Overlap of allergic, eosinophilic and type 2 inflammatory subtypes in moderate-to-severe asthma.

BACKGROUND: Current biologic therapies target allergic, eosinophilic or type 2 inflammation phenotypic asthma. However, frequency and degree of overlap among these subtypes is unclear. OBJECTIVE: To characterize overlap among allergic, eosinophilic and type 2 asthma phenotypes. METHODS: Post hoc analyses of baseline data were performed in two adult populations: (a) not selected for any asthma subtype (N = 935) and (b) selected for allergic asthma (N = 1049). Degree of overlap was examined using commonly accepted phenotypic definitions to guide treatment for allergic asthma (skin prick-positive and/or positive serum-specific immunoglobulin E > 0.35 kU/L) and eosinophilic asthma (blood eosinophil high count ≥ 300 cells/µL; low cut-off ≥ 150 cells/µL). Consistent with previous studies, fractional exhaled nitric oxide high level of ≥ 35 ppb and low cut-off of ≥ 25 ppb were selected as local markers of type 2 inflammation and to prevent overlap with the systemic eosinophilic asthma definition. RESULTS: In the non-subtype-selected population, 78.0% had allergic asthma; of these, 39.5% had eosinophilic asthma and 29.5% had type 2 asthma. Within patients with eosinophilic asthma (40.6% of total), 75.8% had allergic asthma and 41.3% had type 2 asthma. Within patients with type 2 asthma (28.3% of total), 81.1% had allergic asthma and 59.2% had eosinophilic asthma. In the allergic asthma-selected population, 38.3% had eosinophilic asthma and 29.2% had type 2 asthma. Within patients with eosinophilic asthma, 46.3% had type 2 asthma. Within patients with type 2 asthma, 60.8% had eosinophilic asthma. Overlaps among subtypes increased at low cut-off values. CONCLUSIONS AND CLINICAL RELEVANCE: In this post hoc analysis in adults with moderate-to-severe asthma, allergic asthma was the most prevalent phenotype, followed by eosinophilic and type 2 asthma. Despite observed overlaps, a considerable proportion of patients had only a predominantly allergic subtype. Understanding the degree of overlap across phenotypes will help patient management and guide treatment options.

No difference in omalizumab efficacy in patients with asthma by number of asthma-related and allergic comorbidities.

BACKGROUND: Comorbidities are common in asthma and may complicate treatment response. OBJECTIVE: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities. METHODS: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis. RESULTS: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances. CONCLUSION: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden. TRIAL REGISTRATION: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037).

IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling.

BACKGROUND: TH2 cells play a critical role in the pathogenesis of allergic asthma. Established TH2 cells have been shown to resist reprogramming into TH1 cells. The inherent stability of TH2 cells poses a significant barrier to treating allergic diseases. OBJECTIVE: We sought to understand the mechanisms by which CD4(+) T cells from asthmatic patients resist the IL-27-mediated inhibition. METHODS: We isolated and cultured CD4(+) T cells from both healthy subjects and allergic asthmatic patients to test whether IL-27 can inhibit IL-4 production by the cultured CD4(+) T cells using ELISA. Culturing conditions that resulted in resistance to IL-27 were determined by using both murine and human CD4(+) T-cell culture systems. Signal transducer and activator of transcription (STAT) 1 phosphorylation was analyzed by means of Western blotting and flow cytometry. Suppressor of cytokine signaling (Socs) mRNA expression was measured by using quantitative PCR. The small interfering RNA method was used to knockdown the expression of Socs3 mRNA. RESULTS: We demonstrated that CD4(+) T cells from asthmatic patients resisted the suppression of IL-4 production mediated by IL-27. We observed that repeated exposure to TH2-inducing conditions rendered healthy human CD4(+) T cells resistant to IL-27-mediated inhibition. Using an in vitro murine culture system, we further demonstrated that repeated or higher doses of IL-4 stimulation, but not IL-2 stimulation, upregulated Socs3 mRNA expression and impaired IL-27-induced STAT1 phosphorylation. The knockdown of Socs3 mRNA expression restored IL-27-induced STAT1 phosphorylation and IL-27-mediated inhibition of IL-4 production. CONCLUSIONS: Our findings demonstrate that differentiated TH2 cells can resist IL-27-induced reprogramming toward TH1 cells by downregulating STAT1 phosphorylation and likely explain why the CD4(+) T cells of asthmatic patients are resistant to IL-27-mediated inhibition.

Deidentifying Narrative Assessments to Facilitate Data Sharing in Medical Education.

PROBLEM: Narrative assessments are commonly incorporated into competency-based medical education programs. However, efforts to share competency-based medical education assessment data among programs to support the evaluation and improvement of assessment systems have been limited in part because of security concerns. Deidentifying assessment data mitigates these concerns, but deidentifying narrative assessments is time-consuming, resource intensive, and error prone. The authors developed and tested a tool to automate the deidentification of narrative assessments and facilitate their review. APPROACH: The authors met throughout 2021 and 2022 to iteratively design, test, and refine the deidentification algorithm and data review interface. Preliminary testing of the prototype deidentification algorithm was performed using narrative assessments from the University of Saskatchewan emergency medicine program. The algorithm's accuracy was assessed by the authors using the review interface designed for this purpose. Formal testing included 2 rounds of deidentification and review by members of the authorship team. Both the algorithm and data review interface were refined during the testing process. OUTCOMES: Authors from 3 institutions, including 3 emergency medicine programs, an anesthesia program, and a surgical program, participated in formal testing. In the final round of review, 99.4% of the narrative assessments were fully deidentified (names, nicknames, and pronouns removed). The results were comparable for each institution and specialty. The data review interface was improved with feedback obtained after each round of review and found to be intuitive. NEXT STEPS: This innovation has demonstrated viability evidence of an algorithmic approach to the deidentification of assessment narratives while reinforcing that a small number of errors are likely to persist. Future steps include the refinement of both the algorithm to improve its accuracy and the data review interface to support additional data set formats.

Benchmarking a Canadian Anesthesiology Resident Research Program against national norms using a logic model framework: a quality improvement study.

Background: Canadian specialty training programs are expected to deliver curriculum content and assess competencies related to the CanMEDS Scholar role. We evaluated our residency research program and benchmarked it against national norms for quality improvement purposes. Methods: In 2021 we reviewed departmental curriculum documents and surveyed current and recently graduated residents. We applied a logic model framework to assess if our program's inputs, activities, and outputs addressed the relevant CanMeds Scholar competencies. We then descriptively benchmarked our results against a 2021 environmental scan of Canadian anesthesiology resident research programs. Results: Local program content was successfully mapped to competencies. The local survey response rate was 40/55 (73%). In benchmarking, our program excelled in providing milestone-related assessments, research funding, administrative, supervisory, and methodologic support, and requiring a literature review, proposal presentation, and local abstract submission as output. Acceptable activities to meet research requirements vary greatly among programs. Balancing competing clinical and research responsibilities was a frequently reported challenge. Conclusions: The logic model framework was easily applied and demonstrated our program benchmarked well against national norms. National level dialogue is needed to develop specific, consistent scholar role activities and competency assessments to bridge the gap between expected outcome standards and education practice.

Contexte: Les programmes de spécialité canadiens doivent proposer un contenu de formation en lien avec le rôle CanMEDS d'érudit et évaluer les compétences qui s'y attachent. Nous avons évalué notre programme de résidence en recherche par rapport aux normes nationales en la matière à des fins d'amélioration de la qualité. Méthodes: En 2021, nous avons examiné les documents du programme d'études du département et interrogé des résidents et des médecins récemment diplômés. Nous avons utilisé un modèle logique pour déterminer si les intrants, les activités et les extrants de notre programme couvraient adéquatement les compétences pertinentes liées au rôle CanMeds d'érudit. Nous avons ensuite comparé de façon descriptive nos résultats à une analyse du milieu des programmes de résidence canadiens en recherche en anesthésiologie effectuée la même année. Résultats: Nous avons établi une correspondance entre le contenu du programme local et les compétences. Le taux de réponse à l'enquête était de 40/55 (73 %). D'après l'analyse comparative, notre programme se démarque par l'offre d'évaluations d'étape, de fonds de recherche, de soutien administratif, de supervision, d'orientation méthodologique, et, en ce qui concerne les extrants, par l'exigence d'une analyse documentaire, de la présentation d'une proposition et de la soumission d'un résumé à l'université. Les activités admissibles pour répondre aux exigences de la recherche varient considérablement d'un programme à l'autre. De nombreux répondants ont signalé la difficulté de concilier les responsabilités cliniques et de recherche. Conclusions: L'application du modèle logique a été aisée et elle a permis de montrer que notre programme respecte les normes nationales. Un dialogue au niveau national est nécessaire pour définir de manière précise et cohérente les activités et les évaluations des compétences en lien avec le rôle d'érudit afin de combler le fossé entre les normes quant aux résultats attendus et les pratiques des programmes.

The Quality of Assessment for Learning score for evaluating written feedback in anesthesiology postgraduate medical education: a generalizability and decision study.

Background: Competency based residency programs depend on high quality feedback from the assessment of entrustable professional activities (EPA). The Quality of Assessment for Learning (QuAL) score is a tool developed to rate the quality of narrative comments in workplace-based assessments; it has validity evidence for scoring the quality of narrative feedback provided to emergency medicine residents, but it is unknown whether the QuAL score is reliable in the assessment of narrative feedback in other postgraduate programs. Methods: Fifty sets of EPA narratives from a single academic year at our competency based medical education post-graduate anesthesia program were selected by stratified sampling within defined parameters [e.g. resident gender and stage of training, assessor gender, Competency By Design training level, and word count (≥17 or <17 words)]. Two competency committee members and two medical students rated the quality of narrative feedback using a utility score and QuAL score. We used Kendall's tau-b co-efficient to compare the perceived utility of the written feedback to the quality assessed with the QuAL score. The authors used generalizability and decision studies to estimate the reliability and generalizability coefficients. Results: Both the faculty's utility scores and QuAL scores (r = 0.646, p < 0.001) and the trainees' utility scores and QuAL scores (r = 0.667, p < 0.001) were moderately correlated. Results from the generalizability studies showed that utility scores were reliable with two raters for both faculty (Epsilon=0.87, Phi=0.86) and trainees (Epsilon=0.88, Phi=0.88). Conclusions: The QuAL score is correlated with faculty- and trainee-rated utility of anesthesia EPA feedback. Both faculty and trainees can reliability apply the QuAL score to anesthesia EPA narrative feedback. This tool has the potential to be used for faculty development and program evaluation in Competency Based Medical Education. Other programs could consider replicating our study in their specialty.

Contexte: La qualité de la rétroaction à la suite de l'évaluation d'activités professionnelles confiables (APC) est d'une importance capitale dans les programmes de résidence fondés sur les compétences. Le score QuAL (Quality of Assessment for Learning) est un outil développé pour évaluer la qualité de la rétroaction narrative dans les évaluations en milieu de travail. Sa validité a été démontrée dans le cas des commentaires narratifs fournis aux résidents en médecine d'urgence, mais sa fiabilité n'a pas été évaluée dans d'autres programmes de formation postdoctorale. Méthodes: Cinquante ensembles de commentaires portant sur des APC d'une seule année universitaire dans notre programme postdoctoral en anesthésiologie ­ un programme fondé sur les compétences ­ ont été sélectionnés par échantillonnage stratifié selon des paramètres préétablis [par exemple, le sexe du résident et son niveau de formation, le sexe de l'évaluateur, le niveau de formation en Compétence par conception, et le nombre de mots (≥17 ou <17 mots)]. Deux membres du comité de compétence et deux étudiants en médecine ont évalué la qualité de la rétroaction narrative à l'aide d'un score d'utilité et d'un score QuAL. Nous avons utilisé le coefficient tau-b de Kendall pour comparer l'utilité perçue de la rétroaction écrite et sa qualité évaluée à l'aide du score QuAL. Les auteurs ont utilisé des études de généralisabilité et de décision pour estimer les coefficients de fiabilité et de généralisabilité. Résultats: Les scores d'utilité et les scores QuAL des enseignants (r = 0,646, p < 0,001) et ceux des étudiants (r = 0,667, p < 0,001) étaient modérément corrélés. Les résultats des études de généralisabilité ont montré qu'avec deux évaluateurs les scores d'utilité étaient fiables tant pour les enseignants (Epsilon=0,87, Phi=0,86) que pour les étudiants (Epsilon=0,88, Phi=0,88). Conclusions: Le score QuAL est en corrélation avec l'utilité de la rétroaction sur les APC en anesthésiologie évaluée par les enseignants et les étudiants. Les uns et les autres peuvent appliquer de manière fiable le score QuAL aux commentaires narratifs sur les APC en anesthésiologie. Cet outil pourrait être utilisé pour le perfectionnement professoral et l'évaluation des programmes dans le cadre d'une formation médicale fondée sur les compétences. D'autres programmes pourraient envisager de reproduire notre étude dans leur spécialité.

Codeine prescription pattern and treatment responses in patients with chronic cough: a routinely collected institutional database analysis.

Background: Codeine has been long used as an antitussive drug in several countries. However, a prescription pattern of codeine, such as dose or treatment duration, has not been reported in detail. Furthermore, there is few scientific evidence on the efficacy and safety. We aimed to examine codeine prescription pattern and explore treatment response in patients with chronic cough in real-world practice. Methods: This was a retrospective cohort analysis of patients with chronic cough who were newly referred to tertiary allergy and asthma clinics between July 2017 and July 2018. Routinely collected electronic healthcare records (EHRs), including medical notes, prescriptions, and outpatient visits, were analyzed. Codeine prescription records were examined for duration, mean daily dose, and 1-year cumulative dose. Codeine responses were evaluated by manual EHR reviews. Results: Among a total of 1,233 newly referred patients with chronic cough, 666 were prescribed codeine for a median [interquartile range (IQR)] of 27.5 days (IQR 14-60 days); the median daily dose was 30 mg/year (IQR 21.6-30 mg/year), and the 1-year cumulative dose was 720 mg/year (IQR 420-1,800 mg/year). About 14.0% of patients were prescribed codeine for >8 weeks; they were older and had a longer cough duration, throat abnormal sensation and less dyspnea than patients prescribed codeine for ≤8 weeks or who did not receive codeine. Codeine prescription and duration was positively associated with the number of other cough-related medications, diagnostic tests, or outpatient visits. Cough status change was noted in 61.3% of codeine-prescribed patients (as 'improved' in 40.1% and 'not improved' in 21.2%), but not documented in 38.7%. Side effects were described in 7.8%. Conclusions: Codeine prescription may be frequent and chronic in real-world practice of patients with chronic cough, despite the lack of robust clinical evidence on the efficacy. High prescription rates suggest unmet clinical needs. Prospective studies are warranted to identify codeine treatment responses and safety, and to build up clinical evidence to guide appropriate use of narcotic antitussives.

Synthesis of manganese ferrite/graphene oxide nanocomposites for biomedical applications.

In this study, MnFe(2)O(4) nanoparticle (MFNP)-decorated graphene oxide nanocomposites (MGONCs) are prepared through a simple mini-emulsion and solvent evaporation process. It is demonstrated that the loading of magnetic nanocrystals can be tuned by varying the ratio of graphene oxide/magnetic nanoparticles. On top of that, the hydrodynamic size range of the obtained nanocomposites can be optimized by varying the sonication time during the emulsion process. By fine-tuning the sonication time, MGONCs as small as 56.8 ± 1.1 nm, 55.0 ± 0.6 nm and 56.2 ± 0.4 nm loaded with 6 nm, 11 nm, and 14 nm MFNPs, respectively, are successfully fabricated. In order to improve the colloidal stability of MGONCs in physiological solutions (e.g., phosphate buffered saline or PBS solution), MGONCs are further conjugated with polyethylene glycol (PEG). Heating by exposing MGONCs samples to an alternating magnetic field (AMF) show that the obtained nanocomposites are efficient hyperthermia agents. At concentrations as low as 0.1 mg Fe mL(-1) and under an 59.99 kA m(-1) field, the highest specific absorption rate (SAR) recorded is 1588.83 W g(-1) for MGONCs loaded with 14 nm MFNPs. It is also demonstrated that MGONCs are promising as magnetic resonance imaging (MRI) T(2) contrast agents. A T(2) relaxivity value (r(2) ) as high as 256.2 (mM Fe)(-1) s(-1) could be achieved with MGONCs loaded with 14 nm MFNPs. The cytotoxicity results show that PEGylated MGONCs exhibit an excellent biocompatibility that is suitable for biomedical applications.

Impact of Rapid Transition to Telemedicine-Based Delivery on Allergy/Immunology Care During COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) necessitated wide-scale adoption of telemedicine (TM) and restriction of in-person care. The impacts on allergy/immunology (A/I) care delivery are still being studied. OBJECTIVE: To describe the outcomes of rapid transition to TM-based care (video visit followed by in-person visits dedicated to diagnostic and therapeutic procedures when needed) at an academic A/I practice during COVID-19. METHODS: Demographic data were compared for patients originally scheduled for in-person visits between March 10, 2020, and April 30, 2020, who completed a video visit instead between March 10, 2020, and June 30, 2020, and those who did not. Appointment completion, diagnoses, and drug allergy and skin testing completion were compared for visits between March 10, 2020, and June 30, 2020, and 1 year prior (March 10, 2019-June 30, 2019). RESULTS: Sixty-nine percent (265 of 382) of patients originally scheduled between March 10, 2020, and April 30, 2020, were able to complete video visits. Patients who completed video visits were more likely to be white (52% vs 33%; P < .001), English-speaking (96% vs 89%; P = .01), and privately insured (70% vs 54%; P = .004). With TM-based care compared with in-person care, there were significant decreases in environmental and food skin testing completion rates (91% and 92% in 2019 vs 60% and 64% in 2020, respectively, P < .001). Drug allergy testing completed after internal referral remained low but comparable (51% in 2019 vs 52% in 2020). Transitioning nonprocedural visits to video allowed allergen immunotherapy and biologic injection visits to resume at a volume similar to pre-COVID. No COVID-19 infections resulted from in-clinic exposure. CONCLUSIONS: Although transitioning to TM-based care allowed continued A/I care delivery, strategies are needed to achieve higher testing completion rates and ensure video visits do not exacerbate existing health disparities.

Skin conductance fluctuations correlate poorly with postoperative self-report pain measures in school-aged children.

BACKGROUND: The number of fluctuations of skin conductance per second (NFSC) has been shown to correlate with induced pain and self-report pain scales. This study aimed to evaluate the validity and feasibility of NFSC as an objective measurement of nociception intensity in school-aged children after surgery. METHODS: After approval by the research ethics board and obtaining consent, 100 subjects participated in this prospective observational study. Preoperatively, NFSC was measured for 60 s at rest and during response to a self-report pain scale (numeric rating scale [NRS], Faces Pain Scale-Revised) and anxiety scoring (NRS). Postoperative measurements were repeated every 10 min for 30 min or until NRS pain score was or= 7) with 56.3% sensitivity (95% CI = 37.7-73.6%) and 78.4% specificity (95% CI = 71.7-84.1%). The area under receiver operator characteristic curve for NFSC was 69.1%. CONCLUSIONS: NFSC measurement is feasible in a perioperative setting but was not specific for postoperative pain intensity and was unable to identify analgesia requirements when compared with self-report measures.

Synthesis of ZnO-Pt nanoflowers and their photocatalytic applications.

The photocatalytic behaviors of ZnO nanoparticles have been intensively studied recently. However, the photocatalytic efficiency of pure ZnO nanoparticles always suffers from the quick recombination of photoexcited electrons and holes. In order to suppress the electron-hole recombination and then raise the photocatalytic efficiency of ZnO, metal nanoparticles have been combined with ZnO to form ZnO-metal heterostructures. In this work, the feasibility of synthesizing ZnO-Pt composite nanoflowers for optimized catalytic properties was studied. Three different Pt nanocrystals, i.e. cubic Pt nanocrystals enclosed by {100} facets, octahedral Pt nanocrystals enclosed by {111} facets, and truncated octahedral Pt nanocrystals enclosed by both {111} and {100} facets, were selected as seeds for epitaxial growth of ZnO. A ZnO-Pt flowerlike nanostructure was formed by selective growth of ZnO nanolobes at {111} facets of the truncated octahedral Pt nanocrystals. The resultant nanoflowers had well defined ZnO-Pt interfaces and exposed Pt {100} facets, as confirmed by transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) measurements. The photocatalytic behaviors of the resultant ZnO-Pt nanoflowers were demonstrated in the photodegradation of ethyl violet. In comparison with the commercial TiO(2) photocatalyst P25, the ZnO-Pt flowerlike nanostructures showed improved catalytic efficiency. Notable ferromagnetism of the obtained ZnO-Pt flowerlike nanostructures was also observed. It is believed that the ZnO-Pt interface played an important role in the enlarged magnetic coercivity of the ZnO-Pt nanoflowers.

A facile one-step route to synthesize cage-like silica hollow spheres loaded with superparamagnetic iron oxide nanoparticles in their shells.

Cage-like silica hollow spheres loaded with superparamagnetic iron oxide nanoparticles incorporated in their macroporous shells are synthesized in a facile manner through a one-step oil-in-diethylene glycol (DEG) microemulsion route.

Designed Construction of a Graphene and Iron Oxide Freestanding Electrode with Enhanced Flexible Energy-Storage Performance.

In this work, a bendable graphene@iron oxide hybrid film (GFeF) electrode was fabricated through a filtration-assisted self-assembly method. Morphological characterization of GFeF revealed a uniform distribution of iron oxide nanoparticles between graphene nanosheets. Surface chemical characterization confirmed that graphene oxide in the as-prepared hybrid film was effectively reduced after thermal reduction. The electrochemical performance of a GFeF half-cell versus Li/Li(+) exhibited high gravimetric capacity (855.2 mAh g(-1) at 0.02 A g(-1)), high volumetric capacity (1949.9 mAh cm(-3) at 0.02 A g(-1)), and superior cycling stability (93% capacitance retention after 500 cycles). On the basis of such a bendable electrode, a hybrid Li-ion supercapacitor that offers an operation voltage of 3.5 V and delivers a high energy density (129.6 Wh kg(-1)) like a Li-ion battery combined with a high power density (1870 W kg(-1)) like a supercapacitor was fabricated. In addition to the superior energy-storage capability, the as-fabricated prototype pouch cell also exhibited excellent mechanical flexibility and stable electrochemical performances under dynamic bending. The viability of such an energy-storage device provides a possible design pathway for future wearable electronics.

Nanoscaled self-alignment of Fe3O4 nanodiscs in ultrathin rGO films with engineered conductivity for electromagnetic interference shielding.

Ultrathin (∼2 µm) reduced graphene oxide (rGO) film embedded with self-aligned Fe3O4 nanodiscs were successfully fabricated through the filtration-assisted self-assembly method. In the as-fabricated hybrid film, Fe3O4 nanodiscs with thin thickness (26 nm) and high aspect ratio (∼9) were readily self-assembled and aligned in rGO intersheets under the assistance of hydrostatic forces. Compared with spherical Fe3O4 nanoparticles, introducing the Fe3O4 nanodiscs into rGO paper could not only offer high magnetic permeability and magnetic loss in a broad frequency range at the gigahertz level, but also increase the electrical conductivity of rGO film by means of improving the surface roughness without disrupting the conductive network of the rGO layers. Due to the above advantages, the free-standing rGO/Fe3O4 nanodisc magnetic hybrid film (56 wt%) exhibited an EMI shielding effectiveness (SE) of around 11.2 dB in the frequency range of 2-10 GHz, which is about 50% and 72% higher than that of neat rGO film and rGO/Fe3O4 nanosphere hybrid films (with similar particle size and loading weight fraction) prepared under the same conditions, respectively. Furthermore, compared with non-magnetic neat rGO film, the outstanding magnetic properties of the rGO/Fe3O4 nanodisc film paves the way for it to be used as a multifunctional material that can be controlled by magnetic fields. Additionally, the moderate thermal reduction temperature (420 °C) would be meaningful for large scale fabrication. Meanwhile, the strategy of achieving good alignment at the nanoscale could shed light on developing heterogeneous structures with self-aligned two-dimensional (2D) (magnetic or non-magnetic) nano-inclusions for various applications.

Methionine restriction induces apoptosis of prostate cancer cells via the c-Jun N-terminal kinase-mediated signaling pathway.

Tumors are relatively more sensitive to methionine restriction than corresponding normal tissues, a phenomenon known as methionine auxotrophy. The current studies were undertaken to elucidate the molecular mechanisms for methionine auxotrophy of prostate cancer cells. We found that the activity of c-Jun N-terminal kinase 1 (JNK1) increased dramatically in response to methionine restriction. Over expression of wild type JNK1 by transient transfection enhanced apoptosis in response to methionine restriction, whereas over expression of a kinase inactive mutant of JNK1 protected PC-3 human prostate cancer cells from apoptosis. We conclude that JNK1 plays a critical role in signaling cancer cells to undergo apoptosis in response to methionine restriction.

Induction of caspase-dependent and -independent apoptosis in response to methionine restriction.

Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies have demonstrated that methionine restriction causes tumor cell growth arrest and eventually apoptosis. The current studies were undertaken to elucidate the molecular pathways leading to apoptosis induced by methionine restriction. We found that methionine restriction induced formation of oligonucleosomal DNA fragment and cytochrome c release from mitochondria in methionine-dependent PC3 and Hela cells. Methionine restriction also led to cleavage and activation of initiator and effector caspases in Hela cells but not PC3 cells. Furthermore, methionine restriction resulted in cleavage of BID and reduction in Bcl-2 levels in both cell lines. These data suggest that apoptosis induced by methionine restriction is mitochondria-dependent. Methionine restriction induced caspase-independent cell death in PC3 cells, whereas it stimulated caspase-dependent cell death in Hela cells. Cleavage of BID and decreased expression of Bcl-2 upon methionine deprivation may be the underlying mechanism to stimulate release of cytochrome c from mitochondria.

A stepwise surgical procedure to investigate the lymphatic transport of lipid-based oral drug formulations: Cannulation of the mesenteric and thoracic lymph ducts within the rat.

INTRODUCTION: A number of animal models have been described for the assessment of intestinal lymphatic drug transport. Lymphatic transport studies are commonly first conducted in the laboratory rat, with larger more complicated models (i.e., dog or pig) subsequently investigated. However, the utility of lymph fistulation in large animals is limited by considerable logistical and economic constraints. METHODS: This paper describes a stepwise surgical procedure for cannulating the thoracic and mesenteric lymph ducts in male Sprague-Dawley rats. RESULTS: Following surgery, thoracic and mesenteric lymph flow rates during the 24-h period immediately following surgery averaged 12.5+/-2.5 and 2.4+/-1.1 ml/h, respectively. This flow rate is greater than that obtained with previously described methods, which require restraint of the animals and/or a 24-h recovery period and are reported to produce average intestinal lymph flow rates of 2 ml/h. DISCUSSION: This animal model can be utilized for the assessment of drug transport by the lymphatics and for determining what percentage of lymphatic transport is a result of only intestinal lymphatics.