A Systematic Review of Cochlear Implant-Related Magnetic Resonance Imaging Artifact: Implications for Clinical Imaging.

OBJECTIVE: To conduct a systematic review of the existing literature with the aim of evaluating and consolidating the present understanding of strategies for mitigating magnetic resonance imaging (MRI) artifacts related to cochlear implants in adult and pediatric patients, covering both in-vivo and ex-vivo investigations. DATA SOURCES: A systematic review of MEDLINE-Ovid, Embase, Google Scholar, The Cochrane Library, and Scopus was performed from inception through April 2022. The protocol was registered with PROSPERO before commencement of data collection (CRD CRD42022319651). REVIEW METHODS: The data were screened and collected by two authors independently, and eligibility was assessed according to Cochrane Handbook and Preferred Reporting Items for Systematic Review and Meta-Analysis recommendations, whereas the quality of the articles was evaluated using the NIH Study Quality Assessment. RESULTS: The search yielded 2,354 potentially relevant articles, of which 27 studies were included in the final review. Twelve studies looked at 1.5-T MRI, four studies looked at 3-T MRI, eight studies looked at both 1.5 and 3 T, one study looked at 0.2 and 1.5 T, and one study looked at 3- and 7.0-T MRI. Nineteen studies focused on MRI sequences as a means of artifact reduction, nine studies focused on implant magnet positioning, two studies focused on head positioning, and one study focused on both magnet and head positioning. In terms of MRI sequences, diffusion-weighted imaging produced larger artifacts compared with other sequences, whereas fast spin echo/turbo spin echo sequences and fat suppression techniques produced smaller artifacts. The position of the magnet was also found to be important, with a magnet position more than 6.5 cm posterior to the external auditory canal producing the best images with the least distortion. The angle at which the magnet is placed also affects visibility of different brain structures. CONCLUSION: Proper head positioning, magnet placement at a distance of over 6.5 cm from the external auditory canal, use of spin echo sequences, and fat suppression techniques reduce the size and shape of MRI artifacts.

Blue man: Ochronosis in Otolaryngology.

Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria.

Multi-site reproducibility of a human immunophenotyping assay in whole blood and peripheral blood mononuclear cells preparations using CyTOF technology coupled with Maxpar Pathsetter, an automated data analysis system.

High-dimensional mass cytometry data potentially enable a comprehensive characterization of immune cells. In order to positively affect clinical trials and translational clinical research, this advanced technology needs to demonstrate a high reproducibility of results across multiple sites for both peripheral blood mononuclear cells (PBMC) and whole blood preparations. A dry 30-marker broad immunophenotyping panel and customized automated analysis software were recently engineered and are commercially available as the Fluidigm® Maxpar® Direct™ Immune Profiling Assay™. In this study, seven sites received whole blood and six sites received PBMC samples from single donors over a 2-week interval. Each site labeled replicate samples and acquired data on Helios™ instruments using an assay-specific acquisition template. All acquired sample files were then automatically analyzed by Maxpar Pathsetter™ software. A cleanup step eliminated debris, dead cells, aggregates, and normalization beads. The second step automatically enumerated 37 immune cell populations and performed label intensity assessments on all 30 markers. The inter-site reproducibility of the 37 quantified cell populations had consistent population frequencies, with an average %CV of 14.4% for whole blood and 17.7% for PBMC. The dry reagent coupled with automated data analysis is not only convenient but also provides a high degree of reproducibility within and among multiple test sites resulting in a comprehensive yet practical solution for deep immune phenotyping.

Automated Data Cleanup for Mass Cytometry.

Mass cytometry is an emerging technology capable of 40 or more correlated measurements on a single cell. The complexity and volume of data generated by this platform have accelerated the creation of novel methods for high-dimensional data analysis and visualization. A key step in any high-level data analysis is the removal of unwanted events, a process often referred to as data cleanup. Data cleanup as applied to mass cytometry typically focuses on elimination of dead cells, debris, normalization beads, true aggregates, and coincident ion clouds from raw data. We describe a probability state modeling (PSM) method that automatically identifies and removes these elements, resulting in FCS files that contain mostly live and intact events. This approach not only leverages QC measurements such as DNA, live/dead, and event length but also four additional pulse-processing parameters that are available on Fluidigm Helios™ and CyTOF® (Fluidigm, Markham, Canada) 2 instruments with software versions of 6.3 or higher. These extra Gaussian-derived parameters are valuable for detecting well-formed pulses and eliminating coincident positive ion clouds. The automated nature of this new routine avoids the subjectivity of other gating methods and results in unbiased elimination of unwanted events. © 2019 International Society for Advancement of Cytometry.

Preliminary Evidence for Enhanced Thymine Absorption: A Putative New Phenotype Associated With Fluoropyrimidine Toxicity in Cancer Patients.

BACKGROUND: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Thus, the cause of most fluorouracil toxicity cases remains unexplained. METHODS: For this small cohort study, thymine (THY) 250 mg was administered orally to 6 patients who had experienced severe toxicity during treatment with 5FU or capecitabine. Plasma and urine were analyzed for THY and its catabolites dihydrothymine (DHT) and ß-ureidoisobutyrate. RESULTS: Of the 6 patients, 2 had decreased THY elimination and raised urinary THY recovery consistent with inherited partial dihydropyrimidine dehydrogenase deficiency, confirmed by DPYD sequencing. Unexpectedly, 3 patients displayed grossly raised plasma THY concentrations but normal elimination profiles (compared with a normal range for healthy volunteers previously published by the authors). DPYD and DPYS sequencing of these 3 patients did not reveal any significant loss-of-activity allelic variants. The authors labeled the phenotype in these 3 patients as "enhanced thymine absorption". Only 1 of the 6 cases of toxicity had a normal postdose plasma profile for THY and its catabolites. Postdose urine collections from all 6 patients had THY/DHT urinary ratios above 4.0, clearly separated from the ratios in healthy subjects that were all below 3.0. CONCLUSIONS: This small cohort provided evidence for a hypothesis that fluorouracil toxicity cases may include a previously undescribed pyrimidine absorption variant, "enhanced thymine absorption," and elevated THY/DHT ratios in urine may predict fluorouracil toxicity. A prospective study is currently being conducted.

Prediction of glycaemic control in young children and adolescents with type 1 diabetes mellitus using mixed-effects logistic regression modelling.

OBJECTIVES: Glycaemic control in children and adolescents with type 1 diabetes mellitus can be challenging, complex and influenced by many factors. This study aimed to identify patient characteristics that were predictive of satisfactory glycaemic control in the paediatric population using a logistic regression mixed-effects (population) modelling approach. METHODS: The data were obtained from 288 patients aged between 1 and 22 years old recorded retrospectively over 3 years (1852 HbA1c observations). HbA1c status was categorised as 'satisfactory' or 'unsatisfactory' glycaemic control, using an a priori cut-off value of HbA1c ≥ 9% (75 mmol/mol), as used routinely by the hospital's endocrine paediatricians. Patients' characteristics were tested as covariates in the model as potential predictors of glycaemic control. RESULTS: There were three patient characteristics identified as having a significant influence on glycaemic control: HbA1c measurement at the beginning of the observation period (Odds Ratio (OR) = 0.30 per 1% HbA1c increase, 95% confidence interval (CI) = 0.20-0.41); Age (OR = 0.88 per year increase, 95% CI = 0.80-0.94), and fractional disease duration (disease duration/age, OR = 0.80 per 0.10 increase, 95% CI = 0.66-0.93) were collectively identified as factors contributing significantly to lower the probability of satisfactory glycaemic control. CONCLUSIONS: The study outcomes may prove useful for identifying paediatric patients at risk of having unsatisfactory glycaemic control, and who could require more extensive monitoring, support, or targeted interventions.

Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles?

PURPOSE: Anthracyclines are a mainstay of the treatment of several childhood malignancies, but their utility is limited by dose-related cardiotoxicity. This study is aimed to explore the link between exposure of paediatric cancer patients to doxorubicin and its metabolite doxorubicinol, and cardiac troponin I (cTnI). METHODS: In a prospective pilot study plasma doxorubicin, doxorubicinol, and cTnI concentrations were measured in samples from children undergoing cancer chemotherapy. A mixed-effects population pharmacokinetic model for doxorubicin and doxorubicinol and in combination with a turn-over model for cTnI were developed. RESULTS: Seventeen patients, aged 3.4-14.7 year, treated for a variety of cancers had 99 doxorubicin and 119 doxorubicinol concentrations analysed from samples drawn between 0.5 and 336 h after the start of the infusion. Eleven patients had received previous doses of anthracyclines, with a median cumulative prior dose of 90 mg/m2 (range 0-225 mg/m2). The median administered doxorubicin dose was 30 mg/m2 (range 25-75 mg/m2). Doxorubicin disposition was described by a three-compartment model with first-order elimination and metabolism to doxorubicinol. Body surface area was related to all clearance and distribution parameters and age further influenced clearance (CL, 58.7 L/h/1.8 m2 for an average 8.4-year-old patient). Combined doxorubicin and metabolite exposure stimulated a temporary increase in cTnI in plasma, with a concentration of 11.8 µg/L required to achieve half-maximal effect. Prior cumulative anthracycline dosage received by patients was predictive of an increased cTnI baseline prior to a new doxorubicin dose. CONCLUSION: Prior anthracycline exposure increased baseline cTnI in a dose-dependent manner, consistent with the known cumulative risk of anthracycline exposure-induced cardiotoxicity.

Towards a test to predict 5-fluorouracil toxicity: Pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males.

The fluoropyrimidine drugs 5-fluorouracil and its oral prodrug capecitabine remain first line therapy for solid tumours of the neck, breast and colon. However, significant and unpredictable toxicity affects about 10-25% of patients depending upon the mode of 5-fluorouracil delivery. The pharmacokinetics of thymine (5-methyluracil) may provide an approach for screening for 5-fluorouracil toxicity, based on the rationale that thymine is a close structural analogue of 5-fluorouracil and is catabolized by the same enzymatic pathway. Oral thymine loading tests were performed on 12 healthy volunteers. Each subject was given a single oral dose of 250mg thymine in capsule form. Blood, urine and saliva samples were collected pre-dose and up to 5h post-dose. Concentrations of thymine, and its catabolites dihydrothymine and ß-ureidoisobutyrate were analysed by HPLC-tandem mass spectrometry in plasma, urine and saliva. The pharmacokinetic data of healthy volunteers were analysed assuming a non-compartmental model. Thymine peaked quickly (30-45min) in plasma to a maximum concentration of 170±185µg/L (mean±SD). Clearance was high (mean 57.9L/h/kg) exceeding normal human liver blood flow, suggesting low systemic bioavailability; urinary recovery of the thymine dose was low (<1%). Apparent formation rate-limited kinetics were observed for dihydrothymine, and the plasma concentration of dihydrothymine was consistently 10-fold higher than that of thymine. Plasma ß-ureidoisobutyrate concentrations, on the other hand, were similar to that of thymine. Genotyping confirmed that pathological mutations of the DPYD gene were absent. The urinary excretion ratio of thymine/dihydrothymine was informative of the maximum concentration. Saliva thymine was highly variable. These data are potentially useful as a basis for developing of a screening procedure to prospectively identify patients who are at risk of toxicity from fluoropyrimidine drugs.

Breastmilk-Saliva Interactions Boost Innate Immunity by Regulating the Oral Microbiome in Early Infancy.

INTRODUCTION: Xanthine oxidase (XO) is distributed in mammals largely in the liver and small intestine, but also is highly active in milk where it generates hydrogen peroxide (H2O2). Adult human saliva is low in hypoxanthine and xanthine, the substrates of XO, and high in the lactoperoxidase substrate thiocyanate, but saliva of neonates has not been examined. RESULTS: Median concentrations of hypoxanthine and xanthine in neonatal saliva (27 and 19 µM respectively) were ten-fold higher than in adult saliva (2.1 and 1.7 µM). Fresh breastmilk contained 27.3 ± 12.2 µM H2O2 but mixing baby saliva with breastmilk additionally generated >40 µM H2O2, sufficient to inhibit growth of the opportunistic pathogens Staphylococcus aureus and Salmonella spp. Oral peroxidase activity in neonatal saliva was variable but low (median 7 U/L, range 2-449) compared to adults (620 U/L, 48-1348), while peroxidase substrate thiocyanate in neonatal saliva was surprisingly high. Baby but not adult saliva also contained nucleosides and nucleobases that encouraged growth of the commensal bacteria Lactobacillus, but inhibited opportunistic pathogens; these nucleosides/bases may also promote growth of immature gut cells. Transition from neonatal to adult saliva pattern occurred during the weaning period. A survey of saliva from domesticated mammals revealed wide variation in nucleoside/base patterns. DISCUSSION AND CONCLUSION: During breast-feeding, baby saliva reacts with breastmilk to produce reactive oxygen species, while simultaneously providing growth-promoting nucleotide precursors. Milk thus plays more than a simply nutritional role in mammals, interacting with infant saliva to produce a potent combination of stimulatory and inhibitory metabolites that regulate early oral-and hence gut-microbiota. Consequently, milk-saliva mixing appears to represent unique biochemical synergism which boosts early innate immunity.

Population pharmacokinetics of phenytoin in critically ill children.

The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration.

SEQUELAE OF PATIENTS TREATED FOR PULMONARY TUBERCULOSIS IN CHEST CLINIC, TIKUR ANBESSA SPECIALIZED HOSPITAL (TASH), ADDIS ABABA, ETHIOPIA.

BACKGROUND: Pulmonary tuberculosis (PTB) is one of the most common infectious diseases worldwide, and contributes significantly to morbidity and mortality in developing countries. Despite availability of effective treatment, a significant number of patients suffer from permanent lung damage, which predisposes patients to numerous pulmonary complications. OBJECTIVE: To assess chronic sequelae of patients treated for PTB in a chest clinic at Tikur Anbessa Hospital. METHODS: This was a retrospective, cross-sectional analysis of patients registered in a clinical database at the chest clinic of Tikur Anbessa specialized Hospital between January and December 2013. Patients with a history of pulmonary tuberculosis treatment were identified and included in the analysis. RESULTS: Among all patients having follow-up at the chest clinic of TASH during the study period, 134 (18.5%) presented with chronic pulmonary complications of TB. Seventy two patients (54%) were male, and the mean and median ages were 40 and 37 years, respectively. Of the study population, 83 (61.9%) patients had clinically significant parenchymal scarring and fibrosis, 40 (29.9%) had bronchiectasis, 5(3.7%) had Aspergilloma, 4(3%) had granuloma/calcification, one patient (0.7%) had pleural thickening, and one patient (0.7%) underwent pneumonectomy during the study period. CONCLUSIONS: Fibrosis and bronchiectasis were the most common pulmonary complications of tuberculosis among patients encountered at the TASH chest clinic during the study period. This demonstrates the impact of pulmonary tuberculosis is beyond management of active disease.

Should the dosage of controlled-release oxycodone in advanced cancer be modified on the basis of patient characteristics?

PURPOSE: This study aimed to investigate whether the characteristics of patients with advanced cancer explain the variability in oxycodone clearance, with the potential for this information to determine maintenance dosing. METHODS: Patients (n = 36) with advanced cancer who were receiving delayed-release oxycodone (Oxycontin®) (mean dose, 31.4 mg; range, 5-120 mg) mostly twice daily (mean duration = 80 days; range, 5-651 days) provided venous blood samples (n = 139, median = 3 per patient) drawn from 0.25 to 23.4 h post-dose. Plasma was assayed for oxycodone (mean = 39.4 ng/mL; range, 1-256 ng/mL) by high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic modeling was performed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A one-compartment model with first-order absorption and elimination best described the data. Typical population values and between-subject variability (coefficient of variation, percent) for oxycodone clearance and the oral absorption rate constant were 73 L/h (31.9 %) and 0.0735 h (133 %), respectively. The volume of distribution was estimated based on literature values for intravenous oxycodone in cancer patients. The inclusion of weight, sex, age, creatinine clearance, and serum albumin concentration did not significantly explain pharmacokinetic variability in clearance or absorption rate constant. The subject with the most elevated liver function test values also had the lowest clearance per kilogram. CONCLUSIONS: Oxycodone clearance was similar to that reported previously for healthy adults. Despite reports that patient characteristics significantly affect oxycodone pharmacokinetics, our results do not support alteration of current prescribing practices for maintenance dosing of Oxycontin® in most patients with advanced cancer. The influence of marked liver dysfunction on oxycodone clearance requires further investigation.

Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study.

Craniofacial bone dysmorphology is an important but under-explored potential diagnostic feature of fetal alcohol spectrum disorders. This study used longitudinal MicroCT 3D imaging to examine the effect of prenatal alcohol exposure on craniofacial bone growth in a mouse model. C57BL/6J dams were divided into 3 groups: alcohol 4.2% v/v in PMI® liquid diet (ALC), 2 weeks prior to and during pregnancy from embryonic (E) days 7-E16; pair-fed controls (PF), isocalorically matched to the ALC group; chow controls (CHOW), given ad libitum chow and water. The MicroCT scans were performed on pups on postnatal days 7 (P7) and P21. The volumes of the neurocranium (volume encased by the frontal, parietal, and occipital bones) and the viscerocranium (volume encased by the mandible and nasal bone), along with total skull bone volume, head size, and head circumference were evaluated using general linear models and discriminant analyses. The pups in the alcohol-treated group, when compared to the chow-fed controls (ALC vs CHOW) and the isocaloric-fed controls (ALC vs PF), showed differences in head size and circumference at P7 and P21, the total skull volume and parietal bone volume at P7, and volume of all the tested bones except nasal at P21. There was a growth trend of ALC < CHOW and ALC < PF. While covarying for gender and head size or circumference, the treatment affected the total skull and mandible at P7 (ALC > CHOW), and the total skull, parietal bone, and occipital bone at P21 (ALC < CHOW, ALC < PF). While covarying for the P7 measures, the treatment affected only the 3 neurocranial bones at P21 (ALC < CHOW, ALC < PF). Discriminant analysis sensitively selected between ALC and CHOW (AUC = 0.967), between ALC and PF (AUC = 0.995), and between PF and CHOW (AUC = 0.805). These results supported our hypothesis that craniofacial bones might be a reliable and sensitive indicator for the diagnosis of prenatal alcohol exposure. Significantly, we found that the neurocranium (upper skull) was more sensitive to alcohol than the viscerocranium (face).

Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry.

BACKGROUND: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders. OBJECTIVE: The objective of the study is to develop a liquid chromatography-tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders. METHODS: A deuterated internal standard (d7-melatonin) was added to a diluted saliva sample (20 µL) in an autosampler vial insert, and 50 µL were injected. Plasticware was strictly avoided, and all glassware was scrupulously cleaned and then baked at 120°C for at least 48 hours to obtain satisfactory performance. Reverse-phase chromatography was performed on a C8 column using a linear gradient elution profile comprising mobile phases A (0.1% aqueous formic acid) and B (15% methanol in acetonitrile containing 0.1% formic acid), pumped at a total flow rate of 0.8 mL/min. The run time was 8 minutes. After atmospheric pressure chemical ionization, mass spectrometric detection was in positive ion mode. Mass detection was by selected reaction monitoring mode with the following mass transitions used for quantification: melatonin, m/z 233.0 → 173.8 and d7-melatonin, m/z 240.0 → 178.3. RESULTS: Linearity (r > 0.999) was established from 3.9 to 1000 pg/mL. Imprecision (coefficient of variation percent) was less than 11%, and accuracy was 100-105% (7.0-900 pg/mL). The method was selective, and the mean (range) ratio of the slopes of calibrations in water to those in daytime saliva samples collected from 10 healthy adult subjects was 0.989 (0.982-0.997), indicating negligible matrix effects. The application of the assay was demonstrated in healthy adults and in children being clinically investigated for sleep disturbances. CONCLUSIONS: A validated liquid chromatography-tandem mass spectrometry method suitable for monitoring salivary melatonin in children with circadian rhythm sleep disorders is reported. The method also has potential application to pediatric population pharmacokinetic studies using sparse sampling of saliva as the biological sample matrix.

Simultaneous determination of thymine and its sequential catabolites dihydrothymine and ß-ureidoisobutyrate in human plasma and urine using liquid chromatography-tandem mass spectrometry with pharmacokinetic application.

To study in vivo activities of dihydropyrimidine dehydrogenase, dihydropyrimidinase, and ureidoproprionase, a sensitive, accurate, selective and precise method for the determination of the endogenous pyrimidine thymine (THY) and its successive metabolites dihydrothymine (DHT) and ß-ureidoisobutyric (UIB) acid in human plasma and urine has been developed and validated. Plasma or diluted urine (200 µL) was mixed with 1 mL of deuterated-THY (internal standard) in acetonitrile, then centrifuged, the supernatant evaporated, and the residue reconstituted in 150 µL 0.1% (w/w) formic acid in water. Separation was performed on a Waters Symmetry C8 column (150 mm × 3.9 mm; 5 µm particle size), with gradient elution using a mobile phase of 0.1% (w/w) formic acid in water (phase A), and 15% (v/v) methanol in acetonitrile (phase B). The detection system was an Applied Biosystems model 3200 tandem mass spectrometer with atmospheric pressure chemical ionisation, and multiple reaction monitoring mode using the transitions: THY (m/z: 127.1-110.0), DHT (m/z: 129.1-68.9), UIB (m/z: 147.1-86.0), and deuterated-THY (m/z: 131.1-114.0). THY, DHT, and UIB eluted at 5.12 min, 5.17 min and 5.00 min, respectively. Linearity of the calibrations was established from 2 to 500 µg/L. The lower limit of quantification was 5 µg/L in plasma, and 10 µg/L in urine for THY, DHT and UIB. Ion-suppression had negligible effect. A pilot pharmacokinetic study analysed plasmas and urines from 2 healthy male subjects who each received an oral 250 mg THY dose. THY was rapidly absorbed and eliminated with an apparent biphasic log-linear profile. DHT and UIB demonstrated apparent formation-rate limited kinetics.

Sinusitis and chronic cough in children.

BACKGROUND: Chronic cough in children is a common problem, and sinusitis is a common etiology. The diagnosis of sinusitis is often clinical, but confirmation is thought to require a CT scan due to the difficulty of interpreting a Water's view sinus X-ray. OBJECTIVES: The purposes of the study were (1) to examine the frequency of an abnormal sinus X-ray in children with a chronic cough of more than 4 weeks duration; (2) to compare the interpretation of the sinus film between allergy/pulmonary clinicians and radiologists; and (3) to correlate symptoms with X-ray results. METHODS: A chart review of 2- to 18-year-old patients with coughing exceeding 4 weeks was performed. Data was collected for patients who had received a Water's view sinus film as part of their evaluation. Exam, X-ray results, and clinical outcomes were categorized and statistical analyses performed. RESULTS: A total of 86 patients were included. Clinicians found that 65% of the children had positive Water's view films, compared with the radiologist's reading of 62% (non significant). Significant associations between post-tussive emesis (P = 0.01) and purulence (P = 0.03) were noted with a positive film. Positive sinus X-ray was highly associated with all findings except wheeze when present together (P < 0.001). CONCLUSION: Sinus abnormalities on X-ray are associated with prolonged cough in 65% of children. The Water's view sinus film is a clinically useful screening tool for clinicians in the workup of chronic cough. Certain physical findings and clinical complaints, when present concurrently, correlate with the X-ray results.

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

PURPOSE: Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to non-essential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple non-invasive test to investigate opioid PKs. METHODS: Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection. RESULTS: One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day). Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 µg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 µg/L) were much higher than plasma concentrations (mean 38.2 µg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r (2) = 0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method. CONCLUSION: High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.