Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke

Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n=14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors

Can abuse deterrent formulations make a difference? Expectation and speculation

It is critical that issues surrounding the abuse and misuse of prescription opioids be balanced with the need for these medications for the treatment of pain. One way to decrease the abuse of prescription opioid medications is to develop abuse deterrent formulations (or ADFs) that in some way prevent drug abusers from extracting out the active ingredient in order to employ alternate routes of administration, such as injection, snorting, and smoking. Several factors including the pharmacokinetic profile of the drug, the features of the drug formulation that make it attractive or unattractive for abuse, the type of drug abuser, the progression of one's addiction pathway, and one's social environment may all play a role in the abuse of prescription opioids and what methods are used to abuse these drugs. This paper will examine these factors in order to understand how they affect the abuse of prescription opioids and routes of administration, and how the development of ADFs may alter these patterns

Strain and Magnetic Fabric in Santa Catalina and Pinaleno Mountains Metamorphic- Core-Complexes Mylonite Zones, Arizona

Anisotropy of magnetic susceptibility (AMS) is capable of recording finite strain in weakly magnetized rocks. AMS was measured for 228 samples from 20 sites in two mylonite zones with the same deformational history. AMS measurements were compared with finite strains determined from dike rotations and from foliation orientations. In one zone (the Santa Catalina Mountains) the orientations of susceptibility and finite strain ellipsoids are in excellent agreement, and there is a logarithmic relationship between susceptibility difference (ΔKi = [Ki-K]/K) and finite strain magnitude. In the second zone (the Pinaleno Mountains) minimum susceptibility is perpendicular to the finite flattening plane, but the maximum susceptibility does not parallel the maximum extension direction, and there is no systematic relationship between susceptibility magnitude and strain magnitude. Oriented polished thin sections indicate that magnetite in the protolith of the Santa Catalina mylonite occurs as randomly oriented, elongate grains. With subsequent deformation, the long axes are rotated into the maximum extension direction. In the Pinaleno mylonites, both equant and elongate magnetite grains are present. With deformation, the elongate magnetite grains are rotated into the maximum flattening plane but show no preferred orientation within this plane. AMS in the two mylonite zones appears to be predominantly controlled by the orientation of elongate magnetite grains with respect to the megascopic fabric. The final orientation of the elongate grains is a function of their initial orientation as well as the finite strain. Therefore, despite similar deformational histories, the two zones display different AMS patterns due to the differences in occurrence, initial orientation, and shape of ferromagnetic grains

The effect of exogenous glucose infusion on early embryonic development in lactating dairy cows

peer-reviewedThe objective of this study was to examine the effect of intravenous infusion of glucose on early embryonic development in lactating dairy cows. Nonpregnant, lactating dairy cows (n = 12) were enrolled in the study (276 ± 17 d in milk). On d 7 after a synchronized estrus, cows were randomly assigned to receive an intravenous infusion of either 750 g/d of exogenous glucose (GLUC; 78 mL/h of 40% glucose wt/vol) or saline (CTRL; 78 mL/h of 0.9% saline solution). The infusion period lasted 7 d and cows were confined to metabolism stalls for the duration of the study. Coincident with the commencement of the infusion on d 7 after estrus, 15 in vitro-produced grade 1 blastocysts were transferred into the uterine horn ipsilateral to the corpus luteum. All animals were slaughtered on d 14 to recover conceptuses, uterine fluid, and endometrial tissue. Glucose infusion increased circulating glucose concentrations (4.70 ± 0.12 vs. 4.15 ± 0.12 mmol/L) but did not affect milk production or dry matter intake. Circulating β-hydroxybutyrate concentrations were decreased (0.51 ± 0.01 vs. 0.70 ± 0.01 mmol/L for GLUC vs. CTRL, respectively) but plasma fatty acids, progesterone, and insulin concentrations were unaffected by treatment. Treatment did not affect either uterine lumen fluid glucose concentration or the mRNA abundance of specific glucose transporters in the endometrium. Mean conceptus length, width, and area on d 14 were reduced in the GLUC treatment compared with the CTRL treatment. A greater proportion of embryos in the CTRL group had elongated to all length cut-off measurements between 11 and 20 mm (measured in 1-mm increments) compared with the GLUC treatment. In conclusion, infusion of glucose into lactating dairy cows from d 7 to d 14 post-estrus during the critical period of conceptus elongation had an adverse impact on early embryonic development

A comparison of 4 predictive models of calving assistance and difficulty in dairy heifers and cows

peer-reviewedThe aim of this study was to build and compare predictive models of calving difficulty in dairy heifers and cows for the purpose of decision support and simulation modeling. Models to predict 3 levels of calving difficulty (unassisted, slight assistance, and considerable or veterinary assistance) were created using 4 machine learning techniques: multinomial regression, decision trees, random forests, and neural networks. The data used were sourced from 2,076 calving records in 10 Irish dairy herds. In total, 19.9 and 5.9% of calving events required slight assistance and considerable or veterinary assistance, respectively. Variables related to parity, genetics, BCS, breed, previous calving, and reproductive events and the calf were included in the analysis. Based on a stepwise regression modeling process, the variables included in the models were the dam's direct and maternal calving difficulty predicted transmitting abilities (PTA), BCS at calving, parity; calving assistance or difficulty at the previous calving; proportion of Holstein breed; sire breed; sire direct calving difficulty PTA; twinning; and 2-way interactions between calving BCS and previous calving difficulty and the direct calving difficulty PTA of dam and sire. The models were built using bootstrapping procedures on 70% of the data set. The held-back 30% of the data was used to evaluate the predictive performance of the models in terms of discrimination and calibration. The decision tree and random forest models omitted the effect of twinning and included only subsets of sire breeds. Only multinomial regression and neural networks explicitly included the modeled interactions. Calving BCS, calving difficulty PTA, and previous calving assistance ranked as highly important variables for all 4 models. The area under the receiver operating characteristic curve (ranging from 0.64 to 0.79) indicates that all of the models had good overall discriminatory power. The neural network and multinomial regression models performed best, correctly classifying 75% of calving cases and showing superior calibration, with an average error in predicted probability of 3.7 and 4.5%, respectively. The neural network and multinomial regression models developed are both suitable for use in decision-support and simulation modeling

Abuse risks and routes of administration of different prescription opioid compounds and formulations

<p>Abstract</p> <p>Background</p> <p>Evaluation of tamper resistant formulations (TRFs) and classwide Risk Evaluation and Mitigation Strategies (REMS) for prescription opioid analgesics will require baseline descriptions of abuse patterns of existing opioid analgesics, including the relative risk of abuse of existing prescription opioids and characteristic patterns of abuse by alternate routes of administration (ROAs). This article presents, for one population at high risk for abuse of prescription opioids, the unadjusted relative risk of abuse of hydrocodone, immediate release (IR) and extended release (ER) oxycodone, methadone, IR and ER morphine, hydromorphone, IR and ER fentanyl, IR and ER oxymorphone. How relative risks change when adjusted for prescription volume of the products was examined along with patterns of abuse via ROAs for the products.</p> <p>Methods</p> <p>Using data on prescription opioid abuse and ROAs used from 2009 Addiction Severity Index-Multimedia Version (ASI-MV^®) Connect assessments of 59,792 patients entering treatment for substance use disorders at 464 treatment facilities in 34 states and prescription volume data from SDI Health LLC, unadjusted and adjusted risk for abuse were estimated using log-binomial regression models. A random effects binary logistic regression model estimated the predicted probabilities of abusing a product by one of five ROAs, intended ROA (i.e., swallowing whole), snorting, injection, chewing, and other.</p> <p>Results</p> <p>Unadjusted relative risk of abuse for the 11 compound/formulations determined hydrocodone and IR oxycodone to be most highly abused while IR oxymorphone and IR fentanyl were least often abused. Adjusting for prescription volume suggested hydrocodone and IR oxycodone were least often abused on a prescription-by-prescription basis. Methadone and morphine, especially IR morphine, showed increases in relative risk of abuse. Examination of the data without methadone revealed ER oxycodone as the drug with greatest risk after adjusting for prescription volume. Specific ROA patterns were identified for the compounds/formulations, with morphine and hydromorphone most likely to be injected.</p> <p>Conclusions</p> <p>Unadjusted risks observed here were consistent with rankings of prescription opioid abuse obtained by others using different populations/methods. Adjusted risk estimates suggest that some, less widely prescribed analgesics are more often abused than prescription volume would predict. The compounds/formulations investigated evidenced unique ROA patterns. Baseline abuse patterns will be important for future evaluations of TRFs and REMS.</p

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006.

BackgroundMucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319).MethodsPatients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1.Results1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients.ConclusionPembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab

Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers

BACKGROUND: The growing trends in opioid abuse, assessment of the abuse liability of prescription opioid products, and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. METHODS: First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. RESULTS: A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's α = 0.85–0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p < 0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65–0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC = 0.83, p = 0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). CONCLUSION: An initial examination of the psychometric properties of the OAS suggests that it is a valid and reliable scale. The OAS may be useful in providing important guidance on product features that are attractive to potential abusers