A prospective investigation of impacts of comorbid attention deficit hyperactivity disorder (ADHD) on clinical features and long-term treatment response in adult patients with obsessive-compulsive disorder (OCD).

BACKGROUND: A close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. METHODS: We assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD- group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. RESULTS: Of the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD- group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD- group (44.6%). CONCLUSION: The lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients.

Evaluation of hemodynamic changes using near-infrared spectroscopy in patients with tic-related obsessive-compulsive disorder.

AIM: A tic-related specifier is included in the DSM-5 diagnostic criteria to identify a clinically specific obsessive-compulsive disorder (OCD) subtype. The current study sought to evaluate hemodynamic changes during executive function tasks among OCD patients with and without a lifetime history of tic disorder (TD) and healthy controls, and to investigate the relation between brain activation and clinical variables in each group using structured equation modeling. METHODS: Twenty-nine OCD patients diagnosed according to the DSM-IV-TR and 15 healthy controls were recruited. Patients were divided into two groups according to the presence or absence of a lifetime history of TD (TD+, n = 11; TD-, n = 18). Prefrontal hemodynamic changes were measured using multi-channel near-infrared spectroscopy during the Verbal Fluency Task, Trail-Making Task, and Tower of London (ToL) Task. RESULTS: There were significant brain activation differences in the frontopolar cortex between OCD patients with and without TD during Verbal Fluency Task and ToL performance. Brain activation in the dorsolateral prefrontal cortex (DLPFC) during the ToL Task in OCD patients with TD exerted a direct causal effect on the severity of compulsions. In addition, we detected a direct causal effect of the severity of obsessions in OCD patients without TD on brain activation in the DLPFC during the ToL Task. CONCLUSION: Brain activation in the frontopolar cortex exhibits different hemodynamics depending on the task, and DLPFC function may play a different role in the neural basis of developing OCD symptoms between OCD patients with and without TD.

Polyelectrolyte Coatings Can Control Charged Fluorocarbon Nanodroplet Stability and Their Interaction with Macrophage Cells.

Fluorocarbon nanodroplets, ∼100 to ∼400 nm in diameter, are of immense interest in a variety of medical applications including the imaging and therapy of cancer and inflammatory diseases. However, fluorocarbon molecules are both hydrophobic and lipophobic; therefore, it is challenging to synthesize fluorocarbon nanodroplets with the optimal stability and surface properties without the use of highly specialized surfactants. Here, we hypothesize that we can decouple the control of fluorocarbon nanodroplet size and stability from its surface properties. We use a simple, two-step procedure where standard, easily available anionic fluorosurfactants are used to first stabilize the fluorocarbon nanodroplets, followed by electrostatically attaching functionalized polyelectrolytes to the nanodroplet surfaces to independently control their surface properties. Herein, we demonstrate that PEGylated polyelectrolyte coatings can effectively alter the fluorocarbon nanodroplet surface properties to reduce coalescence and its uptake into phagocytic cells in comparison with non-PEGylated polyelectrolyte coatings and uncoated nanodroplets, as measured by flow cytometry and fluorescence microscopy. In this study, perfluorooctyl bromide (PFOB) was used as a representative fluorocarbon material, and PEGylated PFOB nanodroplets with diameters between 250 and 290 nm, depending on the poly(ethylene glycol) block length, were prepared. The PEGylated PFOB nanodroplets had superior size stability in comparison with uncoated and non-PEGylated polyelectrolyte nanodroplets in saline and within macrophage cells. Of significance, non-PEGylated nanodroplets were rapidly internalized by macrophage cells, whereas PEGylated nanodroplets were predominantly colocalized on the cell membrane. This suggests that the PEGylated-polyelectrolyte coating on the charged PFOB nanodroplets may afford adjustable shielding from cells of the reticuloendothelial system. This report shows that using the same fluorosurfactant as a base layer, modularly assembled PFOB nanodroplets tailored for a variety of end applications can be created by selecting different polyelectrolyte coatings depending on their unique requirements for stability and interaction with phagocytic cells.

Ten-year follow-up study of Japanese patients with obsessive-compulsive disorder.

AIM: Obsessive-compulsive disorder (OCD) is a well-known chronic illness. This study retrospectively investigated 10-year outcomes and associated clinical factors in Japanese OCD patients. We focused on the impact of several sociocultural factors, including medical expenses and insurance systems specific to each country, on the differences or biases in follow-up procedures of OCD. METHODS: Seventy-nine patients diagnosed with OCD who received a standardized combination of treatments for 10 continuous years were divided into three groups according to their improvement rates on the Yale-Brown Obsessive-Compulsive Scale after 10 years of treatment. RESULTS: A survival analysis revealed that the rate of patients achieving full remission increased every year. Following 10 years of treatment, 56% of OCD patients experienced 'full remission' for at least 1 year. Consequently, 48% exhibited full remission, and 37% exhibited partial remission at the end-point of this study. We identified several factors that were predictive of poorer outcomes, including lower Global Assessment of Functioning Scale scores and the presence of hoarding symptoms or involvement behaviors. In addition, improvement rates after 1 year significantly predicted better 10-year outcomes. CONCLUSION: Our findings highlight the transcultural nature of long-term outcomes of OCD treatment, which appear to be independent of sociocultural differences.

Clinically related or predictive factors and impacts on long-term treatment outcomes of involvement behaviors in patients with obsessive-compulsive disorder.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) frequently exhibit involvement behaviors (IBs) in which they accommodate their caregivers to their OCD symptoms by 1) asking them for reassurance, 2) forcing them to participate in their rituals, or 3) forcing them to assist in avoidance according to the patients' rules or demands. Such behaviors correspond to those of their caregivers, and are referred to as family accommodation (FA). METHODS: We performed multifactorial comparisons between 256 OCD patients with and without IBs in order to examine the clinical characteristics and long-term treatment outcomes of OCD patients with IBs. A multiple logistic regression analysis was also performed to identify the related and predictive factors of IBs. RESULTS: A total of 108 out of the 256 OCD patients examined (42%) were determined to exhibit IBs. OCD patients with IBs were differentially characterized by demographic and phenomenological characteristics (e.g. female predominance and poorer insight), more severe psychopathological features (e.g. lower GAFS, higher anxiety, or a depressive status), and poorer treatment outcomes. Furthermore, the predictive factors of IBs such as being female, having a higher compulsive score, and lower GAFS were identified by logistic analyses and structural equation modeling. CONCLUSION: The presence of IBs correlated with the severe clinical features, treatment refractoriness, and poorer long-term outcome of OCD. The severity of compulsions, being female, and lower GAFS were identified as predictive factors for the presence of IBs. Similar to FA, these findings appear to support the effectiveness of early identification and family-focused intervention in the treatment of OCD patients with IBs.

Direct incorporation of lipophilic nanoparticles into monodisperse perfluorocarbon nanodroplets via solvent dissolution from microfluidic-generated precursor microdroplets.

Multifunctional medical agents based on imaging or therapy nanoparticles (NPs) incorporated into perfluorocarbon (PFC) droplets are promising new agents for cancer detection and treatment. For the first time, monodisperse PFC nanodroplets labeled with NPs have been produced. Lipophilic, as-synthesized, hydrocarbon-stabilized NPs are directly miscibilized into lipophobic PFCs using a removable cosolvent, diethyl ether (DEE), which eliminates the need of the typical time-consuming and expertise-specific NP surface modification steps previously required for NP incorporation into PFCs. This NP-DEE/PFC solution is then used to synthesize monodisperse, micrometer-scale, DEE-infused NP-PFC precursor droplets in water using microfluidics. After precursor microdroplet generation, the DEE cosolvent is removed by dissolution and evaporation, resulting in dramatically smaller, monodisperse, NP-labeled nanodroplets, with final droplet sizes far smaller than the minimum droplet size limit of the microfluidic system, and easily controlled by the amount of DEE mixed in the PFC phase prior to precursor droplet synthesis. Using this technique, unmodified lipophilic quantum dot (QD) NPs were integrated into monodisperse and PFC nanodroplets 165 times smaller in volume than the precursor microdroplets, with dimensions down to 470 nm. The final droplet sizes scaled with the PFC concentrations in the precursor microdroplets, and the QDs remain localized within the droplets after DEE is removed from the system. This method is robust and versatile, and it comprises a platform technology for other unmodified lipophilic NPs and molecules to be incorporated into different types of PFC droplets for the production of new NP-PFC hybrid agents for medical imaging and therapy applications.

The impacts of elevated autism spectrum disorder traits on clinical and psychosocial features and long-term treatment outcome in adult patients with obsessive-compulsive disorder.

BACKGROUND: While a close relation between obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) has been pointed out, there are few studies that have investigated whether highly elevated ASD traits may have significant impacts on clinical and psychosocial features as well as long-term treatment outcome in adult OCD patients. METHODS: We assessed ASD traits using the Autism Spectrum Quotient (AQ) in 81 Japanese patients with OCD. The relation between degree of ASD traits and clinical and psychosocial variables and the 48-week treatment outcomes was analyzed in the subjects. RESULTS: A substantial proportion of the subjects showed higher ASD traits (35%) with more severe depressive or pervasive anxiety status, and social impairments and lower QOL compared to other OCD individuals. However, elevated ASD traits may exert rather smaller impact on the OCD phenomenology along with on the long-term treatment outcome than expected. CONCLUSIONS: Elevated ASD traits may further emphasize the general psychopathological and socio-dysfunctional features rather than clinical aspects associated with OCD. Co-existing depressive or anxious symptom severity may further exacerbate the core-deficits related to ASD pathology. Thus the assessment of ASD traits should be important for understanding the clinical and psychosocial features and treatment responses in OCD patients.

Theranostics - a sure cure for cancer after 100 years?

Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.

3D CT Radiomic Analysis Improves Detection of Axillary Lymph Node Metastases Compared to Conventional Features in Patients With Locally Advanced Breast Cancer.

OBJECTIVE: Preoperative detection of axillary lymph node metastases (ALNMs) from breast cancer is suboptimal; however, recent work suggests radiomics may improve detection of ALNMs. This study aims to develop a 3D CT radiomics model to improve detection of ALNMs compared to conventional imaging features in patients with locally advanced breast cancer. METHODS: Retrospective chart review was performed on patients referred to a specialty breast cancer center between 2015 and 2020 with US-guided biopsy-proven ALNMs and pretreatment chest CT. One hundred and twelve patients (224 lymph nodes) met inclusion and exclusion criteria and were assigned to discovery (n = 150 nodes) and testing (n = 74 nodes) cohorts. US-biopsy images were referenced in identifying ALNMs on CT, with contralateral nodes taken as negative controls. Positive and negative nodes were assessed for conventional features of lymphadenopathy as well as for 107 radiomic features extracted following 3D segmentation. Diagnostic performance of individual and combined radiomic features was evaluated. RESULTS: The strongest conventional imaging feature of ALNMs was short axis diameter ≥ 10 mm with a sensitivity of 64%, specificity of 95%, and area under the curve (AUC) of 0.89 (95% CI, 0.84-0.94). Several radiomic features outperformed conventional features, most notably energy, a measure of voxel density magnitude. This feature demonstrated a sensitivity, specificity, and AUC of 91%, 79%, and 0.94 (95% CI, 0.91-0.98) for the discovery cohort. On the testing cohort, energy scored 92%, 81%, and 0.94 (95% CI, 0.89-0.99) for sensitivity, specificity, and AUC, respectively. Combining radiomic features did not improve AUC compared to energy alone (P = .08). CONCLUSION: 3D radiomic analysis represents a promising approach for noninvasive and accurate detection of ALNMs.

No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents.

BACKGROUND: Identification of gene × environment interactions (G × E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin-regulating genes. METHODS: This study was designed to ascertain the G × E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother's history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients' depression symptoms. RESULTS: Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression. CONCLUSIONS: To assess G × E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects.

Spatial short-term memory in children with nonverbal learning disabilities: impairment in encoding spatial configuration.

The authors investigated whether impaired spatial short-term memory exhibited by children with nonverbal learning disabilities is due to a problem in the encoding process. Children with or without nonverbal learning disabilities performed a simple spatial test that required them to remember 3, 5, or 7 spatial items presented simultaneously in random positions (i.e., spatial configuration) and to decide if a target item was changed or all items including the target were in the same position. The results showed that, even when the spatial positions in the encoding and probe phases were similar, the mean proportion correct of children with nonverbal learning disabilities was 0.58 while that of children without nonverbal learning disabilities was 0.84. The authors argue with the results that children with nonverbal learning disabilities have difficulty encoding relational information between spatial items, and that this difficulty is responsible for their impaired spatial short-term memory.

Using Machine Learning and Silver Nanoparticle-Based Surface-Enhanced Raman Spectroscopy for Classification of Cardiovascular Disease Biomarkers.

Characterizing complex biofluids using surface-enhanced Raman spectroscopy (SERS) coupled with machine learning (ML) has been proposed as a powerful tool for point-of-care detection of clinical disease. ML is well-suited to categorizing otherwise uninterpretable, patient-derived SERS spectra that contain a multitude of low concentration, disease-specific molecular biomarkers among a dense spectral background of biological molecules. However, ML can generate false, non-generalizable models when data sets used for model training are inadequate. It is thus critical to determine how different SERS experimental methodologies and workflow parameters can potentially impact ML disease classification of clinical samples. In this study, a label-free, broadband, Ag nanoparticle-based SERS platform was coupled with ML to assess simulated clinical samples for cardiovascular disease (CVD), containing randomized combinations of five key CVD biomarkers at clinically relevant concentrations in serum. Raman spectra obtained at 532, 633, and 785 nm from up to 300 unique samples were classified into physiological and pathological categories using two standard ML models. Label-free SERS and ML could correctly classify randomized CVD samples with high accuracies of up to 90.0% at 532 nm using as few as 200 training samples. Spectra obtained at 532 nm produced the highest accuracies with no significant increase achieved using multiwavelength SERS. Sample preparation and measurement methodologies (e.g., different SERS substrate lots, sample volumes, sample sizes, and known variations in randomization and experimental handling) were shown to strongly influence the ML classification and could artificially increase classification accuracies by as much as 27%. This detailed investigation into the proper application of ML techniques for CVD classification can lead to improved data set acquisition required for the SERS community, such that ML on labeled and robust SERS data sets can be practically applied for future point-of-care testing in patients.

Monodisperse, submicrometer droplets via condensation of microfluidic-generated gas bubbles.

Microfluidics (MFs) can produce monodisperse droplets with precise size control. However, the synthesis of monodisperse droplets much smaller than the minimum feature size of the microfluidic device (MFD) remains challenging, thus limiting the production of submicrometer droplets. To overcome the minimum micrometer-scale droplet sizes that can be generated using typical MFDs, the droplet material is heated above its boiling point (bp), and then MFs is used to produce monodisperse micrometer-scale bubbles (MBs) that are easily formed in the size regime where standard MFDs have excellent size control. After MBs are formed, they are cooled, condensing into dramatically smaller droplets that are beyond the size limit achievable using the original MFD, with a size decrease corresponding to the density difference between the gas and liquid phases of the droplet material. Herein, it is shown experimentally that monodisperse, submicrometer droplets of predictable sizes can be condensed from a monodisperse population of MBs as generated by MFs. Using perfluoropentane (PFP) as a representative solvent due to its low bp (29.2 °C), it is demonstrated that monodisperse PFP MBs can be produced at MFD temperatures >3.6 °C above the bp of PFP over a wide range of sizes (i.e., diameters from 2 to 200 µm). Independent of initial size, the generated MBs shrink rapidly in size from about 3 to 0 °C above the bp of PFP, corresponding to a phase change from gas to liquid, after which they shrink more slowly to form fully condensed droplets with diameters 5.0 ± 0.1 times smaller than the initial size of the MBs, even in the submicrometer size regime. This new method is versatile and flexible, and may be applied to any type of low-bp solvent for the manufacture of different submicrometer droplets for which precisely controlled dimensions are required.

Fabrication of Customizable Intraplaque Hemorrhage Phantoms for Magnetic Resonance Imaging.

PURPOSE: Magnetic resonance (MR) imaging detection of methemoglobin, a molecular marker of intraplaque hemorrhage (IPH), in atherosclerotic plaque is a promising method of assessing stroke risk. However, the multicenter imaging studies required to further validate this technique necessitate the development of IPH phantoms to standardize images acquired across different scanners. This study developed a set of phantoms that modeled methemoglobin-laden IPH for use in MR image standardization. PROCEDURES: A time-stable material mimicking the MR properties of methemoglobin in IPH was created by doping agarose hydrogel with gadolinium and sodium alginate. This material was used to create a phantom that consisted of 9 cylindrical IPH sites (with sizes from 1 to 8 mm). Anatomical replicas of IPH-positive atherosclerosis were also created using 3D printed molds. These plaque replicas also modeled other common plaque components including a lipid core and atheroma cap. T1 mapping and a magnetization-prepared rapid acquisition gradient echo (MPRAGE) carotid imaging protocol were used to assess phantom realism and long-term stability. RESULTS: Cylindrical phantom IPH sites possessed a T1 time of 335 ± 51 ms and exhibited little change in size or MPRAGE signal intensity over 31 days; the mean (SD) magnitude of changes in size and signal were 6.4 % (2.7 %) and 7.3 % (6.7 %), respectively. IPH sites incorporated into complex anatomical plaque phantoms exhibited contrast comparable to clinical images. CONCLUSIONS: The cylindrical IPH phantom accurately modeled the short T1 time characteristic of methemoglobin-laden IPH, with the IPH sites exhibiting little variation in imaging properties over 31 days. Furthermore, MPRAGE images of the anatomical atherosclerosis replicas closely matched those of clinical plaques. In combination, these phantoms will allow for IPH imaging protocol standardization and thus facilitate future multicenter IPH imaging.

Capsule robot pose and mechanism state detection in ultrasound using attention-based hierarchical deep learning.

Ingestible robotic capsules with locomotion capabilities and on-board sampling mechanism have great potential for non-invasive diagnostic and interventional use in the gastrointestinal tract. Real-time tracking of capsule location and operational state is necessary for clinical application, yet remains a significant challenge. To this end, we propose an approach that can simultaneously determine the mechanism state and in-plane 2D pose of millimeter capsule robots in an anatomically representative environment using ultrasound imaging. Our work proposes an attention-based hierarchical deep learning approach and adapts the success of transfer learning towards solving the multi-task tracking problem with limited dataset. To train the neural networks, we generate a representative dataset of a robotic capsule within ex-vivo porcine stomachs. Experimental results show that the accuracy of capsule state classification is 97%, and the mean estimation errors for orientation and centroid position are 2.0 degrees and 0.24 mm (1.7% of the capsule's body length) on the hold-out test set. Accurate detection of the capsule while manipulated by an external magnet in a porcine stomach and colon is also demonstrated. The results suggest our proposed method has the potential for advancing the wireless capsule-based technologies by providing accurate detection of capsule robots in clinical scenarios.

The influence of intelligence and cognitive abilities on the reading ability of Japanese students with developmental disorders.

OBJECTIVE: We examined the differences in reading skills between Japanese students with developmental dyslexia (DD) having developmental disorders who had borderline IQ (BIQ) and those who had normal IQ (NIQ), and the influence of cognitive factors through subscale scores of the Wechsler Intelligence Scale for Children - Fourth Edition on the reading skills of all students with DD having developmental disorders. METHODS: One-way analysis of variance revealed differences in reading scores among the four groups (DD with NIQ, DD with BIQ, as well as non-DD with NIQ and non-DD with BIQ as control groups). To examine the influence of cognitive factors, we used multiple regression analysis for all participants, and then for participants with DD. RESULTS: Regarding hiragana nonword fluency reading, no difference was observed between the two DD groups, and cognitive factors did not affect the performance of all participants with DD. Concerning hiragana word fluency reading, DD with NIQ group performed better than DD group with BIQ, and working memory index affected reading skills of participants with DD. Regarding kanji accuracy reading, DD with NIQ group performed better than DD with BIQ group, and processing speed index affected performance of participants with DD. CONCLUSIONS: The results of hiragana reading suggest that the two DD groups shared similar weak sub-lexical route processing, while the acquisition of lexical route processing was hindered by lower IQ and weak phonological working memory in transparent phonographic hiragana reading. For kanji reading, lower IQ and weak visuomotor processing ability hampered the learning of visually complex logographic kanji characters.

Silica-coated quantum dots for optical evaluation of perfluorocarbon droplet interactions with cells.

There has been recent interest in developing new, targeted, perfluorocarbon (PFC) droplet-based contrast agents for medical imaging (e.g., magnetic resonance imaging, X-ray/computed tomography, and ultrasound imaging). However, due to the large number of potential PFCs and droplet stabilization strategies available, it is challenging to determine in advance the PFC droplet formulation that will result in the optimal in vivo behavior and imaging performance required for clinical success. We propose that the integration of fluorescent quantum dots (QDs) into new PFC droplet agents can help to rapidly screen new PFC-based candidate agents for biological compatibility early in their development. QD labels can allow the interaction of PFC droplets with single cells to be assessed at high sensitivity and resolution using optical methods in vitro, complementing the deeper depth penetration but lower resolution provided by PFC droplet imaging using in vivo medical imaging systems. In this work, we introduce a simple and robust method to miscibilize silica-coated nanoparticles into hydrophobic and lipophobic PFCs through fluorination of the silica surface via a hydrolysis-condensation reaction with 1H,1H,2H,2H-perfluorodecyltriethoxysilane. Using CdSe/ZnS core/shell QDs, we show that nanoscale, QD-labeled PFC droplets can be easily formed, with similar sizes and surface charges as unlabeled PFC droplets. The QD label can be used to determine the PFC droplet uptake into cells in vitro by fluorescence microscopy and flow cytometry, and can be used to validate the fate of PFC droplets in vivo in small animals via fluorescence microscopy of histological tissue sections. This is demonstrated in macrophage and cancer cells, and in rabbits, respectively. This work reveals the potential of using QD labels for rapid, preclinical, optical assessment of different PFC droplet formulations for their future use in patients.

Microfluidic assembly of monodisperse, nanoparticle-incorporated perfluorocarbon microbubbles for medical imaging and therapy.

New medical imaging contrast agents that permit multiple imaging and therapy applications using a single agent can result in more accurate diagnosis and local treatment of diseased tissue. Solid nanoparticles (NPs) (5-150 nm in size) have emerged as promising imaging and therapy agents, as have micrometer-scale, perfluorocarbon gas-filled microbubbles (MBs) used in patients as intravascular ultrasound contrast agents. We propose that the modular combination of small, solid NPs and larger, highly compressible MBs into a single agent is an effective way to attain the desired complementary and hybrid properties of two very different agents. Presented here is a new strategy for the simple and robust incorporation of various medical NPs with monodisperse MBs based upon the controlled pH-based regulation of the electrostatic attraction between NPs and the MB shell. Using this simple approach, microfluidic-generated, protein-lipid-coated, perfluorobutane MBs (with size control down to 3 microm) were incorporated with silica-coated NPs, including CdSe/ZnS quantum dots, gold nanorods, iron oxide NPs, and Gd-loaded mesoporous silica NPs. The silica interface permits NP inclusion within MBs to be independent of NP composition, morphology, and size. Significantly, the NP-incorporated MBs (NP-MBs) diluted in saline were detectable using low-pressure ultrasound, and the monodisperse MB platform can be produced at high-throughput, sufficient for in vivo usage (10(6) MB/sec). The modular synthesis of a variety of NP-MBs can facilitate flexible, user-defined, multifunctional imaging and therapy agents tailored for specific applications and disease types.

Tunable rainbow light trapping in ultrathin resonator arrays.

Rainbow light trapping in plasmonic devices allows for field enhancement of multiple wavelengths within a single device. However, many of these devices lack precise control over spatial and spectral enhancement profiles and cannot provide extremely high localised field strengths. Here we present a versatile, analytical design paradigm for rainbow trapping in nanogroove arrays by utilising both the groove-width and groove-length as tuning parameters. We couple this design technique with fabrication through multilayer thin-film deposition and focused ion beam milling, which enables the realisation of unprecedented feature sizes down to 5 nm and corresponding extreme normalised local field enhancements up to 103. We demonstrate rainbow trapping within the devices through hyperspectral microscopy and show agreement between the experimental results and simulation. The combination of expeditious design and precise fabrication underpins the implementation of these nanogroove arrays for manifold applications in sensing and nanoscale optics.