Synthesis of Poly(propylene oxide)-Poly(N,N'-dimethylacrylamide) Diblock Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Solution.

Sterically-stabilized diblock copolymer nanoparticles comprising poly(propylene oxide) (PPO) cores are prepared via reverse sequence polymerization-induced self-assembly (PISA) in aqueous solution. N,N'-Dimethylacrylamide (DMAC) acts as a cosolvent for the weakly hydrophobic trithiocarbonate-capped PPO precursor. Reversible addition-fragmentation chain transfer (RAFT) polymerization of DMAC is initially conducted at 80% w/w solids with deoxygenated water. At 30-60% DMAC conversion, the reaction mixture is diluted to 5-25% w/w solids. The PPO chains become less solvated as the DMAC monomer is consumed, which drives in situ self-assembly to form aqueous dispersions of PPO-core nanoparticles of 120-190 nm diameter at 20 °C. Such RAFT polymerizations are well-controlled (Mw/Mn ≤ 1.31), and more than 99% DMAC conversion is achieved. The resulting nanoparticles exhibit thermoresponsive character: dynamic light scattering and transmission electron microscopy studies indicate the formation of more compact spherical nanoparticles of approximately 33 nm diameter on heating to 70 °C. Furthermore, 15-25% w/w aqueous dispersions of such nanoparticles formed micellar gels that undergo thermoreversible (de)gelation on cooling to 5 °C.

A Survey of Technology Abandonment in US Nursing Homes.

OBJECTIVE: Adoption of health information technology (HIT) in nursing homes (NHs) improves quality of care. Although there is a robust body of research on HIT adoption, the closely related process of technology abandonment is not well understood. As NHs grow more reliant on HIT, problems of technology abandonment, defined as failure to scale up, spread, and sustain HIT need to be studied. Our objective is to describe HIT abandonment and its associations with organizational characteristics among a national sample of US NHs. DESIGN: Longitudinal, retrospective analysis of data from 2 sources: HIT Maturity Survey and Staging model and public data from the Care Compare database. SETTING AND PARTICIPANTS: Random sample of NHs (n = 299) representing each US state that completed the HIT maturity survey in 2 consecutive years: year 1 (Y1) was June 2019-August 2020 and year 2 (Y2) was June 2020-August 2021. METHODS: The primary dependent variable was technology abandonment, operationalized by using total HIT maturity score, HIT maturity stage, and subscale scores within each dimension/domain. Independent variables were NH organizational characteristics including bed size, type of ownership, urbanicity, Centers for Medicare & Medicaid Services Five-Star Overall Rating and Staffing Rating. RESULTS: Over the 2-year period, HIT abandonment occurred in 28% (n = 85) of NHs compared with 44% (n = 133) that experienced growth in HIT systems. HIT capabilities in resident care were abandoned most frequently. Using multivariable multinomial logistic regression, we found that large NHs (bed size greater than 120) were more likely to experience technology abandonment in administrative activities. CONCLUSIONS AND IMPLICATIONS: Technology abandonment can increase strain on scarce resources and may impact administrators' ability to oversee clinical operations, especially in large NHs. This study contributes to the limited understanding of technology abandonment and can serve as a building block for others working to ensure limited resources are used effectively to improve care for NH residents.

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization-Induced Self-Assembly in Aqueous Media.

Hydrolytically degradable block copolymer nanoparticles are prepared via reverse sequence polymerization-induced self-assembly (PISA) in aqueous media. This efficient protocol involves the reversible addition-fragmentation chain transfer (RAFT) polymerization of N,N'-dimethylacrylamide (DMAC) using a monofunctional or bifunctional trithiocarbonate-capped poly(ϵ-caprolactone) (PCL) precursor. DMAC monomer is employed as a co-solvent to solubilize the hydrophobic PCL chains. At an intermediate DMAC conversion of 20-60 %, the reaction mixture is diluted with water to 10-25 % w/w solids. The growing amphiphilic block copolymer chains undergo nucleation to form sterically-stabilized PCL-core nanoparticles with PDMAC coronas. 1 H NMR studies confirm more than 99 % DMAC conversion while gel permeation chromatography (GPC) studies indicate well-controlled RAFT polymerizations (Mw /Mn ≤1.30). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) indicate spheres of 20-120 nm diameter. As expected, hydrolytic degradation occurs within days at 37 °C in either acidic or alkaline solution. Degradation is also observed in phosphate-buffered saline (PBS) (pH 7.4) at 37 °C. However, no degradation is detected over a three-month period when these nanoparticles are stored at 20 °C in deionized water (pH 6.7). Finally, PDMAC30 -PCL16 -PDMAC30 nanoparticles are briefly evaluated as a dispersant for an agrochemical formulation based on a broad-spectrum fungicide (azoxystrobin).

Delayed fatal intracranial hemorrhage in a pediatric patient following resection and adjuvant cranial radiotherapy for ependymoma: illustrative case.

BACKGROUND: Cranial radiotherapy (CRT) is an important treatment modality for malignancies of the central nervous system. CRT has deleterious effects that are commonly classified into acute, early delayed, and late delayed. Late-delayed effects include weakening of the cerebral vasculature and the development of structurally abnormal vasculature, potentially leading to ischemic or hemorrhagic events within the brain parenchyma. Such events are not well reported in the pediatric population. OBSERVATIONS: The authors present the case of a 14-year-old patient 8.2 years after CRT who experienced intracerebral hemorrhage. Autopsy demonstrated minimal pathological change without evidence of vascular malformation or aneurysm. These findings were unexpected given the degree of hemorrhage in this case. However, in the absence of other etiologies, it was believed that late-delayed radiation effect was the cause of this patient's fatal hemorrhage. LESSONS: Although not all cases of pediatric spontaneous intracerebral hemorrhage will have a determined etiology, the authors' patient's previous CRT may represent a poorly defined risk for late-delayed hemorrhage. This correlation has not been previously reported and should be considered in pediatric patients presenting with spontaneous hemorrhage in a delayed fashion after CRT. Neurosurgeons must not be dismissive of unexpected events in the remote postoperative period.

Therapeutic Potential of Combinative shRNA-Encoded Lentivirus-Mediated Gene Silencing to Accelerate Somatosensory Recovery After Spinal Cord Trauma.

Neuropathic pain following spinal cord injury (SCI) remains a difficult problem that affects more than 80% of SCI patients. Growing evidence indicates that neuroinflammatory responses play a key role in neuropathic pain after SCI. Short hairpin RNA (shRNA) interference is an efficient tool for the knockdown of disease-related specific gene expression after SCI, yet insufficient data is available to establish guidelines. In this study, we have constructed the transient receptor potential ankyrin 1 (TRPA1) shRNA encoded-lentiviral vector (LV-shTRPA1) and P38 MAPK shRNA encoded-lentiviral vector (LV-shP38) to investigate the silencing effects of shRNAs and their ability to reprogram the neuroinflammatory responses, thereby enhancing somatosensory recovery after SCI. Our in vitro data employing HEK293-FT and activated macrophages demonstrated that delivered LV-shRNAs showed high transduction efficacy with no cytotoxicity. Furthermore, a combination of LV-shP38 and LV-shTRPA1 was found to be most effective at suppressing target genes, cutting the expression of pro-inflammatory and pro-nociceptive factors in the dorsal horn of the spinal cord and dorsal root ganglia, thus contributing to the alleviation of neuronal hypersensitivities after SCI. Overall, our data demonstrated that the combination LV-shP38/shTRPA1 produced a synergistic effect for immunomodulation and reduced neuropathic pain with a favorable risk-to-benefit ratio. Collectively, our LV-mediated shRNA delivery will provide an efficient tool for gene silencing therapeutic approaches to treat various incurable disorders.

Approaches to Understanding the Solution-State Organization of Spray-Dried Dispersion Feed Solutions and Its Translation to the Solid State.

It is well established that polymers adopt a range of conformations and solution-state organization in response to varying solution environments, although very little work has been done to understand how these effects might impact the physical stability and bioavailability of spray-dried amorphous dispersions (SDDs). Potentially relevant solution-state polymer-solvent/cosolute interactions include preferential solvation, hydrodynamic size (i.e., polymer swelling or collapse), and solvent quality effects (i.e., attractive or repulsive self-interactions). Of particular interest is the investigation of preferential solvation, defined as the relative attraction or rejection of a cosolvent and/or cosolute from the local environment of a solvated macromolecule, which often occurs in multicomponent macromolecular solutions. As spray drying and other solvent-based dispersion processing necessitates the use of complex media consisting of at least three or more components (drug, polymer, solvent(s), and other possible excipients), the prevalence of this phenomenon is likely. This work characterizes largely unexplored solution-state properties in model spray-dried dispersion feed solutions using light scattering and viscometric techniques to add greater context and guidance in studying these information-rich materials. These systems are found to exhibit complex non-intuitive behavior, which serves to highlight the potential utility of preferential solvation in spray-dried dispersion processing and stability. It is hypothesized that solution-state organization of the liquid feed can be engineered and translated to the solid-state for the optimization of SDD properties.

The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.

OBJECTIVES: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. METHODS: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR ≥ 1.6) at the baseline). RESULTS: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04). CONCLUSIONS: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation.

Education of Physicians and Implementation of a Formal Referral System Can Improve Cardiac Rehabilitation Referral and Participation Rates after Percutaneous Coronary Intervention.

BACKGROUND: Cardiac rehabilitation (CR) is an effective preventive measure that remains underutilised in the United States. The study aimed to determine the CR referral rate (RR) after percutaneous coronary intervention (PCI) at an academic tertiary care centre, identify barriers to referral, and evaluate awareness of CR benefits and indications (CRBI) among cardiologists. Subsequently, it aimed to evaluate if an intervention consisting of physicians' education about CRBI and implementation of a formal CR referral system could improve RR and consequently participation rate (PR). METHODS: Data were retrospectively collected for all consecutive patients who underwent PCI over 12 months. Referral rate was determined and variables were compared for differences between referred and non-referred patients. A questionnaire was distributed among the physicians in the Division of Cardiology to assess awareness of CRBI and referral practice patterns. After implementation of the intervention, data were collected retrospectively for consecutive patients who underwent PCI in the following six months. Referral rate and changes in PRs were determined. RESULTS: Prior to the intervention, RR was 17.6%. Different barriers were identified, but the questionnaire revealed lack of physicians' awareness of CRBI and inconsistent referral patterns. After the intervention, RR increased to 88.96% (Odds Ratio 37.73, 95% CI 21.34-66.70, p<0.0001) and PR increased by 32.8% to reach 26%. Personal endorsement of CRBI by cardiologists known to patients increased CR program graduation rate by 35%. CONCLUSIONS: Cardiologists' awareness of CRBI increases CR RR and their personal endorsement improves PR and compliance. Education of providers and implementation of a formal referral system can improve RR and PR.

Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors.

PURPOSE: To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t(1/2)>20h) and altered (A; t(1/2)<20h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine. METHODS: One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250mg gefitinib dispersion preparation (IRESSA AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy. RESULTS: There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified. CONCLUSIONS: There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.

The effects of acute and chronic lipopolysaccharide infusion in rats on the efferent function of sensory nerves in the isolated mesenteric arterial bed.

Capsaicin-sensitive sensory neurons are stimulated by noxious stimuli, and may be activated in endotoxaemia. The present study investigated the acute and chronic effects of lipopolysaccharide upon the efferent function of these nerves. Conscious rats received infusion (i.v.) of lipopolysaccharide (150 microg kg(-1) h(-1)) or saline for 2 or 24 h. Following infusion, animals were killed and the mesenteric arterial bed isolated and perfused with Krebs' solution. Electrical field stimulation of capsaicin-sensitive sensory nerves was investigated. Postjunctional mechanisms of sensory neurotransmission were examined using calcitonin gene-related peptide, and endothelial and smooth muscle function assessed using acetylcholine and sodium nitroprusside, respectively. All preparations exhibited dose dependency to the agonists, and frequency dependency to electrical field stimulation. No significant differences were observed between the four groups (2-h saline, 24-h saline, 2-h lipopolysaccharide and 24-h lipopolysaccharide) with regard to responses to electrical field stimulation, acetylcholine, sodium nitroprusside or calcitonin gene-related peptide. Thus, the efferent function of capsaicin-sensitive sensory nerves is unaltered in the isolated mesenteric arterial bed prepared ex vivo from rats receiving lipopolysaccharide, either acutely (2 h) or chronically (24 h).

Effects of in vivo lipopolysaccharide infusion on vasoconstrictor function of rat isolated mesentery, kidney, and aorta.

Continuous infusion of lipopolysaccharide (LPS) into conscious rats elicits regionally selective cardiovascular disturbances. The aim of the present study was to assess contractile function in different vascular preparations (renal, mesenteric, and thoracic aorta) taken from rats infused with LPS for 2 or 24 h. Sustained responses to continuous infusion of methoxamine but not to KCl were reduced in the aorta (at 2 and 24 h LPS) and mesentery (at 24 h LPS) but not in the renal vascular bed. In contrast, transient responses to bolus doses of methoxamine were unchanged in the mesentery. In Ca2+-imaging experiments with fura-2, challenge with a single concentration of methoxamine (10 microM, which showed an impaired contractile response at 24 h LPS) induced a rise in intracellular Ca2+ in the mesenteric artery that was not different from the control. Furthermore, in the aorta, the contractile response to caffeine was attenuated only in the 2 h LPS group. These results show that there is regional heterogeneity in in vitro vascular responsiveness in preparations taken from LPS-infused rats. Thus, in mesenteric beds and aortae, but not renal beds, there is hypocontractility to methoxamine that is not due to a generalized inability of the smooth muscle to contract, which is evident with sustained but not transient application of agonist (mesentery) and which, in late endotoxemia (24 h LPS), does not appear to involve abnormalities in Ca2+ mobilization or entry.

GABAergic mechanisms involved in the vagally mediated heart rate response to muscle contraction as revealed by studies with benzodiazepines.

The aim of this study was to determine if central GABA mechanisms are involved in the cardiac vagal withdrawal at the beginning of exercise in man. We tested whether GABA-enhancing effects of a benzodiazepine could be observed in the HR change (R-R interval) immediately following the onset of a brief (10s) isometric contraction (60 % maximum) of the biceps muscle. The difference between the change in R-R interval occurring during the same phase of respiration was compared for placebo (Pla) and 10 mg oral diazepam (Dz) treatment in a double blind, crossover trial. ECG, blood pressure, respiration and biceps muscle tension were recorded. The subjects breathed to a metronome and R-R interval measurements were plotted for early and late inspiration and early and late expiration. The mean values of the first late expiration R-R interval immediately following the start of contraction in early expiration were compared to the same measurements without contraction. Contractions initiated following diazepam treatment resulted in a significantly greater reduction in R-R interval (P < 0.05) implying that GABAergic suppression of cardiac vagal outflow may be responsible for contraction-induced tachycardia in man.

Vasoconstrictor responsiveness of tail arteries from endotoxaemic rats.

Continuous infusion of lipopolysaccharide in conscious rats mimics some aspects of cardiovascular dysfunction in septic shock. In the present study, contractile responsiveness of tail arteries taken from rats infused with lipopolysaccharide was investigated. Contractile responses to alpha,beta-methylene ATP and potassium chloride, but not to methoxamine, were greater after 24 h lipopolysaccharide infusion than in 2-h saline, 24-h saline and 2-h lipopolysaccharide groups. N(G)-nitro-L-arginine methyl ester augmented contractions to alpha,beta-methylene ATP and methoxamine in the 2-h saline, 24-h saline and 2-h lipopolysaccharide groups, but had no significant effect in the 24-h lipopolysaccharide group. Endothelium-independent vasorelaxant responses to sodium nitroprusside were greater in the 24-h lipopolysaccharide group compared to the other three groups. Relaxations to acetylcholine were not significantly different. In vitro incubation in medium containing lipopolysaccharide for 24 h had no significant effect on contractile responses of tail arteries compared to controls incubated in medium alone. These data indicate a possible impaired nitric oxide and/or endothelial function in tail arteries isolated from rats 24 h after lipopolysaccharide infusion. As hypercontractility was not evoked following in vitro incubation with lipopolysaccharide, the involvement of in vivo neurohumoral factors/mechanisms in the pathology of these changes is implicated.