Toward a National System of Expanded Testing of Existing Urine Specimens: The Drug Outbreak Testing Service (DOTS).

BACKGROUND: NIDA's National Drug Early Warning System (NDEWS) was established in 2014 with the mission of identifying and monitoring emerging drugs in the United States. Identification of emerging drugs has been complicated, however, by the rapid development of novel psychoactive substances such that users often cannot identify and report the drugs they have ingested. Biologic testing of urine, hair or blood is the only way to reliably identify the substances recently used. Unfortunately, the large number of up-to-date tests required is beyond the resources available to most organizations. METHODS: The DOTS study tested the feasibility of recruiting organizations to submit up to 25 de-identified urine specimens for testing for approximately 240 drugs, at no cost to them. The results were for epidemiologic purposes only and not for clinical use. Eleven sites who had questions about their patients or the results of their organization's more limited urinalysis screens participated. These sites included drug treatment programs, medical examiners, hospitals and a criminal justice testing program. RESULTS: Extensive polydrug use and geographic differences in the drugs detected were found. All sites found the DOTS collaborating laboratory's test results to be very useful for understanding the types of drugs being used recently and to assess the adequacy of their testing protocols. CONCLUSIONS: The U.S. should consider establishing a program of expanded testing of already collected de-identified urine specimens in order to identify emerging drugs and track local patterns of use and availability.

Geospatial Analysis of Drug Poisoning Deaths Involving Heroin in the USA, 2000-2014.

We investigate the geographic patterns of drug poisoning deaths involving heroin by county for the USA from 2000 to 2014. The county-level patterns of mortality are examined with respect to age-adjusted rates of death for different classes of urbanization and racial and ethnic groups, while rates based on raw counts of drug poisoning deaths involving heroin are estimated for different age groups and by gender. To account for possible underestimations in these rates due to small areas or small numbers, spatial empirical Baye's estimation techniques have been used to smooth the rates of death and alleviate underestimation when analyzing spatial patterns for these different groups. The geographic pattern of poisoning deaths involving heroin has shifted from the west coast of the USA in the year 2000 to New England, the Mid-Atlantic region, and the Great Lakes and central Ohio Valley by 2014. The evolution over space and time of clusters of drug poisoning deaths involving heroin is confirmed through the SaTScan analysis. For this period, White males were found to be the most impacted population group overall; however, Blacks and Hispanics are highly impacted in counties where significant populations of these two groups reside. Our results show that while 35-54-year-olds were the most highly impacted age group by county from 2000 to 2010, by 2014, the trend had changed with an increasing number of counties experiencing higher death rates for individuals 25-34 years. The percentage of counties across the USA classified as large metro with deaths involving heroin is estimated to have decreased from approximately 73% in 2010 to just fewer than 56% in 2014, with a shift to small metro and non-metro counties. Understanding the geographic variations in impact on different population groups in the USA has become particularly necessary in light of the extreme increase in the use and misuse of street drugs including heroin and the subsequent rise in opioid-related deaths in the USA.

Clear cell renal cell carcinoma: multiphasic MDCT enhancement can predict the loss of chromosome 8p.

PURPOSE: To investigate whether imaging features on multiphasic multidetector computed tomography (MDCT) can predict the loss of chromosome 8p in clear cell renal cell carcinomas (RCCs), a cytogenetic abnormality associated with a higher tumor grade and greater risk of recurrence. METHODS: With IRB approval for this HIPAA-compliant retrospective study, we queried our institution's pathology database to derive all histologically proven cases of clear cell RCC with preoperative multiphasic MDCT with as many as four phases (unenhanced, corticomedullary, nephrographic, and excretory) from January 2000 to July 2010. Of 170 clear cell RCCs with preoperative multiphasic MDCT, 105 clear cell RCCs, representing 98 unique patients, had karyotypes of the resected specimens. Lesions were evaluated for magnitude and pattern of enhancement, contour, neovascularity, calcifications, and size. RESULTS: The corticomedullary phase mean enhancement of clear cell RCCs with a loss of 8p was significantly greater than that of clear cell RCCs without a loss of 8p (169.5 vs. 127.2 HU, p = 0.004). A threshold of 165 HU predicted the loss of 8p in clear cell RCCs with an accuracy of 78% (69/88), a specificity of 81% (62/77), and a negative predictive value of 94% (62/66). There were no significant differences in the pattern of enhancement, contour, neovascularity, calcification, or size between clear cell RCCs with a loss of 8p and those without this abnormality. CONCLUSION: Enhancement on multiphasic MDCT can predict the loss of 8p in clear cell RCCs and can thus provide a non-invasive means of guiding further management, including surgery, ablation, watchful waiting, or medical management.

Unenhanced MDCT in suspected urolithiasis: improved stone detection and density measurements using coronal maximum-intensity-projection images.

OBJECTIVE: The purpose of this study was to determine whether coronal maximum-intensity-projection (MIP) reformations improve urinary tract stone detection and density measurements compared with routine axial and coronal images. MATERIALS AND METHODS: Forty-five consecutive patients who underwent MDCT for suspected urolithiasis were included. Two radiologists independently determined the number of stones on 5-, 3-, and 1.25-mm axial, 5- and 3-mm coronal, and 5-mm coronal MIP images. The reference standard was obtained by consensus review using all six datasets. Stone density was determined for all calculi 4 mm or larger on all datasets. RESULTS: There were a total of 115 stones. Reader 1 identified 111 (96.5%), 112 (97.4%), 97 (84.3%), 102 (88.7%), 99 (86.1%), and 85 (73.9%) stones and reader 2 identified 105 (91.3%), 102 (88.7%), 85 (73.9%), 89 (77.4%), 89 (77.4%), and 76 (66.1%) stones on the MIP, 1.25-mm axial, 3-mm axial, 3-mm coronal, 5-mm coronal, and 5-mm axial images, respectively. Both readers identified more stones on the MIP images than on the 3- or 5-mm axial or coronal images (p < 0.0001). The mean difference in stone attenuation compared with the thin axial images was significantly less for the MIP images (44.6 HU) compared with 3-mm axial (235 HU), 3-mm coronal (309 HU), and 5-mm coronal (329.6 HU) or axial images (347.8 HU) (p < 0.0001). CONCLUSION: Coronal MIP reformations allow more accurate identification and density measurements of urinary tract stones compared with routine axial and coronal reformations.

Clear cell renal cell carcinoma: multiphasic multidetector CT imaging features help predict genetic karyotypes.

PURPOSE: To determine whether imaging characteristics at multiphasic multidetector computed tomography (CT) correlate with common karyotypic abnormalities in patients with clear cell renal cell carcinomas (ccRCCs). MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was waived for this HIPAA-compliant retrospective study. From January 2000 through September 2007, the prenephrectomy multiphasic (corticomedullary, nephrographic, and excretory phases), multidetector helical CT images of 58 histologically proved and karyotyped ccRCCs were reviewed by two readers with experience in abdominal imaging. Imaging features assessed included degree of attenuation, contour, and presence of calcifications and neovascularity. These features were independently correlated with specific karyotypic abnormalities on the resected specimens. Degree of attenuation data were analyzed with logistic regression for significance (P < .05), and morphologic characteristics were analyzed with odds ratios for assessing their diagnostic power. RESULTS: On unenhanced scans, 7% (two of 28) of ccRCCs with the loss of chromosome 3p were calcified, whereas 37% (11 of 30) of lesions without this anomaly were calcified (odds ratio, 0.13). During the corticomedullary phase, ccRCCs with the loss of chromosome Y enhanced more than those without this anomaly (130.0 vs 102.5 HU, P = .04), and ccRCCs with trisomy 7 enhanced less than those without this anomaly (105.8 vs 139.3 HU, P = .04). During the excretory phase, ccRCCs with trisomy 5 enhanced more than those without this anomaly (115.5 vs 83.4 HU, P = .03). CONCLUSION: The genetic makeup of ccRCCs affects their imaging features at multidetector CT examinations. Multidetector CT imaging characteristics may help suggest differences at the cytogenetic level among ccRCCs.

Detection and grading of esophageal varices on liver CT: comparison of standard and thin-section multiplanar reconstructions in diagnostic accuracy.

OBJECTIVE: The objective of our study was to evaluate the performance of liver CT in the diagnosis of esophageal varices in patients with cirrhosis and to determine whether thin-section multiplanar reconstructions (MPRs) improve accuracy. MATERIALS AND METHODS: We identified 109 patients with cirrhosis who underwent endoscopy within 10 weeks after dual-phase liver MDCT supplemented with thin-section axial and coronal portal venous phase reconstructions. Two blinded radiologists independently evaluated each CT examination for the presence and sizes of varices using standard 5-mm axial versus 1- to 3-mm multiplanar images in separate sessions. Sensitivity, specificity, and predictive value calculations and receiver operating characteristic analysis were performed using endoscopy as the reference standard. Interobserver variability and correlation of CT size to variceal grade were assessed. RESULTS: Twenty-six cases of high-risk esophageal varices were identified; all except two were detected on CT by one of the readers on standard 5-mm images. For both readers, sensitivity and negative predictive value (NPV) for the discrimination of high-risk varices using a criterion of 2 mm or greater were nearly the same for the standard 5-mm images versus the 1- to 3-mm multiplanar images (sensitivity and NPV: reader 1, 96% and 98% vs 96% and 99%; reader 2, and 89% and 95% vs 89% and 96%, respectively). Standard 5-mm images yielded a lower specificity for high-risk esophageal varices than the thin-section multiplanar images, and this difference was statistically significant for reader 2. Substantial interobserver agreement was noted for both esophageal varices detection and size measurements. CONCLUSION: Standard liver CT is sensitive for the detection of high-risk varices and deserves further investigation as a potential cost-effective screening tool for the evaluation of patients with cirrhosis. The addition of 1- to 3-mm MPRs may increase specificity for risk stratification based on size measurements.

Chronic Opioid Therapy in Cancer Survivors at a Specialty Oncology Pain Clinic: Opioid Dosing, Efficacy, and Safety During Five Years of Pain Management.

There are limited data regarding long-term safety and efficacy in cancer survivors receiving chronic opioid therapy. With conflicting recommendations on opioid-prescribing practices and lack of available outcome data, this study aimed to provide a longitudinal perspective on opioid prescribing in cancer survivors. A retrospective chart review at a comprehensive cancer care center pain clinic used data from pain clinic provider notes from 2013 to 2018. Inclusion criteria were patients in clinical remission not receiving active chemotherapy or immunotherapy and receiving opioids during the study period. Opioid dosing changes and outcomes between zero and five years were evaluated by standard statistical analysis. Thirty-two patients met inclusion criteria. Solid malignancies were more common than hematologic malignancies (72% vs. 28%). Common pain complaints were related to postsurgical changes (43%), postradiation (32%), and chemotherapy-induced pain syndromes (25%). There were no serious adverse events. One patient exhibited possible aberrant behavior. At the initial visit, the median morphine milligram equivalent per day (MME/day) was 130. Median MME/day at Year 0 (study start) and Year 5 was 135 and 159, respectively (P = 0.475). Functional status was satisfactory in 58% at Year 0 and increased to 91% of patients meeting their functional goals at Year 5. In a carefully monitored group of cancer survivors with persistent pain, chronic opioid therapy was safely managed during extended periods without significant opioid escalation or evidence of serious adverse events including aberrant behaviors. This population benefited when opioid therapy was managed with a focus on function rather than reduction of pain intensity scores.

Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists.

The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain.

Multidetector computed tomographic features of oncocytic papillary renal cell carcinoma, a new subtype.

The following report describes the computed tomographic (CT) features of oncocytic papillary renal cell carcinoma (OPRCC), a new subtype. An experienced genitourinary pathologist identified each tumor as type 1 or 2, oncocytic, or other. Two radiologists independently reviewed CT images and assessed maximal tumor diameter, degree of homogeneity, calcification, enhancement, and growth pattern. The 6 OPRCC lesions varied from 1.8 to 5 cm in diameter with a mean of 3.5 cm. Three of the oncocytic lesions were staged T1a, 2 T1b, and 1 T3a. All lesions displayed exophytic growth and were confined to the kidney. Five of the 6 lesions were smooth, and 1 was lobular. Four were homogenously enhancing, whereas 2 were heterogeneously enhancing. The mean (SD) corticomedullary phase enhancement was 70.6 (21.7) HU, nephrographic phase was 69.9 (13.3) HU, and excretory phase was 58.7 (6) HU. In conclusion, OPRCC is a newly described subtype that has CT features similar to type 1 papillary renal cell carcinoma.

Plate augmentation in anterior cervical discectomy and fusion with cage for degenerative cervical spinal disorders.

Anterior cervical discectomy and fusion (ACDF) with cage alone (ACDF-C) is associated with a significant incidence of subsidence, local kyphosis, and migration. The use of concurrent plate augmentation may decrease the incidence of these complications while improving the fusion rate. The purpose of the study is to present our results with ACDF with cage and plate augmentation (ACDF-CPA) and to compare these results to previous reports of outcomes following ACDF-C. We evaluated the radiologic and clinical parameters of 83 patients (266 fusion sites) who had an ACDF-CPA between March 2002 and May 2006. Radiologic parameters included fusion rate, fusion time, fusion type, site of pseudoarthrosis and rate and degree of subsidence. Clinical parameters included complications and overall outcomes assessed with Robinson's criteria; 79 of 83 patients showed bony fusion (95.1%) at last follow-up postoperatively, and there was no significant difference in fusion rate between the number of fusion levels. Type I (pseudoarthrosis) was noticed in 9 patients (12 fusion sites), type II in 14 (19 fusion sites), and type III in 60 (235 fusion sites). Five type I and all type II fusions converged into type III by the last follow-up; 76 of 83 patients (91.6%) experienced good clinical outcomes. Pseudoarthrosis occurred more commonly in more proximal locations, and the subsidence rate was significantly greater in two-level fusions when compared with single-level fusions (P = 0.046). There were four metal-related complications. Plate augmentation in one- or two-level anterior cervical fusions for degenerative cervical spine disorders may improve fusion rates and reduce subsidence and complication rates, resulting in improved clinical outcomes.

The efficacy of rhBMP-2 versus autograft for posterolateral lumbar spine fusion in elderly patients.

Few studies have specifically examined the outcomes following rhBMP-2 usage in patients 65 years and older. The purpose of this retrospective study is to evaluate the efficacy of rhBMP-2 with allograft versus autograft for posterolateral lumbar fusion in patients 65 years and older. One hundred twenty-seven patients were divided into three groups based on fusion material and age. Subjects in group A (n = 34) consisted of patients 65 years and older who received rhBMP-2 and allograft. Group B (n = 52) was composed of patients under 65 years of age with rhBMP-2 and allograft. Subjects in group C (n = 41) were 65 years and older with autograft use. A comparison was made of fusion rate, fusion time (noticed, solid), clinical outcome, VAS, perioperative complications and revision rate between each group. The fusion rate and fusion time were similar in groups A and C; however, these were lower than that observed in group B. Clinical outcomes were similar amongst the groups. There were no significant differences in VAS and perioperative complication rate between groups A and C. In patients 65 years and older, rhBMP-2 with allograft may lead to acceptable fusion rates and fusion times, good clinical outcomes and reduced perioperative complications. The combination of rhBMP-2 with allograft yields equivalent outcomes as autograft in elderly patients undergoing instrumented posterolateral lumbar fusion. Additionally, when compared to patients under 65 years of age undergoing posterolateral lumbar fusion, the use of rhBMP-2 was not sufficient to overcome all aspects of the age-related weakened osteoinductive capacity encountered in elderly patients.

Evidence for significant polydrug use among ecstasy-using college students.

Ecstasy (MDMA) has been added to the spectrum of illicit drugs used by college students. In this study, the authors estimated the prevalence of ecstasy use within a large college student sample and investigated the polydrug-use history of those ecstasy users. They administered an anonymous questionnaire to college students (N = 1,206) in classrooms at a large university in the mid-Atlantic United States. The overall student response rate was 91%. Nine percent of the sample reported lifetime ecstasy use. Because 98% of ecstasy users had used marijuana, the authors compared polydrug use between ecstasy users and individuals who had used marijuana but not ecstasy. Ecstasy users, as compared with these marijuana users, were significantly more likely to have used inhalants (38% vs. 10%), LSD (38% vs. 5%), cocaine (46% vs 2%), and heroin (17% vs 1%) in the past year. Significant polydrug use among college student ecstasy users has important implications for their substance abuse treatment.

Time and sequence dependence of hydroxyurea in combination with gemcitabine in human KB cells.

Gemcitabine (Gem) is a deoxycytidine analogue whose active metabolite, dFdCTP, blocks DNA elongation and has a cytotoxic effect. Hydroxyurea (HU) is an S-phase specific inhibitor of ribonucleotide reductase (RR) with a broad spectrum of antitumor effects. We report here that low-dose HU enhanced the activity of Gem in a time- and sequence-dependent manner. Exposure of human oropharyngeal carcinoma KB cells to HU followed by the addition of Gem at various times significantly enhanced cytotoxicity when compared to controls. The greatest enhancement of cytotoxicity occurred when Gem was added 8 hours after HU. By treating KB cells with radiolabeled-Gem following HU treatment, we further confirmed that the incorporation of dFdCTP into DNA increased 6-fold over control reactions under these conditions. The mechanism of the time- and sequence-dependent enhancement is associated with a decrease in hRRM2 RNA, protein, and activity between 4 and 8 hours. The subsequent depletion of dNTP pools allows for increased incorporation of dFdCTP into cells arrested in S-phase, resulting in higher levels of cytotoxicity than either treatment alone.

Synthetic 3-O-methylmannose-containing polysaccharides (sMMPs): design and synthesis.

With the hope of mimicking the chemical and biological properties of natural 3-O-methylmannose-containing polysaccharides (MMPs), synthetic 3-O-methylmannose-containing polysaccharides (sMMPs) were designed and synthesized in a convergent manner. With little modification of the Mukaiyama glycosidation, high alpha-selectivity (>50:1 approximately >20:1) and yields (79 approximately 74%) were achieved for the key glycosidation steps. The exceptionally high alpha-selectivity observed was shown to be consequent to the selective anomerization of beta- to alpha-anomer under the glycosidation conditions. This glycosidation is well suited for a highly convergent oligosaccharide synthesis, particularly because of excellent chemical yields even when using approximately equal-sized donors and acceptors in an approximately 1:1 molar ratio. An iterative reaction sequence allowed the growing oligosaccharide to double in size after each cycle and led to an efficient synthesis of sMMP 8-, 12-, and 16-mers 18-20.

New practical synthesis of indazoles via condensation of o-fluorobenzaldehydes and their O-methyloximes with hydrazine.

The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.

Synthesis of erythromycin derivatives via the olefin cross-metathesis reaction.

Olefin cross metathesis (CM) was applied to the synthesis of 6-O-substituted erythromycin derivatives. The reactions were catalyzed by transition metal alkylidene complexes, particularly bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (Grubbs' first-generation catalyst). This approach allowed for the elaboration of the 6-O-allyl group of highly functionalized macrolides at various stages of the synthetic sequence, affording 6-O-3-aryl-propenyl products with excellent E-selectivity. Little or no self-dimerization of the reacting components was found in the crude mixtures. Preliminary kinetic data accounts for the observed cross-selectivity based on substrate reactivity and steric factors.