The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1ß and IL-10 expression from immune cell culture.

During the onset of neuropathic pain from a variety of etiologies, nociceptors become hypersensitized, releasing neurotransmitters and other factors from centrally-projecting nerve terminals within the dorsal spinal cord. Consequently, glial cells (astrocytes and microglia) in the spinal cord are activated and mediate the release of proinflammatory cytokines that act to enhance pain transmission and sensitize mechanical non-nociceptive fibers which ultimately results in light touch hypersensitivity, clinically observed as allodynia. Pramipexole, a D2/D3 preferring agonist, is FDA-approved for the treatment of Parkinson's disease and demonstrates efficacy in animal models of inflammatory pain. The clinical-stage investigational drug, R(+) enantiomer of pramipexole, dexpramipexole, is virtually devoid of D2/D3 agonist actions and is efficacious in animal models of inflammatory and neuropathic pain. The current experiments focus on the application of a mouse model of sciatic nerve neuropathy, chronic constriction injury (CCI), that leads to allodynia and is previously characterized to generate spinal glial activation with consequent release IL-1ß. We hypothesized that both pramipexole and dexpramipexole reverse CCI-induced chronic neuropathy in mice, and in human monocyte cell culture studies (THP-1 cells), pramipexole prevents IL-1ß production. Additionally, we hypothesized that in rat primary splenocyte culture, dexpramixole increases mRNA for the anti-inflammatory and pleiotropic cytokine, interleukin-10 (IL-10). Results show that following intravenous pramipexole or dexpramipexole, a profound decrease in allodynia was observed by 1 hr, with allodynia returning 24 hr post-injection. Pramipexole significantly blunted IL-1ß protein production from stimulated human monocytes and dexpramipexole induced elevated IL-10 mRNA expression from rat splenocytes. The data support that clinically-approved compounds like pramipexole and dexpramipexole support their application as anti-inflammatory agents to mitigate chronic neuropathy, and provide a blueprint for future, multifaceted approaches for opioid-independent neuropathic pain treatment.

Substituent effects on the UV-visible spectrum and excited electronic states of dithiocarboxylates.

The absorption spectra of a series of dithiocarboxylates were investigated in the ultraviolet-visible region. Two questions that this study aimed to address were as follows: (1) What transitions give rise to the features in the electronic spectra? And (2) what are the long- and short-range substituent effects on the absorption spectra? A series of 11 dithiocarboxylates were prepared as organic soluble salts. Time-dependent density functional theory (TDDFT) was used to calculate excited state energies and oscillator strengths of electronic transitions. TDDFT at the CAM-B3LYP/def2-TZVPD level of theory predicts two low-energy n → π* transitions and two π → π* transitions at higher energy, consistent with the experimental spectra. This state ordering and density is in contrast to the better studied thiocarbonyls for which only two transitions within the singlet manifold appear in the UV-visible region. For derivatives of dithiobenzoate, the energy of the three lowest energy states are insensitive to changes to substituents para to the dithiocarboxylate group. In contrast, the energy of the highest ππ* state varies by 0.78 eV. This work shows that the results of TDDFT calculations can be used to predict the electronic absorption spectra of dithiocarboxylates, providing a useful tool for designing dithiocarboxylate light absorbers.

The role for intra-arterial chemotherapy for refractory retinoblastoma: a systematic review

Background Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma. Methods We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma. Results Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7–74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%). Conclusions Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice (AU)

The role for intra-arterial chemotherapy for refractory retinoblastoma: a systematic review.

BACKGROUND: Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma. METHODS: We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma. RESULTS: Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7-74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%). CONCLUSIONS: Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice.

Stable, Well-Defined Nickel(0) Catalysts for Catalytic C-C and C-N Bond Formation.

The synthesis and catalytic activity of several classes of NHC-Ni(0) pre-catalysts stabilized by electron-withdrawing alkenes are described. Variations in the structure of fumarate and acrylate ligands modulate the reactivity and stability of the NHC-Ni(0) pre-catalysts and lead to practical and versatile catalysts for a variety of transformations. The catalytic activity and efficiency of representative members of this class of catalysts have been evaluated in reductive couplings of aldehydes and alkynes and in N-arylations of aryl chlorides.

Using Expectancy Theory to quantitatively dissociate the neural representation of motivation from its influential factors in the human brain: An fMRI study.

Researchers have yet to apply a formal operationalized theory of motivation to neurobiology that would more accurately and precisely define neural activity underlying motivation. We overcome this challenge with the novel application of the Expectancy Theory of Motivation to human fMRI to identify brain activity that explicitly reflects motivation. Expectancy Theory quantitatively describes how individual constructs determine motivation by defining motivation force as the product of three variables: expectancy - belief that effort will better performance; instrumentality - belief that successful performance leads to particular outcome, and valence - outcome desirability. Here, we manipulated information conveyed by reward-predicting cues such that relative cue-evoked activity patterns could be statistically mapped to individual Expectancy Theory variables. The variable associated with activity in any voxel is only reported if it replicated between two groups of healthy participants. We found signals in midbrain, ventral striatum, sensorimotor cortex, and visual cortex that specifically map to motivation itself, rather than other factors. This is important because, for the first time, it empirically clarifies approach motivation neural signals during reward anticipation. It also highlights the effectiveness of the application of Expectancy Theory to neurobiology to more precisely and accurately probe motivation neural correlates than has been achievable previously.

Stabilization of axisymmetric liquid bridges through vibration-induced pressure fields.

Previous theoretical studies have indicated that liquid bridges close to the Plateau-Rayleigh instability limit can be stabilized when the upper supporting disk vibrates at a very high frequency and with a very small amplitude. The major effect of the vibration-induced pressure field is to straighten the liquid bridge free surface to compensate for the deformation caused by gravity. As a consequence, the apparent Bond number decreases and the maximum liquid bridge length increases. In this paper, we show experimentally that this procedure can be used to stabilize millimeter liquid bridges in air under normal gravity conditions. The breakup of vibrated liquid bridges is examined experimentally and compared with that produced in absence of vibration. In addition, we analyze numerically the dynamics of axisymmetric liquid bridges far from the Plateau-Rayleigh instability limit by solving the Navier-Stokes equations. We calculate the eigenfrequencies characterizing the linear oscillation modes of vibrated liquid bridges, and determine their stability limits. The breakup process of a vibrated liquid bridge at that stability limit is simulated too. We find qualitative agreement between the numerical predictions for both the stability limits and the breakup process and their experimental counterparts. Finally, we show the applicability of our technique to control the amount of liquid transferred between two solid surfaces.

Using "big data" to guide implementation of a web and mobile adaptive learning platform for medical students.

BACKGROUND: Adaptive learning platforms (ALPs) can revolutionize medical education by making learning more efficient, but their potential has not been realized because students do not use them persistently. METHODS: We applied educational data mining methods to study United States medical students who used an ALP called Osmosis ( www.osmosis.org ) from 1 August 2014 to 31 July 2015. Multivariate logistic regressions modeled persistence on Osmosis as the dependent variable and Osmosis-collected variables as predictors. RESULTS: The 6787 students included in our analysis responded to a total of 887,193 items, with 2138 (31.5%) using Osmosis persistently. Number of items per student, mobile device use, subscription payment, and group membership were independently associated with persisting (p < 0.001 in all models). Persistent users rated quality more favorably (p < 0.01) but were not more confident in answer selections (p = 0.80). While persisters were more accurate than non-persisters (55% (SD 18%) vs 52% (SD 22%), p < 0.001), after adjusting for number of items, lower accuracy was associated with persistent use (OR 0.93 [95% CI 0.90-0.97], p < 0.01). CONCLUSIONS: Our study of a large sample of U.S. medical students illustrates big data medical education research and provides guidance for improving implementation of ALPs and further investigation.

Success rates for product development strategies in new drug development.

WHAT IS KNOWN AND OBJECTIVE: While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. METHODS: We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. RESULTS AND DISCUSSION: Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008). These differences are statistically significant. WHAT IS NEW AND CONCLUSION: The primary contribution of this study is that product development strategies combining experience with drugs and indications strategies are the most likely to reach the market, even though they are least common strategy. Therefore, combined experience strategies remain underutilized. The findings also suggest a promising path for pursuing combined experience strategies: gaining expertise with drugs is likely to be a more effective path to gaining the expertise necessary for developing subsequent recombination strategies.

Using Commercial Activity Monitors to Measure Gait in Patients with Suspected iNPH: Implications for Ambulatory Monitoring.

OBJECTIVES: This study seeks to validate the use of activity monitors to detect and record gait abnormalities, potentially identifying patients with idiopathic normal pressure hydrocephalus (iNPH) prior to the onset of cognitive or urinary symptoms. METHODS: This study compared the step counts of four common activity monitors (Omron Step Counter HJ-113, New Lifestyles 2000, Nike Fuelband, and Fitbit Ultra) to an observed step count in 17 patients with confirmed iNPH. RESULTS: Of the four devices, the Fitbit Ultra (Fitbit, Inc., San Francisco, CA) provided the most accurate step count. The correlation with the observed step count was significantly higher (p<0.009) for the Fitbit Ultra than for any of the other three devices. CONCLUSIONS: These preliminary findings suggest that existing activity monitors have variable efficacy in the iNPH patient population and that the MEMS tri-axial accelerometer and algorithm of the Fitbit Ultra provides the most accurate gait measurements of the four devices tested.

Dimer involvement and origin of crossover in nickel-catalyzed aldehyde-alkyne reductive couplings.

The mechanism of nickel(0)-catalyzed reductive coupling of aldehydes and alkynes has been studied. Extensive double-labeling crossover studies have been conducted. While previous studies illustrated that phosphine- and N-heterocyclic carbene-derived catalysts exhibited differing behavior, the origin of these effects has now been evaluated in detail. Many variables, including ligand class, sterics of the ligand and alkyne, temperature, and ring size being formed in intramolecular versions, all influence the extent of crossover observed. A computational evaluation of these effects suggests that dimerization of a key metallacyclic intermediate provides the origin of crossover. Protocols that proceed with crossover are typically less efficient than those without crossover given the thermodynamic stability and low reactivity of the dimeric metallacycles involved in crossover pathways.

Assessing the risk of stroke from neck manipulation: a systematic review.

BACKGROUND: Strokes, typically involving vertebral artery dissection, can follow cervical spinal manipulative therapy, and these types of stroke occur rarely. There is disagreement about whether a strong association between neck manipulation and stroke exists. An earlier systematic review found two relevant studies of association that used controls, which also discussed the limitations of the two papers. Our systematic review updates the earlier review, and aims to determine whether conclusive evidence of a strong association exists. METHODS: PRISMA guidelines for systematic reviews were followed, and the literature was searched using a strategy that included the terms 'neck manipulation' and 'stroke' from the PubMed, Embase, CINAHL Plus and AMED databases. Citations were included if they met criteria such as being case-control studies, and dealt with neck manipulation and/or neck movement/positioning. Papers were scored for their quality, using similar criteria to the earlier review. For individual criteria, each study was assigned a full positive score if the criterion was satisfied completely. RESULTS: Four case-control studies and one case-control study, which included a case- crossover design, met the selection criteria, but all of them had at least three items in the quality assessment that failed to be completely positive. Two studies were assessed to be the most robustly designed, one indicating a strong association between stroke and various intensities of neck movement, including manipulation, and the other suggesting a much reduced relative association when using primary care practitioners' visits as controls. However, potential biases and confounders render the results inconclusive. CONCLUSION: Conclusive evidence is lacking for a strong association between neck manipulation and stroke, but is also absent for no association. Future studies of association will need to minimise potential biases and confounders, and ideally have sufficient numbers of cases to allow subgroup analysis for different types of neck manipulation and neck movement.

Subjective socioeconomic status predicts human ventral striatal responses to social status information.

The enormous influence of hierarchical rank on social interactions [1] suggests that neural mechanisms exist to process status-related information [2] and ascribe value to it. The ventral striatum is prominently implicated in processing value and salience, independent of hedonic properties [3, 4], and a functional magnetic resonance imaging (fMRI) study of social status perception in humans demonstrated that viewing higher-ranked compared to lower-ranked individuals evokes a ventral striatal response [5], indicative of a greater assignment of value/salience to higher status. Consistent with this interpretation, nonhuman primates value information associated with higher-ranked conspecifics more than lower-ranked, as illustrated using a choice paradigm in which monkeys preferentially take the opportunity to view high-status monkeys [6]. Interestingly, this status-related value assignment in nonhuman primates is influenced by one's own hierarchical rank: high-status monkeys preferentially attend to conspecifics of high status, whereas low-status monkeys will also attend to other low-status monkeys [7]. Complementary to these findings, using fMRI and a social status judgment task in humans, we suggest a neurobiological mechanism by which one's own relative hierarchical rank influences the value attributed to particular social status information by demonstrating that one's subjective socioeconomic status differentially influences ventral striatal activity during processing of status-related information.

Phosphine-catalyzed reductions of alkyl silyl peroxides by titanium hydride reducing agents: development of the method and mechanistic investigations.

A method that allows for the reduction of protected hydroperoxides by employing catalytic amounts of phosphine is presented. The combination of a titanium(IV) alkoxide and a siloxane allowed for the chemoselective reduction of phosphine oxides in the presence of alkyl silyl peroxides. Subsequent reduction of the peroxide moiety by phosphine provided the corresponding silylated alcohols in useful yields. Mechanistic experiments, including crossover experiments, support a mechanism in which the peroxide group was reduced and the silyl group was transferred in a concerted step. Labeling studies with (17)O-labeled peroxides demonstrate that the oxygen atom adjacent to the silicon atom is removed from the silyl peroxide.

Stereotactic fields shaped with a micro-multileaf collimator: systematic characterization of peripheral dose.

Despite the highly localized doses that may be delivered via stereotactic radiotherapy, a small dose is nonetheless delivered to out-of-field regions, which may cause detriment to the patient. In this work, a systematic set of dose measurements have been undertaken up to a distance of 45 cm from the isocentre, for stereotactic fields shaped by a BrainLAB mini-multileaf collimator (MMLC) mounted on a Varian 600C linear accelerator. A range of treatment parameters were varied so as to determine the factors of greatest influence and establish relationships with dose. The commercial treatment planning software (TPS) miscalculates the dose to out-of-field regions. Measured dose decreases consistently out to 45 cm, whereas the TPS decreases out to 10-15 cm, at which point the predicted dose is constant. At the 5-10 cm off-axis distance (OAD), measurements indicate doses of about 5-10% of the dose at the isocentre, 1% at 15 cm OAD and 0.1% at 45 cm OAD. There are several observed trends. Greater MMLC field sizes (with static jaw) result in higher out-of-field dose, as do shallower depths. The source-to-surface distance does not greatly influence peripheral dose. However, the results given in this work do indicate that simple treatment arrangements, such as preferable collimator rotation, would in certain cases reduce out-of-field dose by an order of magnitude. Peripheral dose raises questions of treatment optimization, particularly in cases where patients have a long life expectancy in which secondary effects may become manifest, such as in the treatment of paediatric patients or those with a non-malignant primary. For instance, for a 20 Gy hypo-fractionated treatment, dose to out-of-field regions is of the order of cGy-a substantial dose in radiation protection terms.

Improved hospital-level risk adjustment for surveillance of healthcare-associated bloodstream infections: a retrospective cohort study.

BACKGROUND: To allow direct comparison of bloodstream infection (BSI) rates between hospitals for performance measurement, observed rates need to be risk adjusted according to the types of patients cared for by the hospital. However, attribute data on all individual patients are often unavailable and hospital-level risk adjustment needs to be done using indirect indicator variables of patient case mix, such as hospital level. We aimed to identify medical services associated with high or low BSI rates, and to evaluate the services provided by the hospital as indicators that can be used for more objective hospital-level risk adjustment. METHODS: From February 2001-December 2007, 1719 monthly BSI counts were available from 18 hospitals in Queensland, Australia. BSI outcomes were stratified into four groups: overall BSI (OBSI), Staphylococcus aureus BSI (STAPH), intravascular device-related S. aureus BSI (IVD-STAPH) and methicillin-resistant S. aureus BSI (MRSA). Twelve services were considered as candidate risk-adjustment variables. For OBSI, STAPH and IVD-STAPH, we developed generalized estimating equation Poisson regression models that accounted for autocorrelation in longitudinal counts. Due to a lack of autocorrelation, a standard logistic regression model was specified for MRSA. RESULTS: Four risk services were identified for OBSI: AIDS (IRR 2.14, 95% CI 1.20 to 3.82), infectious diseases (IRR 2.72, 95% CI 1.97 to 3.76), oncology (IRR 1.60, 95% CI 1.29 to 1.98) and bone marrow transplants (IRR 1.52, 95% CI 1.14 to 2.03). Four protective services were also found. A similar but smaller group of risk and protective services were found for the other outcomes. Acceptable agreement between observed and fitted values was found for the OBSI and STAPH models but not for the IVD-STAPH and MRSA models. However, the IVD-STAPH and MRSA models successfully discriminated between hospitals with higher and lower BSI rates. CONCLUSION: The high model goodness-of-fit and the higher frequency of OBSI and STAPH outcomes indicated that hospital-specific risk adjustment based on medical services provided would be useful for these outcomes in Queensland. The low frequency of IVD-STAPH and MRSA outcomes indicated that development of a hospital-level risk score was a more valid method of risk adjustment for these outcomes.