Referral to treatment for hospitalized medical patients with an alcohol use disorder: A proof-of-concept brief intervention study.

Substance misuse intervention in healthcare settings is becoming a US national priority, especially in the dissemination and implementation of Screening, Brief Intervention, and Referral to Treatment (SBIRT). Yet, the referral to treatment component of SBIRT is understudied. This proof-of-concept investigation tested an enhanced coordinated hospital-community two session brief intervention designed to facilitate the referral to treatment of hospitalized medical patients with an alcohol use disorder. Participants (N = 9) attended the second session of the brief intervention held in the community in most cases (56%), while one out of three (33%) received some level of post-brief intervention alcohol and/or other drug treatment. Alcohol use and alcohol-related problems also statistically improved. Based, in part, on the results plus the widespread dissemination of SBIRT, next step investigations of brief interventions to help bridge hospitalized medical patients in need to community substance abuse treatment are warranted.

Reducing Psychiatric Inpatient Readmissions Using an Organizational Change Model.

INTRODUCTION: Thirty-day hospital readmission rates have become a quality indicator for many regulators and payers, but published accounts of reducing these rates across a patient population are lacking. OBJECTIVE: This article describes and evaluates the Wisconsin Mental Health Readmissions Project, which aimed to reduce psychiatric inpatient 30-day readmission rates in Wisconsin. METHODS: Nineteen county human services boards representing 23 of Wisconsin's 72 counties and 61% of the state's residential admissions participated in a statewide quality improvement collaborative from January 1, 2010 to December 31, 2013. Participants applied a standardized organizational change model, called NIATx, in the context of a multicounty quality improvement collaborative to reduce 30-day readmission rates. Readmission rates were tracked through national and state databases, using 2009 as a baseline, and analyzed using a chi-square analysis to test the proportion of means. The study team compared readmission rates of Wisconsin counties that participated in the statewide collaborative with those that did not. RESULTS: Between 2009 and 2013, the 30-day readmission rates in Wisconsin declined significantly for counties that participated in the project when compared to those that did not (2009-2013) [Χ2(4) = 54.503, P < .001], based on a 2.5% decline for participants vs a 0.7% decline for nonparticipants. CONCLUSIONS: Reductions to behavioral health inpatient readmission rates beyond individual case examples have been difficult to document. This analysis evaluates a method that Wisconsin behavioral health providers applied as part of a multicounty program addressing readmission rates. The findings highlight quality improvement program design elements and interventions to consider in reducing inpatient behavioral health readmissions, as well as the need for further research on this complex systems issue.

Ultrasoft, highly deformable microgels.

Microgels are colloidally stable, hydrogel microparticles that have previously been used in a range of (soft) material applications due to their tunable mechanical and chemical properties. Most commonly, thermo and pH-responsive poly(N-isopropylacrylamide) (pNIPAm) microgels can be fabricated by precipitation polymerization in the presence of the co-monomer acrylic acid (AAc). Traditionally pNIPAm microgels are synthesized in the presence of a crosslinking agent, such as N,N'-methylenebisacrylamide (BIS), however, microgels can also be synthesized under 'crosslinker free' conditions. The resulting particles have extremely low (<0.5%), core-localized crosslinking resulting from rare chain transfer reactions. AFM nanoindentation of these ultralow crosslinked (ULC) particles indicate that they are soft relative to crosslinked microgels, with a Young's modulus of ∼10 kPa. Furthermore, ULC microgels are highly deformable as indicated by a high degree of spreading on glass surfaces and the ability to translocate through nanopores significantly smaller than the hydrodynamic diameter of the particles. The size and charge of ULCs can be easily modulated by altering reaction conditions, such as temperature, monomer, surfactant and initiator concentrations, and through the addition of co-monomers. Microgels based on the widely utilized, biocompatible polymer polyethylene glycol (PEG) can also be synthesized under crosslinker free conditions. Due to their softness and deformability, ULC microgels are a unique base material for a wide variety of biomedical applications including biomaterials for drug delivery and regenerative medicine.

Internal structure of ultralow-crosslinked microgels: From uniform deswelling to phase separation.

We perform small angle neutron scattering on ultralow-crosslinked microgels and find that while in certain conditions both the particle size and the characteristic internal length scale change in unison, in other instances this is not the case. We show that nonuniform deswelling depends not only on particle size, but also on the particular way the various contributions to the free energy combine to result in a given size. Only when polymer-solvent demixing strongly competes with ionic or electrostatic effects do we observe nonuniform behavior, reflecting internal microphase separation. The results do not appreciably depend on particle number density; even in concentrated suspensions, we find that at relatively low temperature, where demixing is not very strong, the deswelling behavior is uniform, and that only at sufficiently high temperature, where demixing is very strong, does the microgel structure change akin to internal microphase separation.

Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives.

Current observations in the literature suggest that vitamin E may be a suitable candidate for cancer chemotherapy. To investigate this further, we examined the ability of the vitamin E natural homologs [alpha-, beta-, gamma-, delta-tocopherols (alpha-TOC, beta-TOC, gamma-TOC, delta-TOC) and alpha-, beta-, gamma-, delta-tocotrienols (alpha-TT, beta-TT, gamma-TT, delta-TT)] and their corresponding succinate synthetic derivatives [alpha-, beta-, gamma-, delta-tocopheryl succinates and alpha-, beta-, gamma-, delta-tocotrienyl succinates (alpha-TS, beta-TS, gamma-TS, delta-TS)] to induce cell death in AR- (DU145 and PC3) and AR+ (LNCaP) prostate cancer cell lines. The most effective of all the natural homologs of vitamin E was determined to be delta-TT, whereas delta-TS was the most potent of all the natural and synthetic compounds of vitamin E examined. Both gamma-TT and delta-TT induced caspase activity selectively in AR+ LNCaP cells, suggesting a possible role for AR for the activation of caspase-dependent programmed cell death (CD-PCD). More important, however, gamma-TT, delta-TT, gamma-TS, and delta-TS activated dominant caspase-independent programmed cell death (CI-PCD) in all prostate cancer cell lines examined. Thus, vitamin E homologs and synthetic derivatives may find applications in the treatment of prostate tumors that are resistant to caspase-activating therapeutic agents.

Charge segregation in weakly ionized microgels.

We investigate microgels synthesized from N-isopropylacrylamide (NIPAM) copolymerized with a large mol% of acrylic acid, finding that when the acid groups are partially ionized at high temperatures, competition between ion-induced swelling and hydrophobic deswelling of poly(NIPAM) chains results in microphase separation. In cross-linked microgels, this manifests as a dramatic decrease in the ratio between the radius of gyration and the hydrodynamic radius to ∼0.2, indicating that almost all the mass of the microgel is concentrated near the particle center. We also observe a concurrent decrease of the polymer network length scale via small-angle neutron scattering, confirming the presence of a dense, deswollen core surrounded by a diffuse, charged periphery. We compare these results to those obtained for a system of charged ultralow-cross-linked microgels; the form factor shows a distinct peak at high q when the temperature exceeds a threshold value. We successfully fit the form factor to theory developed to describe scattering from weakly charged gels in poor solvents, and we tie this behavior to charge segregation in the case of the cross-linked microgels.

Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers.

D-alpha-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS 1000) is a widely used form of vitamin E. TPGS 1000 is comprised of a hydrophilic polar (water-soluble) head and a lipophilic (water-insoluble) alkyl tail. TPGS 1000 has been used as a solubilizer, an emulsifier and as a vehicle for lipid-based drug delivery formulations. Most recently, TPGS 1000 has been recognized as an effective oral absorption enhancer. An enhancing effect is consistent with a surfactant-induced inhibition of P-glycoprotein (P-gp), and perhaps other drug transporter proteins; however, the exact inhibition mechanism(s) remain unclear. Therefore, in an attempt to generate additional knowledge, we have synthesized and tested various TPGS analogs containing different PEG chain length (TPGS 200/238/400/600/1000/2000/3400/3500/4000/6000). These results demonstrate a relationship between TPGS PEG chain length and influence on rhodamine 123 (RHO) transport in Caco-2 monolayers, a relationship which may be illustrated using a Weibull distribution.

Segregation of mass at the periphery of N-isopropylacrylamide-co-acrylic-acid microgels at high temperatures.

We investigate poly(N-isopropylacrylamide) (pNIPAM) microgels randomly copolymerized with large mol % of protonated acrylic acid (AAc), finding that above the lower critical solution temperature the presence of the acid strongly disrupts pNIPAM's collapse, leading to unexpected new behavior at high temperatures. Specifically, we see a dramatic increase in the ratio between the radius of gyration and the hydrodynamic radius above the theoretical value for homogeneous spheres, and a corresponding increase of the network length scale, which we attribute to the presence of a heterogeneous polymer distribution that forms due to frustration of pNIPAM's coil-to-globule transition by the AAc. We analyze this phenomenon using a Debye-Bueche-like scattering contribution as opposed to the Lorentzian term often used, interpreting the results in terms of mass segregation at the particle periphery.

Reversible Inter- and Intra-Microgel Cross-Linking using Disulfides.

Thermoresponsive hydrogel nanoparticles composed of poly(N-isopropylmethacrylamide) (pNIPMAm) and the disulfide-based cross-linker N,N'-bis(acryloyl)cystamine (BAC) have been prepared using a redox-initiated, aqueous precipitation polymerization approach, leading to improved stability of the disulfide bond compared to traditional thermally-initiated methods. The resultant particles demonstrate complete erosion in response to reducing conditions or thiol competition. This stands in contrast to the behavior of thermally-initiated particles, which retain a cross-linked network following disulfide cleavage due to uncontrolled chain-branching and self-cross-linking side reactions. The synthetic strategy has also been combined with the non-degradable cross-linker N,N-methylenebisacrylamide (BIS) to generate "co-cross-linked" pNIPMAm-BAC-BIS microgels. These particles are redox-responsive, swell upon BAC cross-link scission and present reactive thiols. This pendant thiol functionality was demonstrated to be useful for conjugation of thiol-reactive probes and in reversible network formation by assembling particles cross-linked by disulfide linkages.

Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: a prospective controlled study.

Diabetic foot ulcers (DFU) are common, difficult-to-treat, and prone to complications. A prospective, controlled study was conducted to: 1) examine the clinical efficacy of a pressurized topical oxygen therapy (TWO(2)) device in outpatients (N = 28) with severe DFU referred for care to a community wound care clinic and 2) assess ulcer reoccurrence rates after 24 months. Seventeen (17) patients received TWO(2) five times per week (60-minute treatment, pressure cycles between 5 and 50 mb) and 11 selected a silver-containing dressing changed at least twice per week (control). Patient demographics did not differ between treatment groups but wounds in the treatment group were more severe, perhaps as a result of selection bias. Ulcer duration was longer in the treatment (mean 6.1 months, SD 5.8) than in the control group (mean 3.2 months, SD 0.4) and mean baseline wound area was 4.1 cm2 (SD 4.3) in the treatment and 1.4 cm2 (SD 0.6) in the control group (P = 0.02). Fourteen (14) of 17 ulcers (82.4%) in the treatment group and five of 11 ulcers (45.5%) in the control group healed after a median of 56 and 93 days, respectively (P = 0.04). No adverse events were observed and there was no reoccurrence at the ulcer site after 24 months' follow-up in either group. Although the absence of randomization and blinding may have under- or overestimated the treatment effect of either group, the significant differences in treatment outcomes confirm the potential benefits of TWO(2) in the management of difficult-to-heal DFUs. Clinical efficacy and cost-effectiveness studies as well as studies to elucidate the mechanisms of action of TWO(2) are warranted.

A short and convenient chemical route to optically pure 2-methyl chromanmethanols. Total asymmetric synthesis of beta-, gamma-, and delta-tocotrienols.

With use of inexpensive commercially available raw materials, chromanmethanol precursors to the natural beta-, gamma-, and delta-tocotrienols have been prepared in high yield. Enzymatic resolution afforded chiral chromanmethanols in high enantiomeric excess. Subsequent attachment of the farnesyl side chain was high yielding, thus allowing the preparation of asymmetric beta-, gamma-, and delta-tocotrienols in one final step wherein simultaneous deprotection of the phenol and removal of the sulfone group occurs. This chemistry provides the first synthesis of natural-series beta-tocotrienol.

Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity.

Efflux pump (e.g., P-gp, MRP1, and BCRP) inhibition has been recognized as a strategy to overcome multi-drug resistance and improve drug bioavailability. Besides small-molecule inhibitors, surfactants such as Tween 80, Cremophor EL, several Pluronics, and Vitamin E TPGS (TPGS 1000) are known to modulate efflux pump activity. Competitive inhibition of substrate binding, alteration of membrane fluidity, and inhibition of efflux pump ATPase have been proposed as possible mechanisms. Focusing on TPGS 1000, the aim of our study was to unravel the inhibitory mechanism by comparing the results of inhibition experiments in a Caco-2 transport assay with data from electron spin resonance (ESR) and from ATPase activity studies. ESR results, on Caco-2 cells using 5-doxyl stearic acid (5-SA) as a spin probe, ruled out cell membrane fluidization as a major contributor; change of membrane fluidity was only observed at surfactant concentrations 100 times higher than those needed to achieve full efflux inhibition. Concurrently, TPGS 1000 inhibited substrate induced ATPase activity without inducing significant ATPase activity on its own. By investigating TPGS analogues that varied by their PEG chain length, and/or possessed a modified hydrophobic core, transport studies revealed that modulation of ATPase activity correlated with inhibitory potential for P-gp mediated efflux. Hence, these results indicate that ATPase inhibition is an essential factor in the inhibitory mechanism of TPGS 1000 on cellular efflux pumps.