated their ability to catalyse azide-alkyne cycloaddition, facilitating the formation of triazole-based β-lactamase inhibitors. Initial screening of various β-lactamases and boronic warheads identified compound 3 (3-azidomethylphenyl boronic acid) as the most effective scaffold for kinetic target-guided synthesis (KTGS). KTGS experiments with AmpC and KPC-2 yielded triazole inhibitors with K_i values as low as 140 nM (compound 10a, AmpC) and 730 nM (compound 5, KPC-2). Competitive inhibition studies confirmed triazole formation within the active site, while an LC–MS analysis verified that the reversible covalent interaction of boronic acids did not affect detection of the in situ-synthesised product. While KTGS successfully identified potent inhibitors, limitations in amplification coefficients and spatial constraints highlight the need for optimised warhead designs. This study validates KTGS as a promising strategy for BLI discovery and provides insights for further refinement in fighting β-lactamase-mediated antibiotic resistance. Full article

Objectives: Use of intracoronary imaging (ICI) in cases of stent thrombosis (ST) is recommended and tailored treatment appears reasonable. Nevertheless, data supporting such a strategy are lacking. The aim of this study was to evaluate the clinical impact of ICI in the management of ST. Methods: The unadjusted study population was consecutive patients with definite ST presenting in a single tertiary cardiac centre and undergoing percutaneous coronary intervention (PCI). The presumed major mechanism of ST was assigned according to the real-time ICI interpretation by the PCI operator. Propensity score matching was performed with regard to ICI use to form the adjusted population and Kaplan–Meier analysis was applied to compare survival free of cardiac death (CD) or target lesion revascularization (TLR). Results: The unadjusted population included 130 ST patients, with the majority presenting with ST-elevation myocardial infarction (STEMI) (88%) and very late ST (86%). ICI was performed in 45 patients, of whom optical coherence tomography (OCT) was performed in 30 cases. When the individual ST mechanisms were viewed as groups, there was an interaction observed between type of treatment (stent vs. non-stent) and ST mechanism, with non-stent treatment being more prevalent in cases of underexpansion, malapposition, in-stent restenosis and mechanism uncertainty. After application of matching, two groups of 30 patients were formed. ICI-guided management resulted in better survival free of CD–TLR at 2 years (93% vs. 73%, p = 0.037). Conclusions: Intracoronary imaging guidance during PCI for ST had a direct impact on management (stent vs. non-stent) and resulted in a lower event rate at mid-term follow-up when propensity matched analysis was applied. Full article

African swine fever (ASF) is a severe viral disease characterized by high lethality in suids and caused by the African Swine Fever Virus (ASFV). The ASF genotype I virus was introduced to Europe in 1957, marking the onset of the first European epidemic wave. In 2007, ASFV genotype II was detected in Georgia, affecting domestic pigs and wild boars before spreading to various European and extra-European countries, including Italy. The first case of ASFV in Italy was documented on 7 January 2022, in a wild boar in the Piedmont region. Since then, several ASFV-positive wild boar carcasses have been identified in the Piedmont and Liguria regions. By June 2023, ASFV had spread to Lombardy, one of the major pig-producing regions in northern Italy; the virus was first detected in early summer in wild boar carcasses. Two months later, it was diagnosed in a commercial pig farm as a consequence of the disease’s spread amongst wild boars and an increase in the viral environmental load. This report aims to describe the features of ASFV domestic pig outbreaks that occurred in the Zinasco municipality (Lombardy) and the joint efforts to mitigate potential direct and indirect economic impacts on the Italian and global pig industry. The epidemiological investigation and the measures implemented, which were all performed according to national and European regulations, as well as exceptional ad hoc measures aimed at protecting the pig industry, are described in order to provide a practical and effective approach to combating ASF. Full article

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has been linked to steatotic liver disease susceptibility. However, the impact of biallelic loss-of-function MBOAT7 variants on liver disease is not known. We report on a 2-year-old girl with MBOAT7-related intellectual disability and steatotic liver disease, confirming that MBOAT7 loss-of-function predisposes to liver disease. Full article

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features—such as fibrous cap thickness and large lipid accumulation—beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field. Full article

Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log₁₀ per 1 mmHg increase, 95% c.i. 0.002–0.015; p = 0.016), and inversely correlated with antihypertensive medications (estimate −0.189, 95% c.i. −0.291–−0.088, p = 0.0002). Through multivariable analysis, IL32 levels predicted both systolic blood pressure (estimate 0.746, 95% c.i 0.173–1.318; p = 0.010) and impaired blood pressure control (OR 1.22, 95% c.i. 1.09–1.38; p = 0.0009) independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease. Full article

Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to β-lactams. One of the most important mechanisms is the production of β-lactamase enzymes capable of hydrolyzing β-lactam antibiotics. Co-expression of multiple classes of β-lactamases is present in CRAB; therefore, the design and synthesis of “cross-class” inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical β-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C β-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a K_i = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other β-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum β-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design. Full article

Recent advancements in quantum key distribution (QKD) protocols opened the chance to exploit nonlaser sources for their implementation. A possible solution might consist in erbium-doped light emitting diodes (LEDs), which are able to produce photons in the third communication window, with a wavelength around 1550 nm. Here, we present silicon LEDs based on the electroluminescence of Er:O complexes in Si. Such sources are fabricated with a fully-compatible CMOS process on a 220 nm-thick silicon-on-insulator (SOI) wafer, the common standard in silicon photonics. The implantation depth is tuned to match the center of the silicon layer. The erbium and oxygen co-doping ratio is tuned to optimize the electroluminescence signal. We fabricate a batch of Er:O diodes with surface areas ranging from 1 µm × 1 µm to 50 µm × 50 µm emitting 1550 nm photons at room temperature. We demonstrate emission rates around 5 × 10${}^6$ photons/s for a 1 µm × 1 µm device at room temperature using superconducting nanowire detectors cooled at 0.8 K. The demonstration of Er:O diodes integrated in the 220 nm SOI platform paves the way towards the creation of integrated silicon photon sources suitable for arbitrary-statistic-tolerant QKD protocols. Full article

Since its ability to precisely characterized atherosclerotic plaque phenotypes, to tailor stent implantation, as well as to guide both complex percutaneous coronary interventions (PCI) and invasive diagnostic work-ups (e.g., spontaneous coronary dissections or myocardial infarction with non-obstructive arteries), the adoption of optical coherence tomography (OCT) was raised in the past decades in order to provide complementary information to the traditional angiography and to overcome its limitations. However, the impact of OCT on daily clinical practice is currently modest, firstly because of the lack of both standardized algorithms of PCI guidance and data from prospective clinical trials. Therefore, the aim of our narrative review is to provide a comprehensive overview of the basic OCT interpretation, to summarize the evidence supporting the OCT guidance procedures and applications, to discuss its current limitations, and to highlight the knowledge gaps that need to be filled with more robust evidence. Full article

Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous histological group which is 20–25% of those with renal cell carcinoma (RCC). Patients with nccRCC have limited therapeutic options due to their exclusion from phase III randomized trials. The aim of the present study was to investigate the effectiveness and tolerability of pembrolizumabaxitinib combination in chromophobe and papillary metastatic RCC (mRCC) patients enrolled in the I-RARE (Italian Registry on rAre genitor-uRinary nEoplasms) observational ongoing study (Meet-URO 23). Baseline characteristics, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) and toxicities were retrospectively and prospectively collected from nccRCC patients treated in 14 Italian referral centers adhering to the Meet-Uro group, from December 2020 to April 2022. Only patients with chromophobe and papillary histology were considered eligible for the present pre-specified analysis. There were 32 eligible patients who received pembrolizumab-axitinib as first-line treatment, of whom 13 (40%) had chromophobe histology and 19 (60%) were classified as papillary RCC. The DCR was 78.1% whereas ORR was 43.7% (11 patients achieved stable disease and 14 patients obtained partial response: 9/19 papillary, 5/13 chromophobe). Six patients (18.7%) were primary refractory. Median PFS was 10.8 months (95%CI 1.7–11.5). Eleven patients (34.3%) interrupted the full treatment due to immune-related adverse events (irAEs): G3 hepatitis (n = 5), G3 hypophisitis (n = 1), G3 diarrhea (n = 1), G3 pancreatitis (n = 1), G3 asthenia (n = 1). Twelve patients (37.5%) temporarily interrupted axitinib only due to persistent G2 hand-foot syndrome or G2 hypertension. Pembrolizumab-axitinib combination could be an active and feasible first-line treatment option for patients with papillary or chromophobe mRCC. Full article

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3–G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity. Full article

The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC₅₀ = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in Escherichia coli ATCC BAA-2523 β-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs. Full article

The current challenge worldwide is the administration of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. Even if rarely, severe vascular adverse reactions temporally related to vaccine administration have induced diffidence in the population at large. In particular, researchers worldwide are focusing on the so-called “thrombosis and thrombocytopenia after COVID-19 vaccination”. This study aims to establish a practical workflow to define the relationship between adverse events following immunization (AEFI) and COVID-19 vaccination, following the basic framework of the World Health Organization (WHO). Post-mortem investigation plays a pivotal role to support this causality relationship when death occurs. To demonstrate the usefulness and feasibility of the proposed workflow, we applied it to two exemplificative cases of suspected AEFI following COVID-19 vaccination. Based on the proposed model, we took into consideration any possible causality relationship between COVID-19 vaccine administration and AEFI. This led us to conclude that vaccination with ChAdOx1 nCov-19 may cause the rare development of immune thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4), which clinically mimics heparin-induced autoimmune thrombocytopenia. We suggest the adoption of the proposed methodology in order to confirm or rule out a causal relationship between vaccination and the occurrence of AEFI. Full article

Background: Periprosthetic joint infection (PJI) represents 25% of failed total knee arthroplasties (TKA). The European Knee Associates (EKA) formed a transatlantic panel of experts to perform a literature review examining patient-related risk factors with the objective of producing perioperative recommendations in PJI high-risk patients. Methods: Multiple databases (Pubmed/MEDLINE, EMBASE, Scopus, Cochrane Library) and recommendations on TKA PJI prevention measures from the International Consensus Meetings on PJI from the AAOS and AAHKS were reviewed. This represents a Level IV study. Results: Strong evidence was found on poor glycemic control, obesity, malnutrition, and smoking being all associated with increased rates of PJI. In the preoperative period, patient optimization is key: BMI < 35, diet optimization, Hemoglobin A1c < 7.5, Fructosamine < 292 mmol/L, smoking cessation, and MRSA nasal screening all showed strong evidence on reducing PJI risk. Intraoperatively, a weight-based antibiotic prophylaxis, accurate fluid resuscitation, betadine and chlorhexidine dual skin preparation, diluted povidone iodine solution irrigation, tranexamic acid administration, and monofilament barbed triclosan-coated sutures for soft tissues closure all represented effective prevention measures. In the postoperative period, failure to reach normalization of ESR, CRP, D-dimer, and IL-6 six weeks postoperatively suggested early PJI. Conclusion: The current recommendations from this group of experts, based on published evidence, support risk stratification to identify high-risk patients requiring implementation of perioperative measures to reduce postoperative PJI. Full article