Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Design and development of multifunctional polyphosphoester-based nanoparticles for ultrahigh paclitaxel dual loading

Multifunctional polyphosphoester-based nanoparticles capable of loading paclitaxel (PTX) both chemically and physically were prepared, achieving an ultrahigh equivalent PTX aqueous concentration of 25.30 mg mL(-1). The dual-loaded nanoparticles were effective in killing cancer cells, which has the potential to minimize the amount of nanocarriers needed for clinical applications, due to their ultrahigh loading capacity

Development of Degradable Diblock Copolymer, Polyphosphoester-Block-Poly(L-Lactide), and Its Conversion into Well-Defined Shell Crosslinked Nanoparticles as Delivery Carriers for Antimicrobial Agents

The combination of state-of-the-art polymerization chemistries, post-polymerization chemical modifications, supramolecular assembly processes and further transformations is allowing for the design of highly well-defined polymer nanoparticles that are demonstrating unique performance toward the effective treatment of infectious diseases. A potentially fully degradable, biocompatible diblock copolymer, polyphosphoester-block-poly(L-lactide) (PPE-b-PLLA), was prepared by one-pot sequential ring-opening polymerizations (ROPs) of two cyclic monomers: alkyne-functionalized phospholane and L-lactide. Photo-induced thiol-yne “click”-type reactions with small molecule thiols bearing carboxylic acid then afforded amphiphilic diblock copolymers with carboxylate side-chain functionalities along the PPE segment of the diblock copolymer backbone. Subsequently, well-defined (1) spherical micelles with negative surface charges were prepared by direct dissolution of the anionic diblock copolymers (aPPE-b-PLLA) in aqueous solution, and (2) shell crosslinked knedel-like (SCK) nanoparticles were prepared by crosslinking of hydrophilic shell of the micelles, as confirmed by transmission electron microscopy (TEM), dynamic light scattering (DLS) and zeta potential. The Ag-loading capacities of the anionic micelles and SCKs from aPPE-b-PLLA were determined with three different types of Ag-containing molecules, silver acetate (AgOAc) and silver carbene complexes (SCC22 and SCC10). Similarly, Ag-release kinetics of the Ag-loaded nanoparticles, using dialysis cassettes in nanopure water, was studied. We are currently working on the study of (1) degradation capability of micelles and SCKs of PPE-b-PLLA system under hydrolytic or enzymatic degradation, (2) conjugation with target-specific proteins such as FimHA to evaluate their ability to perform as target delivery carriers, and (3) determination of their in vitro and in vivo efficacies against bacteria

Degradable polyphosphoester-based silver-loaded nanoparticles as therapeutics for bacterial lung infections

In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate

Erythrocyte-Membrane-Camouflaged Nanocarriers with Tunable Paclitaxel Release Kinetics via Macromolecular Stereocomplexation

Biomimetic-cell-membrane-camouflaged polymeric nanocarriers, possessing advantages related to the functional diversity of natural cell membranes and the physicochemical tailorability of synthetic polymers, serve as promising candidates for a therapeutic platform. Herein, we report a facile approach for the fabrication of erythrocyte (red blood cell, RBC)-membrane-camouflaged nanocarriers (RBC-MCNs) that exhibit tunable paclitaxel (PTX) release kinetics via altering macromolecular stereostructure. In this approach, biocompatible isotactic and atactic polylactides (PLAs) with similar molar masses (Mn = 8.2-8.9 kDa, as measured by NMR spectroscopy) and dispersities (&DStrok; < 1.1, as measured by size exclusion chromatography) were synthesized via organocatalyzed ring-opening polymerizations (ROPs), providing tunable crystalline structures via polymer tacticity, while RBC membranes provided biomimetic surfaces and improved colloidal stability of PLA nanoconstructs in phosphate-buffered saline (PBS, pH 7.4). Wide-angle X-ray diffraction (WAXD) and differential scanning calorimetry (DSC) analyses of the lyophilized nanoconstructs suggested significant retention of PLA stereocomplexation upon loading the hydrophobic anticancer drug PTX, enabling control over drug release kinetics. The structure-property relationships were maintained after the RBC coating, with 100% stereocomplexed PLA RBC-MCNs exhibiting the least PTX release during the first 12 h in PBS at 37 °C, compared to 2-, 3-, and 4-fold higher amounts of release for the 50% stereocomplexed, isotactic, and amorphous PLA counterparts, respectively. The extended release of PTX from the 100% stereocomplexed PLA RBC-MCNs resulted in an increased IC50 (0.50 μM) against SJSA osteosarcoma cells, relative to amorphous PLA RBC-MCNs (IC50 = 0.25 μM) or free PTX (IC50 = 0.05 μM). In contrast, non-PTX-loaded RBC-MCNs were not cytotoxic, and they also displayed lower immunotoxic responses against RAW 264.7 macrophage cells compared to RBC membrane vesicles. This work represents fundamental advances toward a potential personalized nanocarrier technology that would be capable of employing an individual's RBCs for membrane isolation, together with tuning of cargo loading and release simply via alteration of the biocompatible PLA stereoisomer feed ratio

Aerosolized Antimicrobial Agents Based on Degradable Dextran Nanoparticles Loaded with Silver Carbene Complexes

Degradable acetalated dextran (Ac-DEX) nanoparticles were prepared and loaded with a hydrophobic silver carbene complex (SCC) by a single-emulsion process. The resulting particles were characterized for morphology and size distribution using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The average particle size and particle size distribution were found to be a function of the ratio of the organic phase to the surfactant containing aqueous phase with a 1:5 volume ratio of Ac-DEX CH₂Cl₂ (organic):PBS (aqueous) being optimal for the formulation of nanoparticles with an average size of 100 ± 40 nm and a low polydispersity. The SCC loading was found to increase with an increase in the SCC quantity in the initial feed used during particle formulation up to 30% (w/w); however, the encapsulation efficiency was observed to be the best at a feed ratio of 20% (w/w). <i>In vitro</i> efficacy testing of the SCC loaded Ac-DEX nanoparticles demonstrated their activity against both Gram-negative and Gram-positive bacteria; the nanoparticles inhibited the growth of every bacterial species tested. As expected, a higher concentration of drug was required to inhibit bacterial growth when the drug was encapsulated within the nanoparticle formulations compared with the free drug illustrating the desired depot release. Compared with free drug, the Ac-DEX nanoparticles were much more readily suspended in an aqueous phase and subsequently aerosolized, thus providing an effective method of pulmonary drug delivery