Staff experience of team case formulation to address challenging behaviour on acute psychiatric wards: a mixed-methods study.

BACKGROUND: Team case formulation on acute psychiatric wards aims to support staff to manage significant levels of challenging behaviour. However, there is limited research on staff experience of case formulation in this setting. AIM: This study aimed to investigate staff experience of team case formulation sessions on acute psychiatric wards and their impact on staff wellbeing. METHODS: Eighteen multidisciplinary staff (nurses, doctors, occupational therapists, support workers, activities coordinators) from five acute wards at a South London psychiatric hospital completed a semi-structured interview and visual analogue scales on their experience of attending case formulation. Thematic analysis was employed to analyse qualitative data. RESULTS: Participants reported that case formulation supported staff to develop a holistic understanding of service users, provided a safe space for staff to discuss the impact of challenging behaviour and improved teamwork and communication. Participants reported that these benefits increased their ability to identify and support the needs of service users and improved therapeutic relationships. Challenges with establishing continuity of care were highlighted. CONCLUSION: Team case formulation is an important intervention to support ward staff and has significant benefits to staff wellbeing and quality of care. Greater integration with existing ward practices may benefit both staff and service users.

Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics.

Nanoassemblies from homostructured polypeptides as efficient nanoplatforms for oral drug delivery.

The assembly of homostructured polypeptides bearing various side groups into well-defined nanostructures was presented, with their size and topology mainly dominated by the chemical structure and molecular weight of peptides. Pharmacokinetic and pharmacodynamic studies based on rat models suggested these newly constructed nanoassemblies with low cytotoxicity may function as novel nanoplatforms to efficiently and safely deliver therapeutics to achieve better efficacy but lower side effects. Other applications in biomedical fields, such as biotechnology, medical imaging, and tissue engineering, may also be expected. FROM THE CLINICAL EDITOR: This research team investigated the assembly of homostructured polypeptides bearing various side groups into well-defined nanostructures, and demonstrated low cytotoxicity in rat disease models, suggesting that these novel nanoplatforms may safely and efficiently deliver therapeutics with low side effects.

Flow-network-controlled shape transformation of a thin membrane through differential fluid storage and surface expansion.

The mechanical properties of a thin, planar material, perfused by an embedded flow network, have been suggested to be potentially changeable locally and globally by fluid transport and storage, which can result in both small- and large-scale deformations such as out-of-plane buckling. In these processes, fluid absorption and storage eventually cause the material to locally swell. Different parts can hydrate and swell unevenly, prompting a differential expansion of the surface. In order to computationally study the hydraulically induced differential swelling and buckling of such a membrane, we develop a network model that describes both the membrane shape and fluid movement, coupling mechanics with hydrodynamics. We simulate the time-dependent fluid distribution in the flow network based on a spatially explicit resistor network model with local fluid-storage capacitance. The shape of the surface is modeled by a spring network produced by a tethered mesh discretization, in which local bond rest lengths are adjusted instantaneously according to associated local fluid content in the capacitors in a quasistatic way. We investigate the effects of various designs of the flow network, including overall hydraulic traits (resistance and capacitance) and hierarchical architecture (arrangement of major and minor veins), on the specific dynamics of membrane shape transformation. To quantify these effects, we explore the correlation between local Gaussian curvature and relative stored fluid content in each hierarchy by using linear regression, which reveals that stronger correlations could be induced by less densely connected major veins. This flow-controlled mechanism of shape transformation was inspired by the blooming of flowers through the unfolding of petals. It can potentially offer insights for other reversible motions observed in plants induced by differential turgor and water transport through the xylem vessels, as well as engineering applications.

Leaf Water Storage and Robustness to Intermittent Drought: A Spatially Explicit Capacitive Model for Leaf Hydraulics.

Leaf hydraulic networks play an important role not only in fluid transport but also in maintaining whole-plant water status through transient environmental changes in soil-based water supply or air humidity. Both water potential and hydraulic resistance vary spatially throughout the leaf transport network, consisting of xylem, stomata and water-storage cells, and portions of the leaf areas far from the leaf base can be disproportionately disadvantaged under water stress. Besides the suppression of transpiration and reduction of water loss caused by stomatal closure, the leaf capacitance of water storage, which can also vary locally, is thought to be crucial for the maintenance of leaf water status. In order to study the fluid dynamics in these networks, we develop a spatially explicit, capacitive model which is able to capture the local spatiotemporal changes of water potential and flow rate in monocotyledonous and dicotyledonous leaves. In electrical-circuit analogs described by Ohm's law, we implement linear capacitors imitating water storage, and we present both analytical calculations of a uniform one-dimensional model and numerical simulation methods for general spatially explicit network models, and their relation to conventional lumped-element models. Calculation and simulation results are shown for the uniform model, which mimics key properties of a monocotyledonous grass leaf. We illustrate water status of a well-watered leaf, and the lowering of water potential and transpiration rate caused by excised water source or reduced air humidity. We show that the time scales of these changes under water stress are hugely affected by leaf capacitance and resistances to capacitors, in addition to stomatal resistance. Through this modeling of a grass leaf, we confirm the presence of uneven water distribution over leaf area, and also discuss the importance of considering the spatial variation of leaf hydraulic traits in plant biology.

Computer-assisted engineering of programmed drug releasing multilayer nanomedicine via indomethacin-mediated ternary complex for therapy against a multidrug resistant tumor.

Nanomedicine with programmed drug release can give full play to the synergistic effect of multi-component system in complicated tumor environment. However, the construction of these programmed drug delivery systems often depends on the sophisticated materials design and synthesis. In this study, we successfully designed an indomethacin (IND)-mediated ternary complex system based on a PEG cleavable polyethyleneimine (PEI), indomethacin (IND) and benzene ring containing chemotherapeutic drugs (such as paclitaxel (PTX), doxorubicin and docetaxel). Based on the difference of hydrophobicity in these components, these components were one-pot self-assembled into drug-loaded IND mediated PEGylation cleavable nanoassemblies (IPCNs) in multilayer structure. In drug-loaded IPCNs, PEG fragments, PEI/IND, and chemotherapeutic drug were respectively distributed from the out layer to core of nanomedicine. When drug-loaded IPCNs reached tumor site through EPR effect, the PEG fragment would firstly responsively release to the acidic tumor microenvironment to expose the intermediate layer of drug-loaded IPCNs that composed by mixture of PEI and IND for increasing the surface potential to promote the uptake by tumor cells. After entering cells, IND would be released faster than chemotherapeutic drug encapsulated in core to efficiently inhibit the expression of multidrug resistance protein 1 to reverse MDR of tumor cells before chemotherapeutic drug releasing. Contributed by the staged responsively releasing of PEG fragments, IND and encapsulated chemotherapeutic drug, the drug-loaded IPCNs exhibited a superior antitumor efficacy against A549/MDR tumor cells both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: The way to develop programmed released drug delivery system is commonly relied on complicated material design and synthesis. Herein, under the computer-assist design, we successfully designed a ternary complex derived from indomethacin (IND), paclitaxel (PTX) and a pH-responsive PEGylated polyethyleneimine (PEG-s-PEI), and employed this ternary complex to successfully prepare a high drug loading and multilayer structured nanomedicine of PTX (PTX IPCNs). Contribute by the different location of PTX, IND and PEG-s-PEI in PTX IPCNs, PEG fragments, IND and PTX molecules could programmed release after reaching tumor for perfectly realizing the synergistic anti-tumor effect of tumor targeting, reversal of MDR and chemotherapy. Based on a fusion of these multiple mechanisms, PTX IPCNs showed a superior antitumor efficacy in mice loading A549/MDR tumor.

Smart pH-sensitive nanoassemblies with cleavable PEGylation for tumor targeted drug delivery.

A new acidly sensitive PEGylated polyethylenimine linked by Schiff base (PEG-s-PEI) was designed to render pH-sensitive PEGylation nanoassemblies through multiple interactions with indomethacin and docetaxel (DTX). DTX nanoassemblies driven by PEG-s-PEI thus formulated exhibited an excellent pH-sensitivity PEGylation cleavage performance at extracellular pH of tumor microenvironment, compared to normal tissues, thereby long circulated in blood but were highly phagocytosed by tumor cells. Consequently, this smart pH-sensitive PEGylation cleavage provided an efficient strategy to target tumor microenvironment, in turn afforded superior therapeutic outcome in anti-tumor activity.

Sustained elevation of NF-κB activity sensitizes offspring of maternal inflammation to hypertension via impairing PGC-1α recovery.

Growing evidence has demonstrated that maternal detrimental factors, including inflammation, contribute to the development of hypertension in the offspring. The current study found that offspring subjected to prenatal exposure of inflammation by lipopolysaccharide (LPS) challenge during the second semester showed significantly increased systolic blood pressure. In addition, these offspring also displayed augmented vascular damage and reactive oxygen species (ROS) levels in thoracic aortas when challenged with deoxycorticosterone acetate and high-salt diet (DOCA-salt). Interestingly, the antioxidant N-acetyl-L-cysteine markedly reversed these changes. Mechanistically, prenatal LPS exposure led to pre-existing elevated peroxisome proliferators-activated receptor-γ co-activator (PGC)-1α, a critical master of ROS metabolism, which up-regulated the ROS defense capacity and maintained the balance of ROS generation and elimination under resting state. However, continued elevation of NF-κB activity significantly suppressed the rapid recovery of PGC-1α expression response to DOCA-salt challenge in offspring that underwent prenatal inflammatory stimulation. This was further confirmed by using a NF-κB inhibitor (N-p-Tosyl-L-phenylalanine chloromethyl ketone) that restored PGC-1α recovery and prevented blood pressure elevation induced by DOCA-salt. Our results suggest that maternal inflammation programmed proneness to NF-κB over-activation which impaired PGC-1α-mediated anti-oxidant capacity resulting in the increased sensitivity of offspring to hypertensive damage.

Facile route to versatile nanoplatforms for drug delivery by one-pot self-assembly.

There is still unmet demand for developing powerful approaches to produce polymeric nanoplatforms with versatile functions and broad applications, which are essential for the successful bench-to-bedside translation of polymeric nanotherapeutics developed in the laboratory. We have discovered a facile, convenient, cost-effective and easily scalable one-pot strategy to assemble various lipophilic therapeutics bearing carboxyl groups into nanomedicines, through which highly effective cargo loading and nanoparticle formation can be achieved simultaneously. Besides dramatically improving water solubility, the assembled nanopharmaceuticals showed significantly higher bioavailability and much better therapeutic activity. These one-pot assemblies may also serve as nanocontainers to effectively accommodate other highly hydrophobic drugs such as paclitaxel (PTX). PTX nanomedicines thus formulated display strikingly enhanced in vitro antitumor activity and can reverse the multidrug resistance of tumor cells to PTX therapy. The special surface chemistry offers these assembled entities the additional capability of efficiently packaging and efficaciously transfecting plasmid DNA, with a transfection efficiency markedly higher than that of commonly used positive controls. Consequently, this one-pot assembly approach provides a facile route to multifunctional nanoplatforms for simultaneous delivery of multiple therapeutics with improved therapeutic significance.

Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel.

Engineering of pH-responsive nanoplatforms can be facilely achieved from acetalated α-cyclodextrin materials. The hydrolysis period of nanoparticles can be precisely tailored by using materials with various acetal types that can be easily controlled by acetalation time. These nanomaterials with pH-modulated hydrolysis and pH-triggered drug delivery capability show good biocompatibility in vitro and in vivo. Incorporation of anticancer drug paclitaxel (PTX) into newly developed pH-sensitive nanosystems leads to nanotherapeutics with significantly improved cytotoxic activity against various tumor cells. Importantly, thus formulated nanomedicines can reverse the multidrug resistance of PTX-resistant cancer cells. In vivo antitumor studies also reveal the superior of pH-sensitive nanosystems over pristine PTX and pH-insensitive PLGA nanoformulations. Moreover, comparison with other two acid-labile materials evidenced the advantages of cyclodextrin-based nanovehicles with respect to drug loading capacity, in vitro and in vivo activity as well as alleviated adverse effects. These pH-responsive nanoparticles may serve as new generation nanocarriers for drug delivery.

Assembled nanomedicines as efficient and safe therapeutics for articular inflammation.

Highly efficient nanomedicines were successfully fabricated by the indomethacin (IND) directed self-assembly of ß-cyclodextrin (ß-CD)-conjugated polyethyleneimine (PEI-CD), taking advantage of the multiple interactions between drug and polymer. These nanoscaled assemblies exhibited spherical shape and positively charged surface. Compared with the commercial tablet, the relative oral bioavailability of IND-nanomedicines was significantly enhanced. Evaluation based on either carrageenan-induced paw edema or complete Freund's adjuvant (CFA)-induced arthritis suggested the newly developed nanomedicines were more effective than raw IND or IND tablet in terms of prophylactic effect and therapeutic activity. Even the low dose of nanomedicines offered the comparable results to those of control groups at the high dosage in most cases. Moreover, the nanoformulation exhibited ameliorated gastrointestinal stimulation. All these positive results indicated that this type of nanomedicines might serve as a highly efficient and effective delivery nanoplatform for the oral delivery of water-insoluble therapeutics.

Highly efficient nanomedicines assembled via polymer-drug multiple interactions: Tissue-selective delivery carriers.

This study presents the construction and evaluation of highly efficient nanomedicines via self-assembly directed by multiple non-covalent interactions between carrier polymer and cargo molecules, including hydrophobic, host-guest recognition, hydrogen bonding and electrostatic forces. ß-Cyclodextrin conjugated polyethyleneimine (PEI-CD) was employed as the model carrier material, while indomethacin (IND), a nonsteroidal anti-inflammatory drug, was used as the drug model. Spontaneous assembly of PEI-CD and IND led to core-shell structured nanoparticles with a positive surface and pH-triggering behavior as well as high drug loading capacity. These nano-assemblies can function as gastro-OFF/intestinal-ON delivery systems to selectively transport payload to enteric sites, thereby dramatically increasing the oral bioavailability of the loaded therapeutic, which can also serve as multifunctional nano-platforms for multiple delivery of various therapeutics. In addition, the strategy employed herein may provide new insights into the design of novel nanocarriers by self-assembling.

Hypoglycemic effect of syringin from Eleutherococcus senticosus in streptozotocin-induced diabetic rats.

Eleutherococcus senticosus (Araliaceae ) is a very powerful adaptogenic agent. In the present study, the effects of syringin, an active principle of this herb, on plasma glucose levels in streptozotocin-induced diabetic rats (STZ-diabetic rats) were investigated. Thirty minutes after syringin was intravenously injected into fasting STZ-diabetic rats, plasma glucose levels dose-dependently decreased. In normal rats, syringin at the effective dose (1.0 mg/kg) significantly attenuated the increase in plasma glucose caused by an intravenous glucose challenge. Syringin dose-dependently (0.01 to 10.0 micromol/L) stimulated glucose uptake in soleus muscle isolated from STZ-diabetic rats. Syringin treatment of hepatocytes isolated from STZ-diabetic rats enhanced glycogen synthesis . The ability of syringin to enhance glucose utilization and lower plasma glucose level in rats suffering from insulin deficiency suggest that this chemical may be useful in the treatment of human diabetes.

Novel ent-Beyeran-19-oic acids from biotransformations of isosteviol metabolites by Mortierella isabellina.

Biotransformations of ENT-16beta-hydroxybeyeran-19-oic acid ( 1) by Mortierella isabellina produced hydroxylated metabolites. The isolated metabolites included three new compounds, ent-14beta,16beta-dihydroxybeyeran-19-oic acid ( 3), ent-12beta-hydroxy-16-oxobeyeran-19-oic acid ( 4), and ent-7alpha,12beta-dihydroxy-16-oxobeyeran-19-oic acid ( 5), and one known compound, ent-7alpha,16beta-dihydroxybeyeran-19-oic acid ( 2). The structural elucidation was achieved by detailed analysis of LC-MS chromatograms, and MS and NMR spectroscopic data. In this study, M. isabellina hydroxylated the basic skeleton beyeran-19-oic acid at the 7beta-, 12alpha-, and 14alpha-positions, and oxidized the skeleton at the 16-position. All compounds were evaluated with the cell viability assay. The results of the bioassay indicated that MTT formazan exocytosis occurs upon treatment of the cells with 1.