Orangutans' Comprehension of Zoo Keepers' Communicative Signals.

Zoological institutions often encourage cooperative interactions between keepers and animals so as to promote animals' welfare. One useful technique has been conditioning training, whereby animals learn to respond to keepers' requests, which facilitates a number of, otherwise sensitive, daily routines. As various media have been used to convey keepers' instructions, the question remains of which modality is best to promote mutual understanding. Here, we explored this question with two captive female orangutans. In the first experiment, we compared orangutans' understanding of previously acquired instructions when those were performed with verbal signals only, gazes only, gestures only, and when all those modalities were combined. Our results showed that gestures were sufficient for successful comprehension by these two apes. In the second experiment, we asked whether this preference could be driven by the non-arbitrary relationship that gestures bear to what they refer to, through iconicity or pointing. Our results revealed that neither iconicity nor pointing helped the subjects comprehend the keepers' instructions. Our results indicate a preference for instructions given through gestural signals in two captive female orangutans, although its cause remains elusive. Future practice may encourage the use of gestures in communication between keepers and orangutans in general or potentially other animals.

Comparative analysis of methods for real-time analytical control of chemotherapies preparations.

Control of chemotherapies preparations are now an obligation in France, though analytical control is compulsory. Several methods are available and none of them is presumed as ideal. We wanted to compare them so as to determine which one could be the best choice. We compared non analytical (visual and video-assisted, gravimetric) and analytical (HPLC/FIA, UV/FT-IR, UV/Raman, Raman) methods thanks to our experience and a SWOT analysis. The results of the analysis show great differences between the techniques, but as expected none us them is without defects. However they can probably be used in synergy. Overall for the pharmacist willing to get involved, the implementation of the control for chemotherapies preparations must be widely anticipated, with the listing of every parameter, and remains according to us an analyst's job.

Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice.

BACKGROUND: Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub potency adverse events in patients or malfunctions in the pump itself. OBJECTIVE: The purpose of this study is to evaluate the accuracy of compounding of intrathecal admixtures through a prospective, systematic quantitative analysis of each component of the mixture before delivery to patients. STUDY DESIGN: Observational follow up prospective study of intrathecal mixtures components concentrations before refills. SETTINGS: Assays were performed on all intrathecal admixtures produced by the ICO-Paul Papin compounding pharmacy between January 2013 and October 2014 using Ultra High Performance Liquid Chromatography (U.H.P.L.C.). In addition, pH levels of admixtures have been measured since June 2014. When measured concentrations were 15% above or below the required concentrations, the mixture was excluded and compounded again. RESULTS: 1729 mixtures were analyzed. Mean deviation from theoretical values was -1.17% ± 0.28% for morphine, -0.95% ± 1.07% for ropivacaine, and 4.82% ± 0.6% for ziconotide. Exclusion rates were 8.33% overall, but fell from 11.67% in 2013 to 4.97% in 2014. Most exclusions were caused by inaccuracy in the dose of ziconotide. Average mixture pH of the 603 tested admixtures was 4.83 ± 0.6%. LIMITATIONS: This study is monocentric and limitations include also its non-randomized nature with no clinical comparison of the rate of adverse events with a refill process without control of each component concentrations. CONCLUSION: Prospective assays provide benefits in ensuring accuracy of intrathecal mixture compounding and in preventing overdosing or sub dosing, most notably concerning Ziconotide.

Influence of pH and temperature on ziconotide stability in intrathecal analgesic admixtures in implantable pumps and syringes.

PURPOSE: The aim of our study was to investigate the influence of pH and temperature on the stability of ziconotide in analgesic admixtures containing morphine and ropivacaine. METHODS: All admixtures were combined using a wide range of concentrations, in implantable pumps and syringes, using temperatures from 4°C to 37°C. Quantification was made thanks to a specific chromatographic technique. pH has also been measured throughout the study. RESULTS: Admixtures confirm excellent stability for morphine and ropivacaine. Concerning ziconotide, an acid hydrolysis has been observed, reducing the time of use of our admixtures in a significant way, but producing non-toxic degradation products. The degradation was linear in all conditions. Inside the implantable pumps at body temperature turned out to be the best conditions for lower protein breakdown. Finally the degradation process showed a high correlation with the pH and the morphine concentration with a median loss of concentration delay due to degradation of 3.5 days [3; 5] when pH<4.5 and 13 days [13; 24] when pH ≥ 4.5. CONCLUSION: Our admixtures showed different stability depending on the drug concentrations, pH and temperature. The great majority of mixtures in real life in our institution have stability highly compatible with our practice and with the delay between two pump refilling.

Retreatment with TACE: the ABCR SCORE, an aid to the decision-making process.

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) and it is the most commonly used treatment for HCC worldwide. However, no prognostic indices, designed to select appropriate candidates for repeat conventional TACE, have been incorporated in the guidelines. METHODS: From January 2007 to April 2012, 139 consecutive HCC patients, mainly with an alcohol- or viral-induced disease, were treated with TACE. Using a regression model on the prognostic variables of our population, we determined a score designed to help for repeat TACE and we validated it in two cohorts. We also compared it to the ART score. RESULTS: In the multivariate analysis, four prognostic factors were associated with overall survival: BCLC and AFP (>200 ng/ml) at baseline, increase in Child-Pugh score by ⩾2 from baseline, and absence of radiological response. These factors were included in a score (ABCR, ranging from -3 to +6), which correlates with survival and identifies three groups. The ABCR score was validated in two different cohorts of 178 patients and proofed to perform better than the ART score in distinguishing between patients' prognosis. CONCLUSIONS: The ABCR score is a simple and clinically relevant index, summing four prognostic variables endorsed in HCC. An ABCR score ⩾4 prior to the second TACE identifies patients with dismal prognosis who may not benefit from further TACE sessions.

Effects of discontinuing or continuing ongoing statin therapy in severe sepsis and septic shock: a retrospective cohort study.

INTRODUCTION: Recent publications suggest potential benefits from statins as a preventive or adjuvant therapy in sepsis. Whether ongoing statin therapy should be continued or discontinued in patients admitted in the intensive care unit (ICU) for sepsis is open to question. METHODS: We retrospectively compared patients with severe sepsis and septic shock in whom statin therapy had been discontinued or continued. The primary endpoint was the number of organ failure-free days at day 14. Secondary end-points included hospital mortality and safety. The association of statin continuation with outcome was evaluated for crude analysis and after propensity score matching and adjustment. We also measured plasma atorvastatin concentrations in a separate set of ICU septic patients continuing the drug. RESULTS: Patients in whom statin therapy had been continued in the ICU (n = 44) had significantly more organ failure-free days (11 67891011121314 vs. 6 [0-12], mean difference of 2.34, 95%CI from 0.47 to 5.21, P = 0.03) as compared to others (n = 32). However, there were important imbalances between groups, with more hospital-acquired infections, more need for surgery before ICU admission, and a trend towards more septic shock at ICU admission in the discontinuation group. The significant association of statin continuation with organ failure free days found in the crude analysis did not persist after propensity-matching or multivariable adjustment: beta coefficients [95% CI] of 2.37 [-0.96 to 5.70] (P = 0.20) and 2.24 [-0.43 to 4.91] (P = 0.11) respectively. We found particularly high pre-dose and post-dose atorvastatin concentrations in ICU septic patients continuing the drug. CONCLUSIONS: Continuing statin therapy in ICU septic patients was not associated with reduction in the severity of organ failure after matching and adjustment. In addition, the very high plasma concentrations achieved during continuation of statin treatment advocates some caution.

Evaluation of the Architect tacrolimus assay in kidney, liver, and heart transplant recipients.

The narrow therapeutic range of tacrolimus requires therapeutic drug monitoring to prevent transplant rejection and to minimize nephrotoxicity. The aim of this study was to evaluate the analytical performance of the tacrolimus chemiluminescent microparticle immunoassay (CMIA) in everyday practice comparatively with other methods. CMIA imprecision and accuracy were tested using low, medium, and high concentrations in control samples. The limits of quantification (LOQ) of CMIA and antibody-conjugated magnetic immunoassay (ACMIA) were evaluated using negative whole-blood samples containing 0.4-5.7 ng/ml of tacrolimus from a stock solution. CMIA was compared with ACMIA, enzyme multiplied immunoassay (EMIT), and liquid chromatography-tandem mass spectrometry (LC-MS/MS), using 176 samples from recipients (135 men and 41 women) of heart (n=19), kidney (n=107), or liver (n=50) transplants. CMIA total precision was 5.7%, 3.7% and 3.6% with the low-, medium-, and high-concentration controls, respectively; corresponding values for accuracy were 98%, 104%, and 104%. LOQ was 0.5 (95%CI, 0.22-1.38) with CMIA and 2.5 ng/ml with ACMIA. Linear regression results were as follows: CMIA=1.2LC-MS/MS+0.14 (r=0.98); CMIA=0.93EMIT+0.36 (r=0.975); CMIA=1.15ACMIA-0.25 (r=0.988); and, for tacrolimus concentrations in the 1-15 ng/ml range, of special interest as many transplant recipients are given low-dose tacrolimus, CMIA=1.05LC-MS/MS+0.38 (r=0.94). Two patients had falsely elevated tacrolimus concentrations due to interference in the ACMIA assay; one was a renal transplant recipient who stopped her treatment and had tacrolimus concentrations of 12.5 ng/ml by ACMIA and <0.5 ng/ml by CMIA; the other was an HIV-positive renal transplant recipient whose tacrolimus concentrations by ACMIA were 1.8-43.7-fold those by CMIA. Such interferences with ACMIA, which may be related to endogenous antibodies in the plasma, are likely to negatively impact patient care. In conclusion, the tacrolimus CMIA assay is suitable for routine laboratory use and does not suffer from the interferences seen with ACMIA in some patients.

Radiofrequency ablation of unresectable liver tumors: factors associated with incomplete ablation or local recurrence.

BACKGROUND: Radiofrequency ablation (RFA) of liver tumors is associated with a risk of incomplete ablation or local recurrence. METHODS: One hundred sixty-eight patients with 311 unresectable liver tumors were included. Effects of different variables on incomplete ablation and local recurrence were analyzed. RESULTS: There were 132 hepatocellular carcinomas and 179 liver metastases. Tumor size was 24 (±13) mm. Two hundred twenty-six tumors were treated percutaneously, and 85 through open approach (associated with liver resection in 42 cases). There was no mortality. Major morbidity rate was 7%. Incomplete ablation and local recurrence rates were 14% and 18.6%. Follow-up was 29 months. On multivariate analysis, factors associated with incomplete ablation were tumor size (>30 mm vs ≤30 mm, P = .004) and approach (percutaneous vs open, P = .0001). Factors associated with local recurrence were tumor size (>30 mm vs ≤30 mm, P = .02) and patient age (>65 years vs ≤65 years, P = .05). CONCLUSIONS: RFA is effective to treat unresectable liver tumors. However, there is a risk of incomplete ablation when percutaneously treating tumors >30 mm. When tumor ablation is completely achieved, the main factor associated with local recurrence is tumor size >30 mm.

Compatibility and stability of binary mixtures of acetaminophen, nefopam, ketoprofen and ketamine in infusion solutions.

BACKGROUND AND OBJECTIVE: Administering various combinations of acetaminophen, ketoprofen, nefopam and ketamine, though sometimes discussed, is expected to provide superior pain relief and reduce opioid analgesic-related side effects. However, some studies have indicated that multimodal analgesia has limited efficacy. We studied the stability of various binary combinations of these four drugs. PATIENTS AND METHODS: The drugs were studied at 25 degrees C. Binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine were produced. Each drug concentration was assessed using a specific high-performance liquid chromatographic technique. Measurements were carried out at T0, +1, +2, +4, +6 and +24 h. A 5% loss of initial concentration was considered to be significant. The changes with time of the concentrations were analysed using linear regression analysis. A P value of less than 0.05 was significant. RESULTS: The four drugs tested in the binary mixtures were stable, showing neither loss of concentration nor degradation products (P > or = 0.05). CONCLUSION: Physicochemical negative interaction is not likely to account for the limited clinical efficacy sometimes reported with binary combinations of these drugs. Coadministration of binary mixtures of acetaminophen, nefopam, ketoprofen and ketamine from the same bottle or infusion bag using the same venous line is demonstrated to be feasible.

Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime.

OBJECTIVE: To evaluate the biliary penetration of ciprofloxacin and cefotaxime in patients with obstructed bile ducts and to determine simple predictive markers of effective biliary concentrations of these drugs. METHODS: Sixty-two patients treated with endoscopic biliary drainage were prospectively included in a nonrandomized way and received intravenous ciprofloxacin (200 mg twice daily) or cefotaxime (1 g three times a day) for more than 24 h before exploration. Blood and bile samples were collected at the time of drainage. Ciprofloxacin and cefotaxime concentrations were measured using high-performance liquid chromatography. Biliary penetration was assessed by the bile-to-plasma ratio of the concentrations of both antibiotics. RESULTS: Biliary penetration ranged from 0.06 to 42.7 for ciprofloxacin and from 0.01 to 1.14 for cefotaxime. The ratio was more than one in only 10 patients (35%) and three patients (9%) in ciprofloxacin and cefotaxime groups, respectively. Biliary concentration of the drug was more than 10 times the minimal inhibitory concentration in only 10 patients (35%) and in 12 patients (35%) in ciprofloxacin and cefotaxime groups, respectively. Serum bilirubin, alkaline phosphatase or gamma-glutamyl-transpeptidase were not good predictive markers of the biliary diffusion of the antibiotics. CONCLUSION: In patients with obstructed bile ducts, the biliary penetration of ciprofloxacin is poor and reaches effective biliary concentrations in a minority of patients. Cefotaxime biliary penetration is even poorer. No liver test can predict accurately the biliary penetration of the drugs.

Cost of radiofrequency ablation in the treatment of hepatic malignancies.

OBJECTIVES: Our primary objective was to assess the cost of radio-frequency ablation (RFA) of hepatic malignancies and to compare it to hospital reimbursement paid in the French Prospective Payment System (PPS). PATIENTS AND METHODS: A series of 305 patients were enrolled into a prospective study. All resources used during the RFA-related hospital stay were recorded. Costs were assessed from the perspective of the health care providers and computed for four groups of patients: percutaneous RFA in an outpatient setting (group Ia, N=44), percutaneous RFA in an inpatient setting (group Ib, N=94), laparoscopic RFA (group II, N=44) and intraoperative RFA combined with resection (group III, N=120). RESULTS: Mean hospital costs were estimated at euro 1581 (group Ia), euro 3824 (group Ib), euro 8194 (group II) and euro 12967 (group III). Costs per stay without intensive care in these groups were respectively euro 1581, euro 3635, euro 6622 and euro 10905 and reimbursement (intensive care excluded) was euro 560, euro 3367, euro 9084 and euro 11780. CONCLUSION: In the French PPS, the cost of RFA is covered by lump sums paid to hospitals exclusively for intraoperative and laparoscopic RFA. For percutaneous RFA, which is the most frequent approach, reimbursement is highly insufficient.

Radiofrequency ablation in palliative supportive care: early clinical experience.

We report our early experience with radiofrequency ablation (RFA) in palliative supportive care. The medical files of eight patients were retrospectively reviewed. Four patients had a renal tumor, and nephrectomy was contraindicated in each patient since they had a poor general status. The fifth patient had a local recurrence in the site of a previous nephrectomy with a pancreatic tail extension, and surgical resection was contraindicated because of abdominal carcinomatosis. Two other patients had bone metastasis, one with a painful metastasis of mammary carcinoma in the head of the humerus resistant to radiotherapy, and the other with metastasis of the tibia of cutaneous melanoma. The last patient had a local recurrence of a sacral chordoma. Management, outcomes and complications were evaluated with 13.1+/-0.3 months follow-up. All five patients with renal carcinomas did not have local recurrence. The two patients treated for bone metastases had no pain 8 weeks after RFA and remained stable over time. One complication occurred 2 months after using the procedure to treat the chordoma, and this patient was hospitalized for a fistula between the sigmoid and hypogastric artery false aneurysm and subsequently died. In conclusion, RFA can be a safe and useful adjuvant treatment in supportive care or unresponsive cancer pain patients. However, the destruction of tumoral tissues in contact with sensitive structures using RFA should be done with caution due to potentially severe complications.