Controlling the Fluctuating Tip-Enhanced Raman Spectra of Chloramben on Silver Nanocubes.

Tip-enhanced Raman (TER) scattering from molecules residing at plasmonic junctions can be used to detect, identify, and image single molecules. This is most evident for flat molecules interrogated under conditions of extreme temperatures and pressure. It is also the case for (bio)molecular systems that feature preferred orientations/conformations under ambient laboratory conditions. More complex molecules that can adopt multiple conformations and/or feature different protonation or charge states give rise to complex TER spectra. We illustrate how the latter can be controlled in the case of chloramben molecules coated onto plasmonic silver nanocubes. We show that characteristic molecular Raman spectra cannot be obtained when tunneling plasmons are operative, i.e., when the tip is in direct contact with the chemically functionalized plasmonic nanoparticles. We rationalize these observations and propose an approach to less invasive and hence more analytical TER spectral imaging.

First-in-class Microbial Ecosystem Therapeutic 4 (MET4) in combination with immune checkpoint inhibitors in patients with advanced solid tumors (MET4-IO trial).

BACKGROUND: The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use. PATIENTS AND METHODS: We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors. RESULTS: The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids. CONCLUSIONS: This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.

A route for the top-down fabrication of ordered ultrathin GaN nanowires.

We introduce a facile route for the top-down fabrication of ordered arrays of GaN nanowires with aspect ratios exceeding 10 and diameters below 20 nm. Highly uniform thin GaN nanowires are first obtained by lithographic patterning a bilayer Ni/SiNxhard mask, followed by a combination of dry and wet etching in KOH. The SiNxis found to work as an etch stop during wet etching, which eases reproducibility. Arrays with nanowire diameters down to (33 ± 5) nm can be achieved with a uniformity suitable for photonic applications. Next, a scheme for digital etching is demonstrated to further reduce the nanowire diameter down to 5 nm. However, nanowire breaking or bundling is observed for diameters below ≈20 nm, an effect that is associated to capillary forces acting on the nanowires during sample drying in air. Explicit calculations of the nanowire buckling states under capillary forces indicate that nanowire breaking is favored by the incomplete wetting of water on the substrate surface during drying. The observation of intense nanowire photoluminescence at room-temperature indicates good compatibility of the fabrication route with optoelectronic applications. The process can be principally applied to any GaN/SiNxnanostructures and allows regrowth after removal of the SiNxmask.

Density control of GaN nanowires at the wafer scale using self-assembled SiNxpatches on sputtered TiN(111).

The self-assembly of heteroepitaxial GaN nanowires using either molecular beam epitaxy (MBE) or metal-organic vapor phase epitaxy (MOVPE) mostly results in wafer-scale ensembles with ultrahigh (>10µm-2) or ultralow (<1µm-2) densities, respectively. A simple means to tune the density of well-developed nanowire ensembles between these two extremes is generally lacking. Here, we examine the self-assembly of SiNxpatches on TiN(111) substrates which are eventually acting as seeds for the growth of GaN nanowires. We first found that if prepared by reactive sputtering, the TiN surface is characterized by {100} facets for which the GaN incubation time is extremely long. Fast GaN nucleation is only obtained after deposition of a sub-monolayer of SiNxatoms prior to the GaN growth. By varying the amount of pre-deposited SiNx, the GaN nanowire density could be tuned by three orders of magnitude with excellent uniformity over the entire wafer, bridging the density regimes conventionally attainable by direct self-assembly with MBE or MOVPE. The analysis of the nanowire morphology agrees with a nucleation of the GaN nanowires on nanometric SiNxpatches. The photoluminescence analysis of single freestanding GaN nanowires reveals a band edge luminescence dominated by excitonic transitions that are broad and blue shifted compared to bulk GaN, an effect that is related to the small nanowire diameter and to the presence of a thick native oxide. The approach developed here can be principally used for tuning the density of most III-V semiconductors nucleus grown on inert surfaces like 2D materials.

Influence of intermolecular interactions on the infrared complex indices of refraction for binary liquid mixtures.

This paper investigates the accuracy of deriving the composite optical constants of binary mixtures from only the complex indices of refraction of the neat materials. These optical constants enable the reflectance spectra of the binary mixtures to be modeled for multiple scenarios (e.g., different substrates, thicknesses, volume ratios), which is important for contact and standoff chemical detection. Using volume fractions, each mixture's complex index of refraction was approximated via three different mixing rules. To explore the impact of intermolecular interactions, these predictions are tested by experimental measurements for two representative sets of binary mixtures: (1) tributyl phosphate combined with n-dodecane, a non-polar medium, to represent mixtures which primarily interact via dispersion forces and (2) tributyl phosphate and 1-butanol to represent mixtures with polar functional groups that can also interact via dipole-dipole interactions, including hydrogen bonding. The residuals and the root-mean-square error between the experimental and calculated index values are computed and demonstrate that for miscible liquids in which the average geometry of the cross-interactions can be considered isotropic (e.g., dispersion), the refractive indices of the mixtures can be modeled using composite n and k values derived from volume fractions of the neat liquids. Conversely, in spectral regions where the geometry of the cross-interactions is more restricted and anisotropic (e.g., hydrogen bonding), the calculated n and k values vary from the measured values. The impact of these interactions on the reflectance spectra are then compared by modeling a thin film of the binary mixtures on an aluminum substrate using both the measured and the mathematically computed indices of refraction.

Antimicrobial resistance gene shuffling and a three-element mobilisation system in the monophasic Salmonella typhimurium strain ST1030.

In this study we describe the genetic elements and the antimicrobial resistance units (RUs) harboured by the Salmonella Typhimurium monophasic variant 1,4,[5],12:i:- strain ST1030. Of the three identified RUs two were chromosomal, RU1 (IS26-blaTEM-1-IS26-strAB-sul2- IS26) and RU2 (IS26-tetR(B)-tetA(B)-ΔIS26), and one, RU3 (a sul3-associated class 1 integron with cassette array dfrA12-orfF-aadA2-cmlA1-aadA1), was embedded in a Tn21-derived element harboured by the conjugative I1 plasmid pST1030-1A. IS26 elements mediated the antimicrobial resistance gene (ARG) shuffling and this gave rise to pST1030-1A derivatives with different sets of ARGs. ST1030 also harboured two ColE1-like plasmids of which one, pST1030-2A, was mobilisable and the target of an intracellular translocation of the Tn21-derived element; the second (pST1030-3) was an orphan mob-associated oriT plasmid co-transferred with pST1030-1A and pST1030-2A. pST1030-2A and pST1030-3 also carried a parA gene and a type III restriction modification system, respectively. Overall analysis of our data reinforces the role played by IS26, Tn21-derived elements and non-conjugative plasmids in the spread of ARGs and supplies the first evidence, at least in Salmonella, for the identification of a natural isolate harbouring a three-element mobilisation system in the same cell.

Innovations in prevention of infections in oncological megaprostheses: a narrative review.

Infection is a significant complication in oncological megaprostheses. The purpose of our study is to indagate the innovations and new trend about the prevention of infection in this kind of surgery. The research focused on the use of antimicrobic prophylaxis, the defensive antibacterial coating and the use of silver coated.

A rare case of post-traumatic infected pilomatricoma of the finger of the hand diagnosed after performing radioiodine therapy.

We present the clinical case of a young woman with pilomatricoma of the finger, a very rare location. The patient got infected after receiving radioiodine therapy to treat a thyroid carcinoma. Given the patient's high functional requirements we choose a minimal treatment which allowed her to maintain a sufficient functionality.

Ankle fracture and necrotizing fasciitis: a common fracture and a dreadful complication.

Necrotizing fasciitis is a dreadful complication of the soft tissue. This pathology could be triggered by many factors, such as a fracture. We present a case of case of a necrotizing fasciitis in ankle fracture.

Predictable risk factors for infections in proximal femur fractures.

Proximal femur fractures are increasing, together with the aging of world population. One of the complications worsening this condition is infection. In this study, we try to identify risk factors that can lead to infection. We identified 122 patients with femoral neck fracture. The occurrence of infectious events were recorded (respiratory, urinary, superficial wound and periprostethic infection). There were 15 infections, mostly urinary and pulmonary, and all were treated using antibiotics. No statistical differences were found between infection and control group regarding waiting time for surgery, mean time of surgery, age, kind of fracture, type of surgery. Fever onset >38° within 72 hours from surgery was statistically correlated with early infections. Future studies must be led to identify risk factors for infection and to create a strategy to prevent this possibly lethal complication.

Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma.

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.

Hip megaprosthesis in oncological surgery: open questions.

Prosthetic replacement with modular implants has become the most common reconstructive tech¬nique of bone loss of the lower limb after tumour resection. The use of the megaprosthesis in bone metastasis, silver-coated megaprosthesis and the use of Trevira tube are not uniform and represent an "open question" about the use of megaprosthesis. The following paper aims to review the current literature in this topic.

Early-drug development in the era of immuno-oncology: are we ready to face the challenges?

The classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. The fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. In this review, we discuss critical issues and caveats in immunotherapy development. A particular emphasis is put on the limitations of pre-clinical toxicology studies, where both murine models and cynomolgus monkeys have underpredicted toxicity in humans. Moreover, relevant issues surrounding dose determination during phase I trials, such as dose-escalation methods or flat versus body-weight dosing, are discussed. A proposal of how to face these different challenges is offered, in order to achieve maximum efficacy with minimum toxicity for our patients.

IS26 mediated antimicrobial resistance gene shuffling from the chromosome to a mosaic conjugative FII plasmid.

In the present study we report the identification of a sul3-associated class 1 integron containing the dfrA12-orfF-aadA2-cmlA1-aadA1-qacH array embedded in a Tn21-derived element that is part of a conjugative FII plasmid named pST1007-1A. The plasmid was identified in the Salmonella Typhimurium strain ST1007, a member of a clinically relevant clonal MDR lineage diffuse in Italy. ST1007 exhibited resistance to ampicillin, chloramphenicol, streptomycin, sulphamethoxazole, tetracycline and trimethoprim encoded by blaTEM-1, cmlA1, (aadA1, aadA2, strAB), (sul2, sul3), tet(B) and dfrA12 genes, respectively. Apart from pST1007-1A, ST1007 also harbours two chromosome-integrated resistance units RU1 (blaTEM-1-sul2-strAB) and RU2 (tet(B)), flanked by IS26 elements. RU1 and RU2 were able to move as translocatable units, respectively TU1 and TU2, and integrate via IS26 mediated recombination into pST1007-1A. A family of conjugative plasmids, harbouring different sets of antimicrobial resistance genes (ARG) was then generated: pST1007-1B (dfrA12-aadA2-cmlA1-aadA1-sul3- tet(B)), pST1007-1C (dfrA12-aadA2-cmlA1-aadA1-sul3-blaTEM-1-sul2-strAB), pST1007-1D (blaTEM-1-sul2-strAB), pST1007-1E (tet(B)) and pST1007-1F (dfrA12-aadA2-cmlA1-aadA1-sul3- tet(B) -blaTEM-1-sul2-strAB). pST1007-1A is also a mosaic plasmid containing two distinct DNA fragments acquired from I1 plasmids through recombination within the repA4, rfsF and repeat-3 sites. This study further highlights the role played by IS26 in intracellular ARGs shuffling. Moreover, attention has been focused on recombination hot spots that might play a key role in generating mosaic plasmids.

Acanthocotyle gurgesiella n. sp. (Monogenea: Acanthocotylidae) from the deep-sea skate Gurgesiella furvescens (Rajidae) in the south-eastern Pacific.

Little is known about the diversity of parasites of the deep-sea fish of the world's oceans. Here, a new species of monogenean parasite of the deep-sea skate Gurgesiella furvescens is described. Specimens of parasites were obtained from the skin of two specimens of the dusky finless skate, G. furvescens (Rajidae), in the vicinity of Valparaiso (33°S, 72°W), central Chile, from midwater trawl fishing at depths of 350-450 m. Both morphological and molecular analyses were conducted to provide a full description of the new species, named Acanthocotyle gurgesiella. For the molecular analyses, nuclear large subunit (LSU) rDNA and the mitochondrial gene cytochrome c oxidase 1 (COI) were used. From the morphological analysis and a comparison with the known species of the genus, A. gurgesiella can be identified by a combination of morphological characteristics, including the number of testes, number of radial rows of sclerites in the pseudohaptor, aperture of the genital pore and shape of the vitelline follicles. The results from the DNA analysis indicated that A. gurgesiella has a genetic divergence of 3.2-3.7% (LSU rDNA gene) from A. urolophi, the only congener species for which molecular data are available.

A novel group of IncQ1 plasmids conferring multidrug resistance.

The IncQ is a group of non-conjugative but mobilisable plasmids that are found and stably maintained in a wide range of bacteria contributing to the spread of antimicrobial resistance genes and to the insurgence of multidrug resistant bacteria. Here we report the identification, in clinical Salmonella Typhimurium strains, of an IncQ1 plasmid (pNUC) which confers resistance to sulfamethoxazole, streptomycin and tetracycline through the presence of sul2, strAB and tetA genes, respectively. pNUC was detected in five multidrug resistant S. Typhimurium strains collected in Southern Italy from various hospitals and years of isolation. Bioinformatics analyses highlighted the presence of pNUC-like plasmids in pathogenic bacteria of various Enterobacteriaceae genera or species. Taken as a whole, these plasmids constitute a novel group of IncQ1 plasmids that might have originated through recombination events between a tetR-tetA gene cluster (possibly derived from a Tn1721) and a recipient IncQ1 plasmid related to RSF1010. Our findings raise concerns regarding the possible contribution of the newly identified group of IncQ1 plasmids to the spread of tetracycline resistance.

Silicon Alleviates Nonalcoholic Steatohepatitis by Reducing Apoptosis in Aged Wistar Rats Fed a High-Saturated Fat, High-Cholesterol Diet.

Background: Lipoapoptosis has been identified as a key event in the progression of nonalcoholic fatty liver disease (NAFLD), and hence, antiapoptotic agents have been recommended as a possible effective treatment for nonalcoholic steatohepatitis (NASH). Silicon, included in meat as a functional ingredient, improves lipoprotein profiles and liver antioxidant defenses in aged rats fed a high-saturated fat, high-cholesterol diet (HSHCD). However, to our knowledge, the antiapoptotic effect of this potential functional meat on the liver has never been tested.Objective: This study was designed to evaluate the effect of silicon on NASH development and the potential antiapoptotic properties of silicon in aged rats.Methods: One-year-old male Wistar rats weighing ∼500 g were fed 3 experimental diets containing restructured pork (RP) for 8 wk: 1) a high-saturated fat diet, as an NAFLD control, with 16.9% total fat, 0.14 g cholesterol/kg diet, and 46.8 mg SiO2/kg (control); 2) the HSHCD as a model of NASH, with 16.6% total fat, 16.3 g cholesterol/kg diet, and 46.8 mg SiO2/kg [high-cholesterol diet (Chol-C)]; and 3) the HSHCD with silicon-supplemented RP with amounts of fat and cholesterol identical to those in the Chol-C diet, but with 750 mg SiO2/kg (Chol-Si). Detailed histopathological assessments were performed, and the NAFLD activity score (NAS) was calculated. Liver apoptosis and damage markers were evaluated by Western blotting and immunohistochemical staining.Results: Chol-C rats had a higher mean NAS (7.4) than did control rats (1.9; P < 0.001). The score in Chol-Si rats (5.4) was intermediate and different from that in both other groups (P < 0.05). Several liver apoptosis markers-including hepatocyte terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate (dUTP) nick end labeling, cytosolic cytochrome c, apoptosis-inducing factor, caspases 9 and 3, and the mitochondrial Bcl-2-associated X protein (BAX)-to-B-cell lymphoma 2 (BCL2) ratio-were 9-45% lower in Chol-Si than in Chol-C rats (P < 0.05) and did not differ from values in the control group.Conclusions: Supplemental silicon substantially affects NASH development in aged male Wistar rats fed an HSHCD by partially blocking apoptosis. These results suggest that silicon-enriched RP could be used as an effective nutritional strategy in preventing NASH.

On the outside looking in: rethinking the molecular mechanism of 1,3-dipolar cycloadditions from the perspective of bonding evolution theory. The reaction between cyclic nitrones and ethyl acrylate.

In this work we report on the progress that has been made towards gaining an understanding of the molecular mechanism of 1,3-dipolar cycloadditions using the bonding evolution theory (BET). A detailed analysis of the flow of electron density along the reaction pathway of the formal 1,3-dipolar cycloaddition reaction between cyclic nitrones (pyrroline-1-oxide and 2,3,4,5-tetrahydropyridine-1-oxide) and ethyl acrylate, as a case study, allowed the nature of the molecular mechanisms to be characterized. The present study provides a deep insight into the reaction mechanism, based on the electron density rearrangements given by the structural stability domains, and their connection with the bond breaking/forming processes along the reaction pathway. The electron pushing formalism is a powerful tool to describe chemical reactivity. Here, we show how the Lewis structures can be recovered and how curly arrows describe electron density transfers in chemical reaction mechanisms based on the BET results. The reaction mechanism is described by four consecutive events taking place as the reaction progresses: (1) the population of the initial N-C double bond is transferred to the N and C atoms; (2) the population of the initial double C-C bond is transferred to the C atoms. Along the ortho pathway the next steps are: (3) the C-C bond-forming process, and (4) the O-C bond-forming process. The order of (3) and (4) is inverted in the meta channel. Based on the sequence of the structural stability domains along the intrinsic reaction coordinate, a new synchronicity index is proposed, allowing us to classify and quantify the (a)synchronicity of the 1,3-DC reactions and, therefore, the nature of the reaction mechanism.

Helminth parasites of South American fishes: current status and characterization as a model for studies of biodiversity.

The South American subcontinent supports one of the world's most diverse and commercially very important ichthyofauna. In this context, the study of South American fish parasites is of increased relevance in understanding their key roles in ecosystems, regulating the abundance or density of host populations, stabilizing food webs and structuring host communities. It is hard to estimate the number of fish parasites in South America. The number of fish species studied for parasites is still low (less than 10%), although the total number of host-parasite associations (HPAs) found in the present study was 3971. Monogeneans, with 835 species (1123 HPAs, 28.5%), and trematodes, with 662 species (1127 HPAs, 30.9%), are the more diverse groups. Data gathered from the literature are useful to roughly estimate species richness of helminths from South American fish, even though there are some associated problems: the reliability of information depends on accurate species identification; the lack of knowledge about life cycles; the increasing number of discoveries of cryptic species and the geographically biased number of studies. Therefore, the closest true estimations of species diversity and distribution will rely on further studies combining both molecular and morphological approaches with ecological data such as host specificity, geographical distribution and life-cycle data. Research on biodiversity of fish parasites in South America is influenced by problems such as funding, taxonomic impediments and dispersion of research groups. Increasing collaboration, interchange and research networks in the context of globalization will enable a promising future for fish parasitology in South America.

What Is the Role of Developmental Disability in Patient Selection for Pediatric Solid Organ Transplantation?

The National Organ Transplant Act stipulates that deceased donor organs should be justly and wisely allocated based on sound medical criteria. Allocation schemes are consistent across the country, and specific policies are publicly vetted. Patient selection criteria are largely in the hands of individual organ transplant programs, and consistent standards are less evident. This has been particularly apparent for patients with developmental disabilities (DDs). In response to concerns regarding the fairness of transplant evaluations for patients with DDs, we developed a transplant centerwide policy using a multidisciplinary, community-based approach. This publication details the particular policy of our center. All patients should receive individualized assessments using consistent standards; disability should be neither a relative nor an absolute contraindication to transplantation. External review can increase trust in the selection process. Patients in persistent vegetative states should not be listed for transplantation.