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The purpose of this study was to compare surgical outcomes in patients who underwent ACL reconstruction, with and without internal bracing, at 1-3, 4-7, and 8-12 months of postoperative physical therapy. Previous studies show that ACL reconstruction with internal bracing allows earlier and more aggressive rehabilitation. Therefore, it was hypothesized that patients with internal bracing would display superior surgical recovery compared to ACL reconstruction alone after adjusting for length of physical therapy.1, 2, 3.Patients who underwent ACL reconstruction and had a minimum two-year follow-up were included. Demographics including age, gender, use of internal bracing, and pre-operative level of activity were collected. Patient-reported outcomes were assessed using KOOS scores.46 patients underwent ACL reconstruction between January 2013 and December 2015. The mean age was 31.53 ± 8.37 years. Patients who received ACL reconstruction with internal bracing reported similar improvement in KOOS scores (mean = 42.82 ± 15.44; median = 46.39 [34.52-51.80]) compared to ACL reconstruction alone (mean = 38.18 ± 19.91; median = 40.17 [29.49-53.90]) (p = 0.475). Patients who received ACL reconstruction with internal bracing reported comparable improvement to ACL reconstruction alone at 0-3 months (Internal bracing: mean = 35.39 ± 15.26, median = 40.45 [26.49-47.73]; No internal bracing: mean = 42.51 ± 12.33, median = 39.32 [35.69-52.94], p = 0.4113), 4-7 months (Internal bracing: 41.96 ± 14.49, 45.55 [33.94-52.68]; No internal bracing: 30.64 ± 32.29, 41.65 [26.17-46.12], p = 0.7491) and 8+ months groups (Internal bracing: 63.36 ± 13.06, 63.36 [58.74-67.98]; No internal bracing: 47.05 ± 10.14, 47.05 [43.46-50.63]) (p = 0.6985).This study demonstrates no statistical difference in functional outcome scores when comparing patients with internally braced ACL reconstruction compared to standard reconstruction. Therefore, the increased structural support provided by use of internal bracing in ACL reconstruction does not afford to quicker improvement in patient-reported recovery.

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: The objective of this study was to assess the safety and effectiveness of the first commercial configuration of a tubeless automated insulin delivery system, Omnipod® 5, in children (6–13.9 years) and adults (14–70 years) with type 1 diabetes (T1D) in an outpatient setting. Materials and Methods: This was a single-arm, multicenter, prospective clinical study. Data were collected over a 14-day standard therapy (ST) phase followed by a 14-day hybrid closed-loop (HCL) phase, where participants (n = 36) spent 72 h at each of three prespecified glucose targets (130, 140, and 150 mg/dL, 9 days total) then 5 days with free choice of glucose targets (110–150 mg/dL) using the Omnipod 5. Remote safety monitoring alerts were enabled during the HCL phase. Primary endpoints were difference in time in range (TIR) (70–180 mg/dL) between ST and HCL phases and proportion of participants reporting serious device-related adverse events. Results: Mean TIR was significantly higher among children in the free-choice period overall (64.9% ± 12.2%, P

Despite the growth of photoredox methods in academia, application of photoredox at scale in the pharmaceutical and fine chemical industries has been slow. In this report, a photoredox trifluoromethylation of a thiophenol was modified from the original literature report and the mechanism was investigated to define key scale-up parameters. The mechanistic insight was leveraged in the design and execution of two different reactor designs: an LED-based plug flow photoreactor as well as a laser-based continuous stirred tank photoreactor. In one of the first examples of commercial scale photoredox chemistry, the process was scaled to provide over 500 kilograms of the desired intermediate and amended to fully continuous manufacturing.

ABT-450 (8), a potent hepatitis C (HCV) NS3/4A protease inhibitor, was approved as part of AbbVie's first generation HCV treatment for the United States in December 2014. A series of process optimizations were developed over six years to support the program starting with recycling of a previous protease inhibitor candidate through route development and final process. This discussion will focus on optimization of the final six steps starting from dipeptide 12 and amino acid 13 and highlights the use of a large scale ring closing metathesis (RCM), reactive crystallizations for isolation of intermediates, and detailed process understanding of the final sulfonamide coupling. The process provides ABT-450 (8) in 72% overall yield for the final 6 steps.

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.

The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with99% area purity.

Concilium medii aevi, Bd. 3 (2000): Concilium medii aevi

Transcatheter embolotherapy of the spermatic vein in males is a minimally invasive therapeutic option in the management of the male varicocele. Indications for treatment include pain, infertility/subfertility, and the presence of a varicocele in a male child or adolescent with testicular atrophy on the side of the varicocele. This chapter presents an overview of technique, indications, complications, and outcomes in managing the male varicocele.

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.

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 r...

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 “parent” order following clinical notification. Incidental critical results frequently occurred in patients who had recent critical values for the same parameter. 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. * Abbreviations : ABG : arterial blood gas CAP : College of American Pathologists CLIA ’88 : Clinical Laboratory Improvement Amendments of 1988 EHR : electronic health record ICU : intensive care unit LIS : laboratory information system MLT : medical laboratory technician MT : medical technologist NICU : neonatal intensive care unit PICU : pediatric intensive care unit

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.