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Abstract This work presents an end‐to‐end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14C‐labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100‐µg i.v. dose of cold‐labeled 13C‐venetoclax at the oral time of maximum concentration (Tmax). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography‐tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.

Background: Electronic health records (EHRs) are commonplace in industrialized countries. Many hospitals are granting their patients access to their medical information through online patient portals. In this report, we describe a retrospective analysis of patient access to diagnostic test results released through the patient portal (MyChart; Epic, Inc.) at a state academic medical center. Methods: We analyzed 6 months of data for anatomic pathology, clinical laboratory, and radiology test results to evaluate variations in results release (automated vs. manual) and subsequent patient access to the institutional patient portal. During this period, diagnostic test results were released for all patient encounters including inpatient units, outpatient clinics, and the emergency department. Results: Manual results release by providers before automated release time occurred most commonly in the outpatient setting. The highest rates of access of diagnostic test results occurred for outpatients (about 30% overall view rate), females (two times or more compared to males in nearly every age bracket), and 20–45-year-old. Access rates of diagnostic tests in the emergency department or inpatient units were

Research has been conducted on the axially chiral biaryls. The atropselective preparation of these compounds carried out via the chirality transfer from the secondary alcohols' stereogenic center to the stereogenic axis is described.

This work presents an end‐to‐end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14C‐labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100‐µg i.v. dose of cold‐labeled 13C‐venetoclax at the oral time of maximum concentration (Tmax). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography‐tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development. [ABSTRACT FROM AUTHOR]

Synthesis of 9(S)-9-dihydro-12-omicron-methylerythromycin A was studied via regioselective methylation. The results suggested that the 12-hydroxyl group of the NaBH4 reduction product is the most active toward methylation. Moreover, it was proposed that the formation of boron complex protected the 6,, 9-, and 11-hydroxyl groups from methylation. The significance of the chemistry used in this study lies on possible synthetic modification of the 12-hydroxyl group of erythromycin A derivatives.

Research has been conducted on nonsteroidal ligand for the glucocorticoid receptor. The authors describe the scaleable and practical synthesis of this ligands which starts from 1,3-dimethoxybenzene.

Background/aims: 2D-shearwave elastography is an established method for liver stiffness measurement (LSM). However, the success rate of LSM using the recommended standard technique in the right lobe is limited by several factors. We aimed to compare LSM in the right and left liver lobe in order to evaluate whether LSM in the left lobe could be an alternative if measurements in the right lobe are not feasible. Methods: A total of 116 subjects, 58 healthy volunteers and 58 patients with chronic liver disease (CLD), were prospectively included. LSM were performed in the right lobe and in the left lobe, both in neutral and in inspiration position. Results: LSM in the left lobe (8.39(±4.83)kPa) was significantly (p <.001) higher than LSM in the right lobe (6.27(±2.45)kPa). LSM in inspiration position (8.60(±4.33) kPa) was significantly (p =.009) higher than LSM in neutral position (7.70(±3.01)kPa). LSM in the left lobe overestimated the grade of fibrosis in 50.0% of the patients with CLD. However, correlation between LSM values right and left was strong (r = 0.856) and additional use of LSM in the left lobe increased the success rate from 106/116 (91.4%) to 112/116 (96.6%; p =.098). High skin-to-liver-capsule-distance and presence of ascites were independent risk factors for non-successful LSM. Conclusions: Despite significantly higher values, LSM in the left lobe may be an alternative if LSM in the right lobe is not feasible, and cirrhosis can be ruled out with high probability if LSM is within the normal range. [ABSTRACT FROM AUTHOR]

Radiation source detection is an important problem in homeland security-related applications. Deploying a network of detectors is expected to provide improved detection due to the combined, albeit dispersed, capture area of multiple detectors. Recently, localization-based detection algorithms provided performance gains beyond the simple “aggregated” area as a result of localization being enabled by the networked detectors. We propose the following three localization-based detection approaches: 1) source-attractor radiation detection (SRD); 2) triangulation-based radiation source detection (TriRSD); and 3) the ratio of square distance-based radiation source detection (ROSD-RSD). We use canonical datasets from Domestic Nuclear Detection Office's intelligence radiation sensors systems tests to assess the performance of these methods. Extensive results illustrate that SRD outperforms TriRSD and ROSD-RSD, and other existing detection algorithms based on the sequential probability ratio test and maximum likelihood estimation in terms of both false alarm and detection rates. [ABSTRACT FROM AUTHOR]

Background: Blood smear reviews by pathologists (BSR) are ordered frequently at our institution, take time to evaluate, and result in a written report. Minimal research has been done regarding the amount of novel data reported and its clinical utility. Methods: Detailed chart review was performed on BSR orders from January 1, 2015 to March 31, 2015 to assess reasons for smear review, if results were mentioned in the chart, if laboratory-driven reviews were already performed, and if novel, clinically influential data was reported. The trends in ordering was also evaluated. Results: A total of 277 reviews were performed and were most commonly ordered to evaluate the presence of malignancy (43%), hemolysis (18%), and anemia (16%). For 130 of the 277 specimens, laboratory-driven smear review was already performed. The BSR smear review findings were not mentioned in the patient chart in 52% of cases. The report provided novel data in 187 cases (68%) which mainly were minor findings such as low levels of red blood cell abnormalities. The novel data appeared to influence clinical decision making in only 3 cases (1%). Conclusions: Although novel data are often reported, only rarely does it appear to be clinically significant and the information frequently overlaps with information already provided by laboratory-initiated smear reviews. Discussion with, and education of, clinical staff may increase appropriate utilization. [ABSTRACT FROM AUTHOR]

Background: Electronic health records (EHRs) are commonplace in industrialized countries. Many hospitals are granting their patients access to their medical information through online patient portals. In this report, we describe a retrospective analysis of patient access to diagnostic test results released through the patient portal (MyChart; Epic, Inc.) at a state academic medical center. Methods: We analyzed 6 months of data for anatomic pathology, clinical laboratory, and radiology test results to evaluate variations in results release (automated vs. manual) and subsequent patient access to the institutional patient portal. During this period, diagnostic test results were released for all patient encounters including inpatient units, outpatient clinics and the emergency department. Results: Manual results release by providers before automated release time occurred most commonly in the outpatient setting. The highest rates of access of diagnostic test results occurred for outpatients (about 30% overall view rate), females (two times or more compared to males in nearly every age bracket) and 20-45-year-old. Access rates of diagnostic tests in the emergency department or inpatient units were <10% across all populations. Access of diagnostic test results was very low for 12-17-year-old, likely influenced by institutional policies limiting parental proxy access within this pediatric age range. Approximately 20% of outpatient laboratory results were viewed by patients within 8 h of release from the EHR to the patient portal and 10% within 2 h of release. Conclusions: Patient accessing of diagnostic test results were generally higher for females, outpatients and 20-45-year-old. Approximately, 20% of outpatient results were viewed quickly by patients after release to the EHR. [ABSTRACT FROM AUTHOR]

Objective: Panels of clinical laboratory testing may generate "incidental" critical values from unordered parameters. Existing regulations do not clearly delineate guidelines for handling incidental critical values. The objective of this study was to examine the patterns and clinical utility of incidental critical values at 2 critical care laboratories within an academic medical center. Methods: In this retrospective study, the electronic health record and laboratory information system were reviewed for incidental critical results obtained from blood gas analyzer analysis of whole blood specimens between November 2010 and August 2014. Results: Within the retrospective time period, 9,092 incidental critical results were documented, of which only 11.8% were added to the Conclusion: In this study, at an academic medical center, incidental critical values associated with blood gas analyzers were added on at a low rate and often provided redundant information. Relative to the manual effort involved in care providers' notification and documentation of results, incidental critical values appear to have low clinical utility. [ABSTRACT FROM AUTHOR]

Abstract: A practical and highly efficient process for the preparation of β-arylethylamines 7 was developed. Benzylic organozinc compounds 10 were reacted with the iminium salts 9 generated in situ from the amine salt 8 and paraformaldehyde in one pot and in a polar and aprotic solvent, such as NMP. A variety of the β-arylethylamines were prepared in 43–91% yields. [Copyright &y& Elsevier]

Examines the asymmetric synthesis for atropselective preparation of axially chiral biaryl with chirality transfer. Induction of the glucocorticoid receptor; Formation of the intramolecular silyl group; Observation of the phenolic anions.

A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized high-yielding and high-throughput Negishi protocol. The quinoline core 8 was constructed by using a modified Skraup reaction. The final product was obtained by a direct allylation reaction of lactol 10 with allyltrimethylsilane. The process was accomplished efficiently to produce 1A in 25% overall yield and >99% purity with simple and practical isolation and purification procedures. [ABSTRACT FROM AUTHOR]

The use of DNA barcoding in fish diet studies is becoming more widespread, but the effect of prey digestion on barcoding accuracy has been poorly studied. We conducted a series of controlled feeding experiments, with red lionfish (Pterois volitans) as predators and Gulf killifish (Fundulus grandis) as prey, designed to test the effect of digestion time (12–42 h), prey item (sample) preservation (inside versus outside stomach), and sample preparation (washed versus unwashed) on DNA barcoding classification accuracy. Competitive interactions occurred between lionfish and killifish DNA during PCR amplification when universal COI primers were utilized; thus, primers were designed that matched the same priming site in both killifish and lionfish DNA. The proportion of amplified killifish DNA relative to lionfish DNA per sample was estimated using multiplex quantitative PCR (qPCR) and shown to decrease with longer digestion times, especially when samples were retained within lionfish stomachs for preservation. The effects of digestion and preservation method on amplifiable DNA resulted in significant effects on barcoding accuracy, resulting in erroneous identification of the predator (i.e., self-DNA) for nearly 25% of samples. Removing prey from predator stomachs prior to preservation significantly increased the proportion of amplified killifish DNA from samples, and enhanced barcoding accuracy. Overall, study results have important implications for the probability of false negatives for prey items, as well as false positives for self-DNA, when utilizing barcoding to characterize piscine diet. Results also highlight the need to conduct more method validation research given the increasing prevalence of DNA barcoding as a means to identify specific prey items in fish diet studies. • Degree of digestion highly influenced the quantity of prey DNA amplified via qPCR. • Contaminating predator DNA impacted the ability of DNA barcoding to identify prey. • DNA barcoding accuracy decreased significantly when digestion of prey exceeded 24 h. • Preserving fish prey outside of predator stomachs increased DNA barcoding accuracy. [ABSTRACT FROM AUTHOR]