Photoelectron Spectroscopy of Oppositely Charged Molecular Switches in the Aqueous Phase: Theory and Experiment.

XUV photoelectron spectroscopy (XPS) is a powerful method for investigating the electronic structures of molecules. However, the correct interpretation of results in the condensed phase requires theoretical models that account for solvation. Here we present experimental aqueous-phase XPS of two organic biomimetic molecular switches, NAIP and p-HDIOP. These switches are structurally similar, but have opposite charges and thus present a stringent benchmark for solvation models which need to reproduce the observed ΔeBE = 1.1 eV difference in electron binding energy compared to the 8 eV difference predicted in the gas phase. We present calculations using implicit and explicit solvent models. The latter employs the average solvent electrostatic configuration and free energy gradient (ASEC-FEG) approach. Both nonequilibrium polarizable continuum models and ASEC-FEG calculations give vertical binding energies in good agreement with the experiment for three different computational protocols. Counterions, explicitly accounted for in ASEC-FEG, contribute to the stabilization of molecular states and reduction of ΔeBE upon solvation.

The duration of ketamine detection in hair after treatment cessation: Case study and review of the literature in forensic and clinical casework.

The disappearance of drug from hair does not occur immediately after abstinence because dormant hair may contribute to the positivity of freshly grown hair. The aim of this study was to assess ketamine disappearance from hair after treatment cessation and to review the literature data. A 22-year-old female received three intravenous doses of ketamine (171 mg) for major depression treatment. Seventeen weeks later, a 26 cm lock of hair was sampled, and ketamine was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) on seven segments: A (proximal, 0-2 cm), B (2-4 cm), C (4-6 cm, period of ketamine therapy), and D to G (4 × 5 cm). Ketamine concentration was 58 pg/mg in Segment C and remained detectable over 4 months after treatment cessation at 67 pg/mg in Segment B and 2 pg/mg in Segment A, representing a 97% drop from the initial concentration. Ketamine elimination half-life in hair was estimated at 0.88 month, implying that indetectable concentration should be expected 7 months after cessation. Axial diffusion was excluded as ketamine was not detected in Segments D-G. Given the low ketamine concentrations, norketamine was not detected. While no data on ketamine disappearance from hair have been published to date, previous studies have shown that discontinuation resulted in negative hair results after 3 months for heroin, 3-4 months for cocaine and tramadol, 6 months for amphetamine and methamphetamine, and 6-7 months for THC-COOH. This study provides useful findings for ketamine hair concentration interpretation, which should be validated by more consistent and comprehensive investigations.

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.

BACKGROUND: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. METHODS: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. RESULTS: We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32). CONCLUSION: Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

[Improve of efficiency of patients management admitted in an Intermediate Respiratory Care Unit by means of an integrated delivery of health care]. / Mejora en la eficiencia del manejo del paciente ingresado en una unidad de cuidados respiratorios intermedios tras la introducción de un proceso asistencial integrado.

INTRODUCTION: Patients admitted to Intermediate Respiratory Care Units are common sharpeners. We describe their overall improvement by the introduction of an Integrated Care Process. METHODS: We conducted an observational descriptive study based on an Intermediate Respiratory Care Unit during 2015-2017. We considered 2 groups: those in-patients during 2016-2017, who took profit from the Integrated Care Process (group A), and those other ones admitted before 2015 when the Integrated Care Process didn't exist yet (group B). We collected sociodemographic variables, clinical ones, those related to care process and economic index. We described them according their type and distribution. RESULTS: The readmission rate within B was 23.65% vs 10.20% within A. These last ones had a mean length of hospital stay of 7.19 days (0.12-14.08), a rate reduction of face-to-face specialized consultations of 45.8% and 28.8% at Emergency Department admissions when compared to B. Prior to the introduction of the Integrated Care Process, 64.9% would have been admitted to the Intensive Care Unit (according to Global Diagnostics Group). We saved 735.1 days of stay at the Intensive Care Unit and therefore over 135,118.204 and 214,649 euros. CONCLUSION: The Integrated Care Process for severe respiratory patients allows a direct and safe relationship with them at home through the Primary Care Teams, so we can save readmissions at hospital, face-to-face consultations at the Emergency Departments and Specialized Consultations and we save money.

Towards a better understanding of adult idiopathic epidermal necrolysis: a retrospective study of 19 cases.

BACKGROUND: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]). OBJECTIVE: We sought to better describe adult IEN and understand the aetiology. METHODS: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls. RESULTS: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL. CONCLUSIONS: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

Postmortem fatal and non-fatal concentrations of amlodipine.

Amlodipine is a dihydropyridine calcium channel blocker widely used in the treatment of high blood pressure and coronary heart disease. Intoxication can lead to reflex tachycardia following massive hypotension and death. The objective of this work was to study the post-mortem concentrations of amlodipine in 62 patients in order to determine whether the use of the reference concentrations from the living patients was applicable in postmortem setting, and to define more precisely the fatal and non-fatal postmortem concentrations of amlodipine. The amlodipine concentrations were measured in femoral whole blood by LC-MS/MS validated method. When sufficient information was available, the data were classified into 2 different groups, based on the conclusions of the autopsy and toxicological results: G1: non-toxic death and G2: fatal poisoning involving amlodipine alone or as part of a multidrug poisoning. The median concentration of amlodipine [1st quartile - 3rd quartile] of the whole population (n = 62) was 81 [42-134] ng/mL. Twenty-two cases were classified as G1 and thirteen as G2. The observed median [1st quartile - 3rd quartile] concentration of amlodipine was 66 [40.5-79.5] ng/mL in G1 and 240 [170-404] ng/mL in G2. The median concentrations observed in "non-toxic" deaths (66 ng/mL) were three times higher than those usually observed in living patients. Amlodipine distribution ratio between plasma and whole blood concentrations seems insufficient to explain this difference and postmortem redistribution from organs should be considered, and could suggest the same redistribution pattern for other drugs belonging to the same family.

Electronic and optical competence of TiO2/BiVO4 nanocomposites in the photocatalytic processes.

Nanocomposites with different ratios of titanium dioxide and bismuth vanadate [TiO2]/[BiVO4] give rise to compatible electronic band structure alignment at their interfaces to ensure enhanced photoactivated charge transfer under visible light. The sol-gel method and suitable post-synthesis thermal treatments were used to synthesize different compositions with stabilized anatase phase of TiO2 and monoclinic scheelite polymorph BiVO4. Structural, electronic and optical characterizations were performed and the results were analysed as a function of the stoichiometry, in which both crystalline structures show a clear junction formation among their characteristic stacking planes. Photocatalytic and (photo) electrochemical responses of the nanocomposites were investigated and tested for the degradation of azo dyes (Acid Blue-113, AB-113) (~ 99%) under visible light radiation. The nanocomposite with a mass ratio of (1:10) shows the highest photocatalytic efficiency compared to the other compositions. HRTEM images showed marked regions in which both crystalline structures form a clear junction and their characteristic planes. However, the increase of BiVO4 content in the network overcomes the photocatalytic activity due to the decrease in the reduction potential of the photo-generated electrons with high recombination rates.

Fatal intoxication with ivabradine: First case report.

Ivabradine is a bradycardic drug used worldwide in the treatment of chronic stable angina and chronic heart failure. We presented here a case of a 61-year-old woman who was admitted to emergency department for overdose. She presented with drowsiness, bradycardia (45bpm) and a low blood pressure (116/21mmHg). She died ten hours after admission from multiple organ failure. Ivabradine was quantified in different matrices sampled during autopsy using a method on LC-MS/MS (TSQ Vantage Thermo Fisher Scientific®), after a double liquid-liquid extraction with a mixture of hexane/ethyl acetate (1/1; v/v) and then chloroform/isopropanol (80/20; v/v). Chromatographic separation was achieved using a Hypersyl gold PFP column (200×2.1mm, 1.9µm) and an acetonitrile/formiate 2mM, 0.1% formic acid buffer gradient. Method was fully validated on whole blood. The mean overall recovery was 90%. Linearity was validated in the 5-500ng/mL range, with intra and inter-day precision lower than 14.3%. The ivabradine concentration found in patient post-mortem blood was 1210ng/mL. Ivabradine was also quantified in different viscera like lung (2910ng/g), kidney (1510ng/g), liver (1050ng/g), heart (900ng/g), and brain (110ng/g). The vitreous humor concentration was 760ng/mL. Pregabalin and zopiclone were also found in blood at 50µg/mL and 206ng/mL, respectively. This case seems to be the first report of a fatal intoxication involving ivabradine and the first published concentrations in organs.

Prevalence of New Psychoactive Substances (NPS) and conventional drugs of abuse (DOA) in high risk populations from Paris (France) and its suburbs: A cross sectional study by hair testing (2012-2017).

BACKGROUND: The aim of the present study is to describe the prevalence of NPS and conventional DOA in Paris and its suburbs over a six-year period using hair testing approach. METHOD: Hair was sampled in patients admitted to different departments of Paris hospitals between 2012 and 2017. Two high-risk populations were mainly considered: 1) drug-dependent and 2) acutely intoxicated patients. Segmental hair analysis was performed by validated LC-MS/MS method to screen for DOA and 83 NPS. RESULTS: 480 patients (280 M/200 F, 15-70 years) were included. 141 patients tested positive for NPS (99 M/42 F; median age: 33). NPS prevalence was 29%, that of amphetamines, cocaine and opioids were 32%, 38.5% and 52%, respectively. 27 NPS were identified, 4-MEC and mephedrone (number of cases n = 24 each) were the most detected cathinones. JWH-122 (n = 1) was the only detected synthetic cannabinoid while ketamine (n = 104) was present in numerous NPS users (67%). 3-fluorofentanyl (n = 1), furanylfentanyl (n = 1), N-ethylpentylone (n = 2), pentedrone (n = 2), mexedrone (n = 1), methcathinone (n = 3), 6-APDB (n = 2), TFMPP (n = 2), 2-CE (n = 1), 3,4-MD-αPHP (n = 1) and dextromethorphan (n = 27) were identified for the first time in hair. Users were found to have more than one NPS in 53% of cases, mostly in combination with conventional DOA. The number of detected NPS rose from 5 in 2012 to 42 in 2017. A broad range of hair concentrations (0.001-318 ng/mg) was found, but the low median concentrations seem to show an occasional exposure more than chronic use. CONCLUSION: NPS screening should be assessed in routine clinical practice, especially in high-risk populations.

Enhanced molecular visualization of root colonization and growth promotion by Bacillus subtilis EA-CB0575 in different growth systems.

Bacillus subtilis EA-CB0575 is a plant growth-promoting bacterium (PGPB) associated with banana and tomato crops. Root colonization is an important trait for PGPB microorganisms and potentiates the bacterial effect related to the mechanisms of plant growth promotion. Therefore, detection of bacterial colonization of roots in different culture systems is important in the study of plant-microorganism interactions. In this study, fluorescent in situ hybridization (FISH) and catalyzed reporter deposition-FISH (CARD-FISH) were evaluated to determine the colonization ability of B. subtilis EA-CB0575 on banana and tomato roots planted on solid and liquid Murashige and Skoog medium (MS(S) and MS(L), respectively) and in soil for tomato plants. Results showed B. subtilis colonization 0-30 days post inoculation for banana and tomato plants in different culture systems with differential distribution of bacterial cells along tomato and banana roots. FISH and CARD-FISH methodologies were both successful in detecting B. subtilis colonies, but CARD-FISH proved to be superior due to its enhanced fluorescence signal. The presence of bacteria correlated with the promotion of plant growth in both plant species, providing clues to relate rhizospheric colonization with improvement in plant growth. FISH and CARD-FISH analysis results suggested the presence of native microbiota on the roots of in vitro banana plants, but not on those of tomato plants.

LC-MS/MS method for quantification of baclofen in hair: A useful tool to assess compliance in alcohol dependent patients?

To evaluate adherence to treatment, we developed and validated a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for baclofen quantification in hair.Twenty mg was washed twice with dichloromethane, incubated in phosphate buffer (pH 5) for 10 minutes at 95°C, then extracted by liquid-liquid extraction in alkaline condition. Baclofen-d4 was used as the internal standard. This method was applied to assess compliance in4 treated alcohol-dependent patients (3 dead and one living). Blood quantification of baclofen and ethanol were performed in the 4 cases. Hair ethylglucuronide (ethanol metabolite, EtG) measurement (2x3 cm) was associated in 1 patient. Baclofen quantification in hair was validated over the range 10-5000 pg/mg. The accuracy was within 96.0%-110.9% and the precision was less than 9.3%. Baclofen segmental (3x2cm) hair concentrations found in the living patient were 4420, 4260, and 4380 pg/mg, reflecting a regular exposure over the last 6 months and suggesting patient compliance. However, the high EtG level found in this patient in the analyzed segments (225 pg/mg and 215 pg/mg) showed excessive alcohol consumption during the same period, suggesting therapeutic failure. In the 3 deceased patients, the non-segmental analysis of hair showed baclofen concentrations of 15, 545, and 2475 pg/mg. The low concentrations in the 2 first cases are compatible either with a poor compliance or to a beginning of a treatment. This is the first measurement of baclofen in hair of alcohol dependent patients. It could be used as a monitoring biomarker to assess patient's compliance.

Glycated haemoglobin (HbA1c ) and fasting plasma glucose relationships in sea-level and high-altitude settings.

AIM: Higher haemoglobin levels and differences in glucose metabolism have been reported among high-altitude residents, which may influence the diagnostic performance of HbA1c . This study explores the relationship between HbA1c and fasting plasma glucose (FPG) in populations living at sea level and at an altitude of > 3000 m. METHODS: Data from 3613 Peruvian adults without a known diagnosis of diabetes from sea-level and high-altitude settings were evaluated. Linear, quadratic and cubic regression models were performed adjusting for potential confounders. Receiver operating characteristic (ROC) curves were constructed and concordance between HbA1c and FPG was assessed using a Kappa index. RESULTS: At sea level and high altitude, means were 13.5 and 16.7 g/dl (P > 0.05) for haemoglobin level; 41 and 40 mmol/mol (5.9% and 5.8%; P < 0.01) for HbA1c ; and 5.8 and 5.1 mmol/l (105 and 91.3 mg/dl; P < 0.001) for FPG, respectively. The adjusted relationship between HbA1c and FPG was quadratic at sea level and linear at high altitude. Adjusted models showed that, to predict an HbA1c value of 48 mmol/mol (6.5%), the corresponding mean FPG values at sea level and high altitude were 6.6 and 14.8 mmol/l (120 and 266 mg/dl), respectively. An HbA1c cut-off of 48 mmol/mol (6.5%) had a sensitivity for high FPG of 87.3% (95% confidence interval (95% CI) 76.5 to 94.4) at sea level and 40.9% (95% CI 20.7 to 63.6) at high altitude. CONCLUSION: The relationship between HbA1c and FPG is less clear at high altitude than at sea level. Caution is warranted when using HbA1c to diagnose diabetes mellitus in this setting.

Analysis of uni and bi-parental markers in mixture samples: Lessons from the 22nd GHEP-ISFG Intercomparison Exercise.

Since 1992, the Spanish and Portuguese-Speaking Working Group of the ISFG (GHEP-ISFG) has been organizing annual Intercomparison Exercises (IEs) coordinated by the Quality Service at the National Institute of Toxicology and Forensic Sciences (INTCF) from Madrid, aiming to provide proficiency tests for forensic DNA laboratories. Each annual exercise comprises a Basic (recently accredited under ISO/IEC 17043: 2010) and an Advanced Level, both including a kinship and a forensic module. Here, we show the results for both autosomal and sex-chromosomal STRs, and for mitochondrial DNA (mtDNA) in two samples included in the forensic modules, namely a mixture 2:1 (v/v) saliva/blood (M4) and a mixture 4:1 (v/v) saliva/semen (M8) out of the five items provided in the 2014 GHEP-ISFG IE. Discrepancies, other than typos or nomenclature errors (over the total allele calls), represented 6.5% (M4) and 4.7% (M8) for autosomal STRs, 15.4% (M4) and 7.8% (M8) for X-STRs, and 1.2% (M4) and 0.0% (M8) for Y-STRs. Drop-out and drop-in alleles were the main cause of errors, with laboratories using different criteria regarding inclusion of minor peaks and stutter bands. Commonly used commercial kits yielded different results for a micro-variant detected at locus D12S391. In addition, the analysis of electropherograms revealed that the proportions of the contributors detected in the mixtures varied among the participants. In regards to mtDNA analysis, besides important discrepancies in reporting heteroplasmies, there was no agreement for the results of sample M4. Thus, while some laboratories documented a single control region haplotype, a few reported unexpected profiles (suggesting contamination problems). For M8, most laboratories detected only the haplotype corresponding to the saliva. Although the GHEP-ISFG has already a large experience in IEs, the present multi-centric study revealed challenges that still exist related to DNA mixtures interpretation. Overall, the results emphasize the need for further research and training actions in order to improve the analysis of mixtures among the forensic practitioners.

[Injection of Lipotransplants for Wound Healing Complications after Radiotherapy]. / Injektion von Bauchfett bei radiogenen Wundheilungsstörungen.

Wound healing complications in irradiated tissues represent a major clinical challenge. Fistula or even major vessel rupture may occur. The injection of adipose tissue derived stem cells seem to be a promising therapeutical strategy. The article describes the clinical case of a patient suffering from a pharyngo-cutaneous fistula after laryngectomy and radiotherapy. The patient was successfully treated by the injection of fat tissue.

Characterisation of genetic structure of the Mayan population in Guatemala by autosomal STR analysis.

BACKGROUND: Currently, the Guatemalan population comprises genetically isolated groups due to geographic, linguistic and cultural factors. For example, Mayan groups within the Guatemala population have preserved their own language, culture and religion. These practices have limited genetic admixture and have maintained the genetic identity of Mayan populations. AIM: This study is designed to define the genetic structure of the Mayan-Guatemalan groups Kaqchiquel, K'iche', Mam and Q'eqchi' through autosomal short tandem repeat (STR) polymorphisms and to analyse the genetic relationships between them and with other Mayan groups. SUBJECTS AND METHODS: Fifteen STR polymorphisms were analysed in 200 unrelated donors belonging to the Kaqchiquel (n = 50), K'iche' (n = 50), Mam (n = 50) and Q'eqchi' (n = 50) groups living in Guatemala. Genetic distance, non-metric MDS and AMOVA were used to analyse the genetic relationships between population groups. RESULTS: Within the Mayan population, the STRs D18S51 and FGA were the most informative markers and TH01 was the least informative. AMOVA and genetic distance analyses showed that the Guatemalan-Native American populations are highly similar to Mayan populations living in Mexico. CONCLUSIONS: The Mayan populations from Guatemala and other Native American groups display high genetic homogeneity. Genetic relationships between these groups are more affected by cultural and linguistic factors than geographical and local flow. This study represents one of the first steps in understanding Mayan-Guatemalan populations, the associations between their sub-populations and differences in gene diversity with other populations. This article also demonstrates that the Mestizo population shares most of its ancestral genetic components with the Guatemala Mayan populations.

Environmental fate of naproxen, carbamazepine and triclosan in wastewater, surface water and wastewater irrigated soil - Results of laboratory scale experiments.

Lab-scale photolysis, biodegradation and transport experiments were carried out for naproxen, carbamazepine and triclosan in soil, wastewater and surface water from a region where untreated wastewater is used for agricultural irrigation. Results showed that both photolysis and biodegradation occurred for the three emerging pollutants in the tested matrices as follows: triclosan>naproxen>carbamazepine. The highest photolysis rate for the three pollutants was obtained in experiments using surface water, while biodegradation rates were higher in wastewater and soil than in surface water. Carbamazepine showed to be recalcitrant to biodegradation both in soil and water; although photolysis occurred at a higher level than biodegradation, this compound was poorly degraded by natural processes. Transport experiments showed that naproxen was the most mobile compound through the first 30cm of the soil profile; conversely, the mobility of carbamazepine and triclosan through the soil was delayed. Biodegradation of target pollutants occurred within soil columns during transport experiments. Triclosan was not detected either in leachates or the soil in columns, suggesting its complete biodegradation. Data of these experiments can be used to develop more reliable fate-on-the-field and environmental risk assessment studies.

Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance.

BACKGROUND: Vemurafenib improves survival in advanced BRAFV600(mut) melanoma patients, but tolerance is often poor and resistance frequently occurs, without predictive factor. Our aim was to investigate for the first time a relationship between plasma vemurafenib concentration (PVC) and efficacy or tolerance. METHODS: Plasma samples from unresectable metastatic BRAFV600(mut) melanoma patients treated with vemurafenib monotherapy were prospectively collected at each tumour response evaluation (RECIST 1.1) or when adverse event occurred (CTCAE 4.0). PVC was measured with liquid chromatography-tandem mass spectrometry. Herein, we report on PVC at steady state (≥14 days after vemurafenib introduction or dose modification). Samples collected after first melanoma progression were excluded from the response analysis. All samples were analysed in the tolerance analysis. We kept the closest collected sample from the onset of each adverse effect or the one with the highest PVC in the absence of this adverse effect. Comparisons of means (Student's t-tests and Wilcoxon rank sum tests) and of frequencies (χ(2) tests) were carried out. A logistic regression analysis identified predictors of progression. RESULTS: We included 105 plasma samples in 23 patients (10M/13F). Initial vemurafenib dose was 960 mg b.i.d., reduced by 25% (8 patients) or 50% (2 patients) for intolerance in 10 patients (44%). PVC displayed high inter-individual variability (13.0-109.8 µg/ml, median 54.0). Mean PVC was lower at time of first progression (38.8 ± 19.7 µg/ml) than mean PVC found when tumour was stable or in partial or complete response (56.4 ± 21.0 µg/ml, P = 0.013, 21 patients). Logistic regression revealed that having a low PVC (P = 0.01) or brain metastasis (P = 0.01) were both significantly and independently associated with tumour progression. High PVC was not statistically significantly associated with the occurrence of adverse effects. CONCLUSION: PVC at steady state is highly variable and low PVC was associated with tumour progression, suggesting a new path to melanoma resistance to vemurafenib.