Optical Effects of Focused Fractional Nanosecond 1064-nm Nd:YAG Laser: Techniques of Application on Human Skin.

BACKGROUND AND OBJECTIVES: Considering the pulse widths of picosecond and nanosecond lasers used in cutaneous laser surgery differ by approximately one order of magnitude, can nanosecond lasers produce the optical effect in human skin similar to laser-induced optical breakdown (LIOB) caused by picosecond lasers? METHODS: Cutaneous changes induced by a focused fractional nanosecond 1064-nm Nd:YAG laser were evaluated by VISIA-CR imaging, histological examination, and harmonic generation microscopy (HGM). RESULTS: A focused fractional nanosecond 1064-nm Nd:YAG laser can generate epidermal vacuoles or dermal cavities similar to the phenomenon of LIOB produced by picosecond lasers. The location and extent of photodisruption can be controlled by the laser fluence and focus depth. Moreover, laser-induced shock wave propagation and thermal degeneration of papillary collagen can be observed by HGM imaging. CONCLUSION: Focused fractional nanosecond lasers can produce an optical effect on human skin similar to LIOB caused by picosecond lasers. With techniques of application, the treatment can induce epidermal and dermal repair mechanisms in a tunable fashion to improve skin texture, wrinkles, scars, and dyspigmentation, without disrupting the epidermal surface.

Characterization of picosecond laser-induced optical breakdown using harmonic generation microscopy.

BACKGROUND AND OBJECTIVES: By creating microinjuries usually confined to the epidermis, a fractional picosecond 1064-nm Nd:YAG laser that delivers an array of highly focused beamlets can be effectively used for facial rejuvenation or resurfacing. However, the mechanism of dermal remodeling underlying this nonablative treatment remains unclear. METHODS: Five participants having skin phototype III-IV were recruited for intervention using a fractional picosecond 1064-nm Nd:YAG laser system equipped with a holographic diffractive beam-splitting optic. The laser-induced histopathological changes on human skin were examined in vivo using a harmonic generation microscopy (HGM), visualizing second harmonic generation (SHG), and third harmonic generation (THG) contrasts dichromatically. SHG refers for collagen distribution, while THG represents for epidermal components in the HGM signal. RESULTS: Histological hematoxylin and eosin staining and in vivo HGM imaging studies revealed the presence of epidermal vacuoles below the stratum granulosum along with keratinocyte degeneration or cytolysis. In addition to the epidermal vacuoles, HGM imaging exclusively demonstrated laser-induced shock wave propagation arranged as a THG-bright concentric pattern in the epidermis and loss of SHG signals in the papillary dermis immediately beneath the epidermal vacuoles. CONCLUSIONS: Alongside generating epidermal vacuoles, the fractional picosecond 1064-nm Nd:YAG laser induced collagen changes. These collagen changes may lead to dermal remodeling and neocollagenesis underlying the fractional picosecond laser treatment.

Generating Novel Aroma Phenotypes Using Commercial Wine Samples to Characterize an F1 Population.

Due to their disease tolerance and cold hardy nature, interspecific hybrid grapes are widely grown in the Midwestern and Northeastern United States, with additional interest worldwide in the face of increased abiotic and biotic stresses from climate change. However, the aroma profile of these hybrids is unique and generally less popular in comparison with Vitis vinifera grapes. One of the challenges in any phenotyping project is first defining the traits of interest. As wine quality was our ultimate metric of interest, the aroma profile of commercial wines produced from the parents of a breeding population (Vitis aestivalis derived 'Norton' x V. vinifera. 'Cabernet Sauvignon') was first assessed for traits of interest. We investigated 11 commercial wines each of Norton, a popular hybrid in Missouri and Cabernet Sauvignon (Cab) for their volatile profiles using the more inclusive metabolomics-based workflow. We then analyzed 21 Norton and 21 Cab grapes from different sites and vintages for the free and bound volatile compounds using HS-SPME-GCMS to validate the differences in wine. The GCMS data was processed using XCMS software to find features that were different between the two cultivars. The two cultivars were found to have differences in their volatile profiles, with 304 features different for wine volatiles, 418 features different for free volatiles, and 302 features different for bound volatiles at 0.05 significance level and with at least a 1.5-fold change between the two cultivars. Those features were used to identify several odor-active compounds in both grapes and wines, including ß-damascenone, ß-ionone, eugenol, 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN), and methyl salicylate. Some of the identified compounds were higher in Norton than Cab; however, several features were higher in Cab. Using the identified aroma compounds as markers, we phenotyped an F1 population of Norton and Cab. The F1 population was found to be segregating for many aroma compounds with some genotypes demonstrating an even higher concentration of aroma volatiles than either of the parents. Ultimately, using commercially available samples paired with untargeted analysis proved to be an efficient way to determine phenotypes of interest for further analysis and may offer an easy way to choose potential parents with desired traits for breeding.

Interactions between poloxamer, PEOx-PPOy-PEOx, and non-ionic surfactant, sucrose monolaurate: A study on potential allergenic effect using model phospholipid membrane.

Sugar-based surfactants are involved in skin related allergy cases in the past decade. Skin irritation starts with the interaction of the surfactant with the skin lipids leading to lipid emulsification and eventual barrier damage. Polymers or co-surfactants can be used to mitigate the allergenic effect but the mechanism of formulation mildness on skin remains unclear. We have used the quartz crystal microbalance (QCM) together with dissipative particle dynamics (DPD) simulation, small angle x-ray scattering (SAXS) as well as cell viability tests to decipher the interactions between poloxamers and sucrose monolaurate (SML), and how these interactions could prevent the disruption of a model supported phospholipid bilayer (SLB). Poloxamer addition to the SML solution can delay or totally prevent the disruption of the SLB depending on poloxamer type and concentration. Poloxamer P407 (Pluronic® F127) delays the onset of disruption while poloxamer P188 (Pluronic® F68) does not preserve the bilayer integrity even at high concentration of up to 15% w/w. Preservation of the SLB is likely due to the differences in the aggregates formation between SML-F127 and SML-F68 mixtures with corresponding retarded motion of SML micelles through the SML-F127 polymer matrix that improved cell viability.

High molecular weight hyper-branched PCL-based thermogelling vitreous endotamponades.

Vitreous endotamponades play essential roles in facilitating retina recovery following vitreoretinal surgery, yet existing clinically standards are suboptimal as they can cause elevated intra-ocular pressure, temporary loss of vision, and cataracts while also requiring prolonged face-down positioning and removal surgery. These drawbacks have spurred the development of next-generation vitreous endotamponades, of which supramolecular hydrogels capable of in-situ gelation have emerged as top contenders. Herein, we demonstrate thermogels formed from hyper-branched amphiphilic copolymers as effective transparent and biodegradable vitreous endotamponades for the first time. These hyper-branched copolymers are synthesised via polyaddition of polyethylene glycol, polypropylene glycol, poly(ε-caprolactone)-diol, and glycerol (branch inducing moiety) with hexamethylene diisocyanate. The hyper-branched thermogels are injected as sols and undergo spontaneous gelation when warmed to physiological temperatures in rabbit eyes. We found that polymers with an optimal degree of hyper-branching showed excellent biocompatibility and was able to maintain retinal function with minimal atrophy and inflammation, even at absolute molecular weights high enough to cause undesirable in-vivo effects for their linear counterparts. The hyper-branched thermogel is cleared naturally from the vitreous through surface hydrogel erosion and negates surgical removal. Our findings expand the scope of polymer architectures suitable for in-vivo intraocular therapeutic applications beyond linear constructs.

Workflow to Investigate Subtle Differences in Wine Volatile Metabolome Induced by Different Root Systems and Irrigation Regimes.

To allow for a broad survey of subtle metabolic shifts in wine caused by rootstock and irrigation, an integrated metabolomics-based workflow followed by quantitation was developed. This workflow was particularly useful when applied to a poorly studied red grape variety cv. Chambourcin. Allowing volatile metabolites that otherwise may have been missed with a targeted analysis to be included, this approach allowed deeper modeling of treatment differences which then could be used to identify important compounds. Wines produced on a per vine basis, over two years, were analyzed using SPME-GC-MS/MS. From the 382 and 221 features that differed significantly among rootstocks in 2017 and 2018, respectively, we tentatively identified 94 compounds by library search and retention index, with 22 confirmed and quantified using authentic standards. Own-rooted Chambourcin differed from other root systems for multiple volatile compounds with fewer differences among grafted vines. For example, the average concentration of ß-Damascenone present in own-rooted vines (9.49 µg/L) was significantly lower in other rootstocks (8.59 µg/L), whereas mean Linalool was significantly higher in 1103P rootstock compared to own-rooted. ß-Damascenone was higher in regulated deficit irrigation (RDI) than other treatments. The approach outlined not only was shown to be useful for scientific investigation, but also in creating a protocol for analysis that would ensure differences of interest to the industry are not missed.

Clostridium difficile treatment in neutropenic patients: Clinical outcomes of metronidazole, vancomycin, combinations, and switch therapy.

BACKGROUND: Clostridium difficile infection treatment guidelines exist for immunocompetent patients; however, there is a paucity of data evaluating clinical outcomes and time to C. difficile-associated diarrhea resolution in neutropenic patients. OBJECTIVE: To assess clinical outcomes in neutropenic patients treated with metronidazole, oral vancomycin, the combination of metronidazole plus oral vancomycin, and switch of metronidazole to oral vancomycin. METHODS: This retrospective, observational cohort study assessed adult neutropenic inpatients with C. difficile-associated diarrhea treated with metronidazole, oral vancomycin, combination (metronidazole and oral vancomycin), or switch therapy (metronidazole to oral vancomycin). The primary outcome was time to diarrhea resolution based on treatment regimen. Secondary outcomes included C. difficile-associated diarrhea resolution of diarrhea by day 14, recurrence, and occurrence of major complications. RESULTS: Overall, 44 patients met full inclusion criteria (52.2% metronidazole monotherapy, 22.7% combination, and 25.0% switch therapy). Two patients on oral vancomycin monotherapy were excluded due to insufficient sample size. Overall time to C. difficile-associated diarrhea resolution was 9.1 ± 10.7 days. The Cox regression results suggested both switch and combination therapy were associated with 65.5% (p = 0.002) and 65.9% (p = 0.046) longer time to C. difficile-associated diarrhea resolution compared to metronidazole monotherapy, respectively. An increasing absolute neutrophil count was associated with an increase in C. difficile-associated diarrhea resolution (p = 0.007). CONCLUSION: Switch or combination therapy was associated with a prolonged time to C. difficile-associated diarrhea resolution. The decision to use switch or combination therapy may represent a surrogate marker for more severe disease and need for therapy escalation. It is unknown if initial therapy with oral vancomycin would provide better outcomes as this could not be assessed.

Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor.

Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene-knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that, in contrast to ALVAC, the Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate the STING-type I IFN pathway and to provide inflammasome-priming signals. In preconditioned APCs, the Ad5 vector could stimulate inflammasome activation through an AIM2-independent mechanism. Therefore, our study identifies the AIM2 inflammasome and cGAS/IFI16-STING-type I IFN pathway as a novel mechanism for host innate immunity to the ALVAC vaccine vector.

Anabolic actions of Notch on mature bone.

Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response.

The Importance of Global Health Experiences in the Development of New Cardiologists.

As the global burden of cardiovascular disease continues to increase worldwide, nurturing the development of early-career cardiologists interested in global health is essential to create a cadre of providers with the skill set to prevent and treat cardiovascular diseases in international settings. As such, interest in global health has increased among cardiology trainees and early-career cardiologists over the past decade. International clinical and research experiences abroad present an additional opportunity for growth and development beyond traditional cardiovascular training. We describe the American College of Cardiology International Cardiovascular Exchange Database, a new resource for cardiologists interested in pursuing short-term clinical exchange opportunities abroad, and report some of the benefits and challenges of global health cardiovascular training in both resource-limited and resource-abundant settings.

CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy.

Growing evidence suggests that tumor-associated macrophages (TAM) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling, and immunosuppression. In this study, prostate cancer under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to prostate cancer disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF1 or CSF1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF1 signaling through its receptor, CSF1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared with ABT alone.

MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.

MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

Self-assembly of didodecyldimethylammonium surfactants modulated by multivalent, hydrolyzable counterions.

The self-assembly behavior of double-chained didodecyldimethylammonium (DDA(+)) surfactants with hydrolyzable phosphate (PO4(3-), HPO4(2-), and H2PO4(-)), oxalate (HC2O4(-) and C2O4(2-)), and carbonate (HCO3(-)/CO3(2-)) counterions was found to depend on both the counterion and its hydrolysis state, as determined by the pH of the system. Carbonate and phosphate ions at all hydrolysis states successfully stabilize an extended isotropic micellar solution region. These micelles are well-described as prolate ellipsoids which vary in size and aspect ratio depending on the surfactant concentration and hydrolysis state of the counterion. Both oxalate counterions form bilayer structures in dilute solution. The structures found with divalent oxalate, C2O4(2-), ions possessed very limited swelling capacity compared to the bilayer structures formed with monovalent oxalate, HC2O4(-), ions. The lamellar (Lα) phase was universally formed at sufficiently high surfactant concentrations for all hydrolyzable counterions. Two intermediate structures corresponding to a disordered mesh (Lα(D)) and tetragonal ordered mesh (T) phase were found to form with DDA2HPO4 prior to the Lα phase but not with other phosphate counterions.

HARVEST, a longitudinal patient record summarizer.

OBJECTIVE: To describe HARVEST, a novel point-of-care patient summarization and visualization tool, and to conduct a formative evaluation study to assess its effectiveness and gather feedback for iterative improvements. MATERIALS AND METHODS: HARVEST is a problem-based, interactive, temporal visualization of longitudinal patient records. Using scalable, distributed natural language processing and problem salience computation, the system extracts content from the patient notes and aggregates and presents information from multiple care settings. Clinical usability was assessed with physician participants using a timed, task-based chart review and questionnaire, with performance differences recorded between conditions (standard data review system and HARVEST). RESULTS: HARVEST displays patient information longitudinally using a timeline, a problem cloud as extracted from notes, and focused access to clinical documentation. Despite lack of familiarity with HARVEST, when using a task-based evaluation, performance and time-to-task completion was maintained in patient review scenarios using HARVEST alone or the standard clinical information system at our institution. Subjects reported very high satisfaction with HARVEST and interest in using the system in their daily practice. DISCUSSION: HARVEST is available for wide deployment at our institution. Evaluation provided informative feedback and directions for future improvements. CONCLUSIONS: HARVEST was designed to address the unmet need for clinicians at the point of care, facilitating review of essential patient information. The deployment of HARVEST in our institution allows us to study patient record summarization as an informatics intervention in a real-world setting. It also provides an opportunity to learn how clinicians use the summarizer, enabling informed interface and content iteration and optimization to improve patient care.

NCOA5, a molecular link between type 2 diabetes and liver cancer.

It is reported that nuclear receptor co-activator 5 (NCOA5) is a possible susceptibility gene to both type 2 diabetes (T2D) and hepatocellular carcinoma (HCC). The link between these two diseases is an important area of study with the growing prevalence of T2D. Thus, discovery of a genetic link may have great impact on the field. The group used NCOA5 (+/-) mice to observe the effects of the gene's haploinsufficiency on the symptoms of T2D and HCC and claimed NCOA5's regulation of IL-6 in the pathogenesis of the diseases.

Hexagonal closest-packed spheres liquid crystalline phases stabilised by strongly hydrated counterions.

The sequence and structure of lyotropic liquid crystals formed in C12-C16 alkyltrimethylammonium surfactants with hydrolysable and multivalent phosphate (PO4(3-), HPO4(2-) and H2PO4(-)), oxalate (HC2O4(-) and C2O4(2-)), and carbonate (HCO3(-)/CO3(2-)) counterions were determined using a concentration gradient method coupled with polarising optical microscopy and small angle X-ray scattering. In addition to the discrete cubic (I1, space group Pm3n) and hexagonal (H1, p6m) phases, almost all of these surfactants also formed the (previously) rare hexagonally closest-packed spheres (HCPS, P63/mmc) phase at compositions between the Pm3n cubic and L1 micellar phases. This structure has not been previously observed in cationic surfactants, but is readily achieved by using strongly hydrated counterions to stabilise spherical micelles at high concentrations.

Developing an eBook-Integrated High-Fidelity Mobile App Prototype for Promoting Child Motor Skills and Taxonomically Assessing Children's Emotional Responses Using Face and Sound Topology.

Developing gross and fine motor skills and expressing complex emotion is critical for child development. We introduce "StorySense", an eBook-integrated mobile app prototype that can sense face and sound topologies and identify movement and expression to promote children's motor skills and emotional developmental. Currently, most interactive eBooks on mobile devices only leverage "low-motor" interaction (i.e. tapping or swiping). Our app senses a greater breath of motion (e.g. clapping, snapping, and face tracking), and dynamically alters the storyline according to physical responses in ways that encourage the performance of predetermined motor skills ideal for a child's gross and fine motor development. In addition, our app can capture changes in facial topology, which can later be mapped using the Facial Action Coding System (FACS) for later interpretation of emotion. StorySense expands the human computer interaction vocabulary for mobile devices. Potential clinical applications include child development, physical therapy, and autism.

A rocket-like encapsulation and delivery system with two-stage booster layers: pH-responsive poly(methacrylic acid)/poly(ethylene glycol) complex-coated hollow silica vesicles.

Rocket-like vesicles formed are composed of poly(acrylic aicd) (PMAA )/poly(ethylene glycol) (PEG) complex coated hollow silica spheres, and the structure and composition of the vesicles are characterized using TGA, (1)H NMR, FTIR, and TEM. Although only one-third of EG units of PEG brushes grafted to hollow silica spheres form the complex with PMAA via hydrogen bonding, the first "booster" layer composed of PMAA/PEG complex can provide secure encapsulation of model compound calcein blue under an acidic condition. The second "booster" layer composed of PEG brushes can be formed by changing acidic pH to 7.4 through the disassociation of the PMAA/PEG complex. A higher molecular weight PMAA exhibits a faster disassembly due to the formation of a looser PMAA/PEG complex on the surfaces of hollow silica spheres.