Direct H2O2 Synthesis, without H2 Gas.

We report here the direct hydrogenation of O2 gas to form hydrogen peroxide (H2O2) using a membrane reactor without H2 gas. Hydrogen is sourced from water, and the reactor is driven by electricity. Hydrogenation chemistry is achieved using a hydrogen-permeable Pd foil that separates an electrolysis chamber that generates reactive H atoms, from a hydrogenation chamber where H atoms react with O2 to form H2O2. Our results show that the concentration of H2O2 can be increased ∼8 times (from 56.5 to 443 mg/L) by optimizing the ratio of methanol-to-water in the chemical chamber, and through catalyst design. We demonstrate that the concentration of H2O2 is acutely sensitive to the H2O2 decomposition rate. This decomposition rate can be minimized by using AuPd alloy catalysts instead of pure Pd. This study presents a new pathway to directly synthesize H2O2 using water electrolysis without ever using H2 gas.

Rhenium Complexes of Pyridyl-Mesoionic Carbenes: Photochemical Properties and Electrocatalytic CO2 Reduction.

Mesoionic carbenes have found wide use as components of homogeneous catalysts. Recent discoveries have, however, shown that metal complexes of such ligands also have huge potential in photochemical research and in the activation of small molecules. We present here three ReI complexes with mesoionic pyridyl-carbene ligands. The complexes display reduction steps which were investigated via UV-vis-NIR-IR spectro-electrochemistry, and these results point toward an EC mechanism. The ReI compounds emit in the visible range in solution at room temperature with excited state lifetimes that are dependent on the substituents of the mesoionic carbenes. These complexes are also potent electrocatalysts for the selective reduction of CO2 to CO. Whereas the substituents on the carbenes have no influence on the reduction potentials, the electrocatalytic efficiency is strongly dependent on the substituents. This fact is likely a result of catalyst instability. The results presented here thus introduce mesoionic carbenes as new potent ligands for the generation of emissive ReI complexes and for electrocatalytic CO2 reduction.

Halogen Bonding Promotes Higher Dye-Sensitized Solar Cell Photovoltages.

We report here an enhancement in photovoltage for dye-sensitized solar cells (DSSCs) where halogen-bonding interactions exist between a nucleophilic electrolyte species (I(-)) and a photo-oxidized dye immobilized on a TiO2 surface. The triarylamine-based dyes under investigation showed larger rate constants for dye regeneration (kreg) by the nucleophilic electrolyte species when heavier halogen substituents were positioned on the dye. The open-circuit voltages (VOC) tracked these kreg values. This analysis of a homologous series of dyes that differ only in the identity of two halogen substituents provides compelling evidence that the DSSC photovoltage is sensitive to kreg. This study also provides the first direct evidence that halogen-bonding interactions between the dye and the electrolyte can bolster DSSC performance.

Evidence for Interfacial Halogen Bonding.

A homologous series of donor-π-acceptor dyes was synthesized, differing only in the identity of the halogen substituents about the triphenylamine (TPA; donor) portion of each molecule. Each Dye-X (X=F, Cl, Br, and I) was immobilized on a TiO2 surface to investigate how the halogen substituents affect the reaction between the light-induced charge-separated state, TiO2 (e(-) )/Dye-X(+) , with iodide in solution. Transient absorption spectroscopy showed progressively faster reactivity towards nucleophilic iodide with more polarizable halogen substituents: Dye-F < Dye-Cl < Dye-Br < Dye-I. Given that all other structural and electronic properties for the series are held at parity, with the exception of an increasingly larger electropositive σ-hole on the heavier halogens, the differences in dye regeneration kinetics for Dye-Cl, Dye-Br, and Dye-I are ascribed to the extent of halogen bonding with the nucleophilic solution species.

A self-driving laboratory advances the Pareto front for material properties.

Useful materials must satisfy multiple objectives, where the optimization of one objective is often at the expense of another. The Pareto front reports the optimal trade-offs between these conflicting objectives. Here we use a self-driving laboratory, Ada, to define the Pareto front of conductivities and processing temperatures for palladium films formed by combustion synthesis. Ada discovers new synthesis conditions that yield metallic films at lower processing temperatures (below 200 °C) relative to the prior art for this technique (250 °C). This temperature difference makes possible the coating of different commodity plastic materials (e.g., Nafion, polyethersulfone). These combustion synthesis conditions enable us to to spray coat uniform palladium films with moderate conductivity (1.1 × 105 S m-1) at 191 °C. Spray coating at 226 °C yields films with conductivities (2.0 × 106 S m-1) comparable to those of sputtered films (2.0 to 5.8 × 106 S m-1). This work shows how a self-driving laboratoy can discover materials that provide optimal trade-offs between conflicting objectives.

Evidence for altered synthesis of type II collagen in patients with osteoarthritis.

There is evidence to suggest that the synthesis of type II collagen is increased in osteoarthritis (OA). Using an immunoassay, we show that the content of the C-propeptide of type II procollagen (CPII), released extracellularly from the newly synthesized molecule, is directly related to the synthesis of this molecule in healthy and osteoarthritic articular cartilages. In OA cartilage, CPII content is often markedly elevated (mean 7.6-fold), particularly in the mid and deep zones, reaching 29.6% of the content in newborn. Synthesis is also directly related to total collagen II content in OA, suggesting its importance in maintaining collagen content and cartilage structure. The release of CPII from cartilage is correlated directly with cartilage content. However, the increase in CPII in OA cartilage is not reflected in serum, where a significant reduction is observed. Together these studies provide evidence for alterations in procollagen II synthesis in vivo in patients with OA.

Spectroscopic detection of halogen bonding resolves dye regeneration in the dye-sensitized solar cell.

The interactions between a surface-adsorbed dye and a soluble redox-active electrolyte species in the dye-sensitized solar cell has a significant impact on the rate of regeneration of photo-oxidized dye molecules and open-circuit voltage of the device. Dyes must therefore be designed to encourage these interfacial interactions, but experimentally resolving how such weak interactions affect electron transfer is challenging. Herein, we use X-ray absorption spectroscopy to confirm halogen bonding can exist at the dye-electrolyte interface. Using a known series of triphenylamine-based dyes bearing halogen substituents geometrically positioned for reaction with halides in solution, halogen bonding was detected only in cases where brominated and iodinated dyes were photo-oxidized. This result implies that weak intermolecular interactions between photo-oxidized dyes and the electrolyte can impact device photovoltages. This result was unexpected considering the low concentration of oxidized dyes (less than 1 in 100,000) under full solar illumination.

Kinetic pathway for interfacial electron transfer from a semiconductor to a molecule.

Molecular approaches to solar-energy conversion require a kinetic optimization of light-induced electron-transfer reactions. At molecular-semiconductor interfaces, this optimization has previously been accomplished through control of the distance between the semiconductor donor and the molecular acceptor and/or the free energy that accompanies electron transfer. Here we show that a kinetic pathway for electron transfer from a semiconductor to a molecular acceptor also exists and provides an alternative method for the control of interfacial kinetics. The pathway was identified by the rational design of molecules in which the distance and the driving force were held near parity and only the geometric torsion about a xylyl- or phenylthiophene bridge was varied. Electronic coupling through the phenyl bridge was a factor of ten greater than that through the xylyl bridge. Comparative studies revealed a significant bridge dependence for electron transfer that could not be rationalized by a change in distance or driving force. Instead, the data indicate an interfacial electron-transfer pathway that utilizes the aromatic bridge orbitals.

Antibiotic optimization. An evaluation of patient safety and economic outcomes.

BACKGROUND: Although numerous reports have described interventions designed to influence antibiotic utilization, to our knowledge none have been evaluated in a randomized study. METHODS: Adult inpatients receiving 1 or more of 10 designated parenteral antibiotics for 3 or more days during a 3-month period were randomized to an intervention (n = 141) and a control (n = 111) group using an unblocked, computer-generated random number table. Obstetric patients and those seen in infectious disease consultation were excluded. The intervention group received antibiotic-related suggestions from a team consisting of an infectious disease fellow and a clinical pharmacist. Both groups were evaluated for clinical and microbiological outcomes as well as antibiotic utilization via prospective chart reviews and analysis of the hospital's administrative database. RESULTS: Sixty-two (49%) of the intervention group patients received a total of 74 suggestions. Sixty-three (84%) of these suggestions were implemented; the majority involved changes in antibiotic choice, dosing regimen, or route of administration. Per patient antibiotic charges were nearly $400 less in the intervention group vs controls (P = .05). Almost all the savings were related to lower intravenous antibiotic charges. Clinical and microbiological response, antibiotic-associated toxic effects, in-hospital mortality, and readmission rates were similar for both groups. Multiple linear regression analysis identified randomization to the intervention group and female sex as the sole predictors of lower antibiotic charges. There was a trend toward a shorter length of stay for the intervention group (20 vs 24.7 days, P = .11). CONCLUSIONS: This is the first randomized study to evaluate whether antibiotic choices can be influenced in a cost-effective fashion without sacrificing patient safety. We demonstrate that 50% of patients initially treated with expensive parenteral antibiotics can have their regimens refined after 3 days of therapy and that these modifications result in good clinical outcomes with a substantial reduction in antibiotic expense.

Antihyperalgesic effects of delta opioid agonists in a rat model of chronic inflammation.

Opioid receptors in the brain activate descending pain pathways to inhibit the nociceptive response to acute noxious stimuli. The aim of the present study was to clarify the role of supraspinal opioid receptors in modulating the nociceptive response to persistent inflammation in rats. Subcutaneous administration of 50 microl of complete Freund's Adjuvant (CFA) into the plantar surface of the hindpaw induced a significant decrease in paw withdrawal latency to thermal stimuli (P<0.01) at 24 h post-injection. Intracerebroventricular (i.c.v.) administration of the mu opioid receptor agonists, DAMGO and morphine, and the delta opioid receptor agonists, deltorphin II and SNC80, significantly reversed the hyperalgesic response associated with peripheral inflammation in a dose-dependent manner (P<0.0001). The mu and delta agonists also significantly attenuated the antinociceptive response to acute thermal stimulation in rats (P<0.001). However, deltorphin II and SNC80 were less potent, and in the case of SNC80 less efficacious, in modulating the response to acute thermal nociception in comparison to hyperalgesia associated with persistent inflammation. These results indicate that mu and delta opioid receptors in the brain modulate descending pain pathways to attenuate the nociceptive response to acute thermal stimuli in both normal and inflamed tissues. The heightened response to delta agonists in the hyperalgesia model suggests that delta opioid receptors in the brain are promising targets for the treatment of pain arising from chronic inflammation.

kappa-Opioid receptor recognition sites are not modulated by local anaesthetics.

Local anaesthetics and opioid drugs function synergistically to provide analgesia. In the present study, the nature of this synergy has been investigated using in vitro radioligand binding to determine whether the local anaesthetics bupivacaine and tetracaine modulate the binding of two kappa-opioid receptor ligands, [3H]U-69593 (5-alpha,7-alpha,8-beta-(-)-N-methyl-N[7-(1-pyrrolodinyl)-1-oxa spiro(4,5)dec-8-yl]-benzene acetamide) and [3H](-)-EKC (ethylketocyclazocine). [3H]U-69593 bound with a KD of 0.88 nM and a Bmax of 2.39 +/- 0.22 fmol/mg wet weight in guinea pig cerebellar membranes. The binding was inhibited by bremazocine and morphine with Hill slopes near unity and pI50 values of 9.96 and 6.84-6.86, respectively. [3H]U-69593 binding was inhibited by Gpp(NH)p (5'-guanylyl imidodiphosphate) and NaCl, consistent with an agonist action of the compound. The binding characteristics of the ligand were not changed by bupivacaine or tetracaine. [3H](-)-EKC bound with KD values of 0.55 and 0.97 nM and Bmax values of 4.22 and 0.99 fmol/mg wet weight in guinea pig cerebellar membranes and rat spinal cords, respectively. In the rat spinal cord, [3H](-)-EKC appeared to act as an agonist/antagonist, since the presence of Gpp(NH)p and NaCl only produced a small (21%) reduction in binding, but reduced the pI50 for the residual binding to inhibition by morphine from 6.33-6.39 to 5.95. As with [3H]U-69593, the binding characteristics of [3H](-)-EKC were not affected by bupivacaine or tetracaine. These studies demonstrate that effects of kappa-opioid receptor recognition site conformation are unlikely to explain the clinically observed synergy between local anaesthetics and opioids.

Movement disorders associated with withdrawal from high-dose intravenous haloperidol therapy in delirious ICU patients.

Intravenous haloperidol is recommended as the drug of choice to treat delirium in ICU patients. Movement disorders and other adverse events commonly occur with oral haloperidol use but are rarely seen with IV haloperidol use, and withdrawal symptoms have not been reported with short-term ICU use. We describe self-limited dyskinesia during withdrawal of high-dose continuous IV haloperidol therapy in five ICU patients.

Mu-, delta-, kappa-opioid receptors and their subtypes. A critical review with emphasis on radioligand binding experiments.

Since the early 1970's, when specific binding sites for opiates were first described, there has been a vast literature on opiate receptors, their subtypes, and even the multiplicity of these subtypes. In the present review, the signal transduction pathways, structure, and brain and spinal cord localization of the established subtypes (mu, delta, kappa) are reviewed. In addition, evidence suggesting heterogeneity of these subtypes, in particular from radioligand binding studies, is discussed critically.

Validating the Sedation-Agitation Scale with the Bispectral Index and Visual Analog Scale in adult ICU patients after cardiac surgery.

OBJECTIVE: To validate the Sedation-Agitation Scale (SAS) with the Visual Analog Scale (VAS) and Bispectral Index (BIS) in adult ICU patients after cardiac surgery. DESIGN: Prospective study comparing blinded evaluations of the SAS, VAS and BIS. SETTING: Forty-two-bed multidisciplinary ICU. PATIENTS AND PARTICIPANTS: Convenience sample of 39 adults after cardiac surgery. MEASUREMENTS AND RESULTS: Bispectral Index 3.2 was continuously recorded using the Aspect A-1000 and evaluators were blinded to this value. The bedside nurse and a trained researcher independently rated wakefulness using a 100 mm VAS upon patient arrival on the ICU, at first awakening, when ventilator weaning was started and after extubation; the researcher also evaluated patients using SAS. Upon arrival on the ICU, the median SAS score was 2 (interquartile range = 1-3), the mean VAS was 26+/-30 and the mean BIS was 70+/-16. Twenty-four patients underwent a trial of weaning from mechanical ventilation with a SAS of 4 (IQR = 4), VAS of 86+/-12 and BIS of 87+/-10. SAS correlated well with VAS performed by one researcher (r = 0.91, p < 0.001) or by 19 different bedside nurses (r = 0.43, p < 0.001) and with BIS 3.2 (r = 0.60, p < 0.001). The correlation between SAS and BIS was reduced in patients with above average electromyogram (EMG) power. As a measure of construct validity, significant differences were noted for the BIS, SAS, VAS and EMG between ICU arrival and extubation (all p < 0.001). CONCLUSIONS: Sedation-Agitation Scale and BIS are valid measures of wakefulness after cardiac surgery, but EMG interference may affect the accuracy of BIS for a small percentage of patients not receiving neuromuscular blockade.

Characterization of [125I]AR-M100613, a high-affinity radioligand for delta opioid receptors.

AR-M100613 ([I]-Dmt-c[-D-Orn-2-Nal-D-Pro-D-Ala-]) is the iodinated analog of a cyclic casomorphin previously shown to be a potent antagonist at the delta opioid receptor. Specific [125I]AR-M100613 binding to rat whole brain membranes was saturable, reversible, and best fit to a one-site model (Kd = 0.080 +/- 0.008 nM, Bmax = 45.2 +/- 4.4 fmol/mg protein). [125I]AR-M100613 binding was displaced with high affinity by the delta opioid receptor ligands SNC-80, Deltorphin II and DPDPE but not the mu or kappa-selective receptor ligands DAMGO and U69593. Residual non-selective binding of [125I]AR-M 100613 to mu opioid receptors is blocked by the addition of CTOP to the assay buffer. [35S]GTPgammaS binding assays indicate that AR-M100613 is a potent, selective, and reversible antagonist for delta opioid receptors in rat brain membranes. The high-affinity, high specific activity, low nonspecific binding and antagonist profile of [125I]AR-M100613 favor its use as a radiochemical probe for delta opioid receptors.

The frequency and cost of patient-initiated device removal in the ICU.

OBJECTIVE: To determine the frequency and pattern with which patients in the intensive care unit (ICU) remove medical devices on their own, and the costs associated with this problem. DESIGN: Prospective observational study. SETTING: Two 10-bed sections of a multidisciplinary ICU in a tertiary care teaching hospital. PATIENTS: Adults admitted to the ICU for longer than 24 hours during October 1998. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed prospectively for the occurrence of patient-initiated device removal and the responses to those events by health care providers. Associated costs were estimated using hospital databases and Medicare physician reimbursement schedules. Annual cost estimates were calculated using 1997 admission statistics for 1211 adults in an ICU for more than 24 hours. Thirty-six patients were studied for 199 patient-days. Ten patients (28%) removed 42 devices: 88% of these events involved gastrointestinal tubes and vascular catheters. Significant agitation was documented within 2 hours before 74% of the events. Estimated cost associated with device removal was $7606, or $181/event. The estimated annual cost in this 42-bed ICU was more than $250,000. CONCLUSIONS: Patients commonly remove medical devices on their own, and this represents significant consumption of health care resources.

Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU.

STUDY OBJECTIVE: To study the frequency, duration, severity, and treatment of agitation in patients in the intensive care unit (ICU) to determine if the elderly represent a distinct population. DESIGN: Prospective cohort study SETTING: Tertiary care, 10-bed, multidisciplinary ICU. PATIENTS: All patients older than 18 years of age admitted for longer than 24 hours during a 4-month period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty patients were studied for 916 patient-days; 63 (48%) were elderly (> 65 yrs). Nurses and physicians described agitated behavior in 92 patients (70.8%) during 534 (58.3%) patient-days, and it was severe or dangerous in 60 patients (46.1%) during 273 (30%) patient-days. There were no age-related differences in frequency, severity, and duration of agitation. Opiates, benzodiazepines, and haloperidol were administered during 72%, 62%, and 29% of agitated patient-days, respectively. Haloperidol was administered more often to elderly patients (p=0.015); otherwise no between-group differences were noted. Daily dosing requirements were less in the elderly for intermittent intravenous lorazepam, haloperidol, and morphine but not for midazolam (p=0.15). When these dosages were corrected for body mass, no statistical differences between young and old were found. CONCLUSION: In the ICU, the elderly are not a distinct population for agitation.

The effects of delta agonists on locomotor activity in habituated and non-habituated rats.

The effects of the delta agonists SNC80 and deltorphin II on ambulation and rearing activity were measured in habituated and non-habituated rats. SNC80 (30, 100, 200, 400 nmol, i.c.v.) and deltorphin II (3, 15, 30, 60 nmol, i.c.v.) induced similar, dose-dependent biphasic locomotor effects in non-habituated subjects. An initial decrease in exploratory activity was associated with anxiogenic signs such as pilo-erection, freezing behaviour and pupil dilation for each drug. Pre-treatment with the delta antagonist naltrindole (10 nmol, i.c.v.) inhibited the depressant effect, but not the subsequent stimulant effect, on locomotor activity in response to 30 nmol deltorphin II in this assay (P<0.05). In habituated rats, deltorphin II (0.03, 0.1, 0.3, 3 nmol, i.c.v.) caused significant, naltrindole-reversible increases in locomotor activity (P<0.05 for all doses) at 1,000-fold lower doses than those required for a similar response to SNC80 (10, 30, 100, 300 nmol, i.c.v.). Pharmacokinetic studies suggest that these compounds penetrate the brain to similar extents following i.c.v. injection. The substantial potency difference between deltorphin II and SNC80 in stimulating locomotor activity in habituated rats suggests pharmacological heterogeneity for these delta opioid receptor agonists.

Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: is HPTP an intermediate?

The metabolism of haloperidol (HP) to the potentially neurotoxic pyridinium species, HPP+ and RHPP+, has been demonstrated in humans. In vitro studies in microsomes harvested from various animal species indicate that the tetrahydropyridines, HPTP and RHPTP, could be intermediates in this pathway. However, this has not yet been demonstrated in vivo in humans. In this study, plasma and urine collected from eight critically ill patients treated with high doses of intravenous HP were analyzed for HPTP and RHPTP using HPLC with electrochemical detection. However, neither HPTP nor RHPTP were detected despite plasma concentrations of HP and RHP higher than any previously reported. HPP+ and RHPP+ were both present in the urine in high concentrations and accounted for 1.1 +/- 0.5% and 5.3 +/- 3.6%, respectively, of the administered dose of HP. The apparent elimination half-lives of HPP+ and RHPP+ were 67.3 +/- 11.0 hr and 63.3 +/- 11.6 hr, respectively. The absence of HPTP and RHPTP in plasma and urine suggests that in humans these tetrahydropyridines either are insignificant intermediates in the metabolism of HP in vivo or are present only transiently at their site of formation and are not released into the circulation.