Measurement of the coracohumeral distance on magnetic resonance imaging in a large patient cohort.

BACKGROUND: Coracoid impingement syndrome is an increasingly recognized etiology of anterior shoulder pain. Numerus studies have documented the coracohumeral distance (CHD) as a primary or secondary measurement in symptomatic individuals, but there lacks an evaluation of CHD in a large cohort of asymptomatic individuals. The purpose of this study was to quantify a normative distribution of the CHD in a large cohort of healthy, asymptomatic subjects with no history of impingement or shoulder instability. METHODS: Incoming first-year students in the United States Military Academy were offered enrollment in this study as part of a prospective cohort to assess the normal anatomic relationships of the shoulder girdle. Magnetic resonance images were obtained, and a board-certified, fellowship-trained musculoskeletal radiologist performed measurements of the smallest distance from the coracoid to the humeral head on axial images. RESULTS: Magnetic resonance images of 714 subjects were available for analysis, including 630 males and 84 females, with a total of 1120 individual shoulders with images of adequate quality. The mean CHD for all shoulders imaged was 13.7 mm. The mean CHD in male shoulders was 13.8 mm, and in female subjects the average was 12.4 mm. CONCLUSIONS: This study is the largest of its kind to evaluate the CHD in asymptomatic, healthy shoulders to date and demonstrates a mean CHD of 13.7 mm for all subjects. This information can help to standardize "normal" ranges and act as a comparison for future work, when taken in the context of age and imaging in neutral rotation.

Increased Glenoid Retroversion Is Associated With Increased Rotator Cuff Strength in the Shoulder.

BACKGROUND: The rotator cuff muscles are critical secondary stabilizers in the shoulder. Increased glenoid retroversion and rotator cuff strength have been associated with the risk of posterior shoulder instability; however, the effect of increased glenoid retroversion on rotator cuff strength remains unclear. PURPOSE/HYPOTHESIS: The purpose was to examine the association between glenoid version and rotator cuff strength in the shoulder in a young and healthy population with no history of shoulder instability. The hypothesis was that increased glenoid retroversion would be associated with increases in rotator cuff muscle strength. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A prospective cohort study was conducted over a 4-year period within a high-risk population to identify the risk factors for shoulder instability. Analyzed participants included 574 freshmen entering a United States service academy. Baseline data collected upon entry into the study included magnetic resonance imaging measurements of glenoid version. Rotator cuff strength was also assessed at baseline using a handheld dynamometer. Internal and external rotation strength were assessed with the glenohumeral joint positioned in neutral and in 45° of abduction. The current study represents an analysis of the baseline data from this cohort. RESULTS: The mean age, height, and weight of participants was 18.77 ± 0.97 years, 176.81 ± 8.48 cm, and 73.80 ± 12.45 kg, respectively. The mean glenoid version at baseline was 7.79°± 4.85° of retroversion. Univariate linear regression analyses demonstrated that increased glenoid retroversion was associated with increased internal and external rotation strength of the rotator cuff in neutral and 45° of abduction (P < .001). Similar results were observed in multivariable models controlling for important confounding variables. CONCLUSION: The results of this study demonstrate that as glenoid retroversion increases, internal and external rotation strength of the rotator cuff also increase in a young and healthy athletic population. These compensatory changes may contribute to increased glenohumeral dynamic stability in the presence of worse static stability with increasing retroversion.

Prospective Evaluation of Glenoid Bone Loss After First-time and Recurrent Anterior Glenohumeral Instability Events.

BACKGROUND: Determining the amount of glenoid bone loss in patients after anterior glenohumeral instability events is critical to guiding appropriate treatment. One of the challenges in treating the shoulder instability of young athletes is the absence of clear data showing the effect of each event. PURPOSE: To prospectively determine the amount of bone loss associated with a single instability event in the setting of first-time and recurrent instability. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The authors conducted a prospective cohort study of 714 athletes surveilled for 4 years. Baseline assessment included a subjective history of shoulder instability. Bilateral noncontrast shoulder magnetic resonance imaging (MRI) was obtained for all participants with and without a history of previous shoulder instability. The cohort was prospectively followed during the study period, and those who sustained an anterior glenohumeral instability event were identified. Postinjury MRI with contrast was obtained and compared with the screening MRI. Glenoid width was measured for each patient's pre- and postinjury MRI. The projected total glenoid bone loss was calculated and compared for patients with a history of shoulder instability. RESULTS: Of the 714 athletes (1428 shoulders) who were prospectively followed during the 4-year period, 22 athletes (23 shoulders) sustained a first-time anterior instability event (5 dislocations, 18 subluxations), and 6 athletes (6 shoulders) with a history of instability sustained a recurrent anterior instability event (1 dislocation, 5 subluxations). On average, there was statistically significant glenoid bone loss (1.84 ± 1.47 mm) after a single instability event ( P < .001), equivalent to 6.8% (95% CI, 4.46%-9.04%; range, 0.71%-17.6%) of the glenoid width. After a first-time instability event, 12 shoulders (52%) demonstrated glenoid bone loss ≥5% and 4 shoulders, ≥13.5%; no shoulders had ≥20% glenoid bone loss. Preexisting glenoid bone loss among patients with a history of instability was 10.2% (95% CI, 1.96%-18.35%; range, 0.6%-21.0%). This bone loss increased to 22.8% (95% CI, 20.53%-25.15%; range, 21.2%-26.0%) after additional instability ( P = .0117). All 6 shoulders with recurrent instability had ≥20% glenoid bone loss. CONCLUSION: Glenoid bone loss of 6.8% was observed after a first-time anterior instability event. In the setting of recurrent instability, the total calculated glenoid bone loss was 22.8%, with a high prevalence of bony Bankart lesions (5 of 6). The findings of this study support early stabilization of young active patients after a first-time anterior glenohumeral instability event.

Incidence of Anterolateral Ligament Tears in the Anterior Cruciate Ligament-Deficient Knee: A Magnetic Resonance Imaging Analysis.

PURPOSE: The purpose of this study is to determine the incidence of anterolateral ligament (ALL) tears on magnetic resonance imaging (MRI) in patients diagnosed with anterior cruciate ligament (ACL) tears. Furthermore, this study sought to determine the inter- and intraobserver reliability in diagnosing an ALL tear. METHODS: The MRI radiologic database at a community military hospital was queried for ACL tears over the period of January 2011 to April 2015. During this time, 181 MRIs were identified as having ACL tears. The MRIs were then independently reviewed by an orthopaedic surgeon and a musculoskeletal (MSK) trained radiologist. Both reviewers, independently confirmed the ACL tears, and the ALL was noted to be either torn, intact, or not visualized on axial, sagittal, and coronal images. Four weeks later the same MRIs were then reviewed for the presence and location of an ALL tear to determine inter- and intraobserver reliability. RESULTS: The MSK radiologist found ALL tears on MRI in 28.2% of the cases, while the orthopaedic surgeon found ALL tears in 39.8% of the cases; 5.5% of the MRIs were characterized as having a nonvisualized ALL. The interobserver reliability was noted to have a kappa value of 0.333. The intraobserver reliability of the MSK radiologist and orthopaedic surgeon demonstrated a kappa value of 0.654 and 0.251, respectively. CONCLUSIONS: This study shows that the majority of patients with a known ACL tear on MRI do not have a tear of the ALL. Additionally, the interobserver reliability of surgeons and radiologist is fair. In this study, the MSK radiologist had higher intraobserver reliability when looking for an ALL tear. LEVEL OF EVIDENCE: Level IV, case control study.

N-Methylation of BI 187004 by Thiol S-Methyltransferase.

BI 187004, an 11ß-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite [N-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N-methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro-α-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

Carbon-13 and carbon-14 labeled dabigatran etexilate and tritium labeled dabigatran.

Dabigatran etexilate or pradaxa, a novel oral anticoagulant, is a reversible, competitive, direct thrombin inhibitor. It is used to prevent strokes in patients with atrial fibrillation and the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or a knee. Pradaxa is the only novel oral anticoagulant available with both proven superiority to warfarin and a specific reversal agent for use in rare emergency situations. The detailed description of the synthesis of carbon-13 and carbon-14 labeled dabigatran etexilate, and tritium labeled dabigatran is described. The synthesis of carbon-13 dabigatran etexilate was accomplished in eight steps and in 6% overall yield starting from aniline-13 C6 . Ethyl bromoacetate-1-14 C was the reagent of choice in the synthesis of carbon-14 labeled dabigatran etexilate in six steps and 17% overall yield. Tritium labeled dabigatran was prepared using either direct tritium incorporation under Crabtree's catalytic conditions or tritium-dehalogenation of a diiodo-precursor of dabigatran.

Effect of Microfracture on Meniscal Tear Healing in a Goat (Capra hircus) Model.

Meniscal injuries are an extremely common cause of knee pain. Meniscal repairs performed with concomitant anterior cruciate ligament reconstruction appear to heal at a higher rate than meniscal repairs performed in isolation. This may be due in part to the release of marrow elements into the knee and the time of meniscal repair. In cases of isolated meniscal repair, some orthopedic surgeons use microfracture to release marrow elements into the joint as an adjunct to enhance meniscal healing. This study evaluated rates of meniscal tear healing with or without the performance of microfracture in a goat (Capra hircus) model. Forty castrated young adult male goats underwent either a horizontal or a longitudinal 1.0-cm meniscal tear with or without microfracture. All procedures were performed open, in a bloodless field. Meniscal tears were created in the peripheral half of the body of the medial meniscus. The goats were euthanized at 6 months, and meniscal tears were analyzed and classified as complete healing, partial healing, or no healing by direct visualization. A probe was used as an aid to evaluate and classify the meniscal tears. Twenty (87%) of 23 goat meniscal tears showed at least partial healing when performed with concomitant microfracture. Only 5 (29%) of 17 menisci showed any healing in goats that did not receive microfracture. This difference in healing rates was statistically significant (P<.001). Fifteen (65%) meniscal tears accomplished with microfracture were completely healed, whereas only 2 (12%) menisci showed complete healing without microfracture (P<.001). The results of this study suggest that the release of bone marrow elements into the knee by microfracture improves meniscal healing rates.

Peroneus Brevis Tendon Variant Insertion on the Calcaneus.

Insertion of the peroneus brevis tendon normally occurs at the lateral aspect of the fifth metatarsal base. However, there is new evidence that congenital variant insertion of the tendon on the calcaneal peroneal tubercle occurs in a small segment of the population. We report a case of 24-year old male presenting with non-traumatic ankle pain who underwent ankle magnetic resonance imaging. Imaging demonstrated insertion of the peroneus brevis tendon on the calcaneal peroneal tubercle with absence of the tendon distal to the calcaneus. Furthermore, in reviewing 200 consecutive ankle magnetic resonance examinations, the authors discovered one additional case of this variant. We discuss the magnetic resonance imaging characteristics of this anatomic variant, the implications for clinical management, and review the literature on peroneal anatomic variations.

Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon-13 and carbon-14.

Deleobuvir, (2E)-3-(2-{1-[2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol-6-yl)prop-2-enoic acid (1), is a non-nucleoside, potent, and selective inhibitor of hepatitis C virus NS5B polymerase. Herein, we describe the detailed synthesis of this compound labeled with carbon-13 and carbon-14. The synthesis of its three major metabolites, namely, the reduced double bond metabolite (2) and the acyl glucuronide derivatives of (1) and (2), is also reported. Aniline-(13) C6 was the starting material to prepare butyl (E)-3-(3-methylamino-4-nitrophenyl-(13) C6 )acrylate [(13) C6 ]-(11) in six steps. This intermediate was then used to obtain [(13) C6 ]-(1) and [(13) C6 ]-(2) in five and four more steps, respectively. For the radioactive synthesis, potassium cyanide-(14) C was used to prepare 1-cylobutylaminoacid [(14) C]-(23) via Buchrer-Bergs reaction. The carbonyl chloride of this acid was then used to access both [(14) C]-(1) and [(14) C]-(2) in four steps. The acyl glucuronide derivatives [(13) C6 ]-(3), [(13) C6 ]-(4) and [(14) C]-(3) were synthesized in three steps from the acids [(13) C6 ]-(1), [(13) C6 ]-(2) and [(14) C]-(1) using known procedures.

Synthesis of empagliflozin, a novel and selective sodium-glucose co-transporter-2 inhibitor, labeled with carbon-14 and carbon-13.

Empagliflozin, (2S,3R,4R,5S,6R)-2-[4-chloro-3-[[4-[(3S)-oxolan-3-yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol was recently approved by the FDA for the treatment of chronic type 2 diabetes mellitus. Herein, we report the synthesis of carbon-13 and carbon-14 labeled empagliflozin. Carbon-13 labeled empagliflozin was prepared in five steps and in 34% overall chemical yield starting from the commercially available α-D-glucose-[(13)C6]. For the radiosynthesis, the carbon-14 atom was introduced in three different positions of the molecule. In the first synthesis, Carbon-14 D-(+)-gluconic acid δ-lactone was used to prepare specifically labeled empagliflozin in carbon-1 of the sugar moiety in four steps and in 19% overall radiochemical yield. Carbon-14 labeled empagliflozin with the radioactive atom in the benzylic position was obtained in eight steps and in 7% overall radiochemical yield. In the last synthesis carbon-14 uniformly labeled phenol was used to give [(14)C]empagliflozin in eight steps and in 18% overall radiochemical yield. In all these radiosyntheses, the specific activities of the final compounds were higher than 53 mCi/mmol, and the radiochemical purities were above 98.5%.

Risk factors for anterior glenohumeral instability.

BACKGROUND: While anterior glenohumeral instability has been shown to be common in young athletes, the risk factors for injury are poorly understood. PURPOSE/HYPOTHESIS: To determine the modifiable and nonmodifiable risk factors for anterior shoulder instability in a high-risk cohort. The hypothesis was that specific baseline factors would be associated with the subsequent risk of injury. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: We conducted a prospective cohort study in which 714 young athletes were followed from June 2006 through May 2010. Baseline assessments included a subjective history of instability, physical examination by a sports medicine fellowship-trained orthopaedic surgeon, range of motion, strength with a handheld dynamometer, and bilateral noncontrast shoulder magnetic resonance imaging (MRI). A musculoskeletal radiologist measured glenoid version, glenoid height, glenoid width, glenoid index (height-to-width ratio), glenoid depth, rotator interval (RI) height, RI width, RI area, RI index, and the coracohumeral interval. Subjects were followed to document all acute anterior shoulder instability events during the 4-year follow-up period. The time to anterior shoulder instability event during the follow-up period was the primary outcome of interest. Univariate and multivariable Cox proportional hazards regression models were used to analyze the data. RESULTS: Complete data were available for 714 subjects. During the 4-year surveillance period, there were 39 anterior instability events documented at a mean of 285 days. While we controlled for covariates, significant risk factors of physical examination were as follows: apprehension sign (hazard ratio [HR], 2.96; 95% CI, 1.48-5.90; P = .002) and relocation sign (HR, 4.83; 95% CI, 1.75-13.33; P = .002). Baseline range of motion and strength measures were not associated with subsequent injury. Significant anatomic risk factors on MRI measurement were glenoid index (HR, 8.12; 95% CI, 1.07-61.72; P = .043) and the coracohumeral interval (HR, 1.20; 95% CI, 1.08-1.34; P = .001). CONCLUSION: This prospective cohort study revealed significant risk factors for shoulder instability in this high-risk population. Physical examination findings of apprehension and relocation were significant while controlling for history of injury. The anatomic variables of significance were not surprising-tall and thin glenoids were at higher risk compared with short and wide glenoids, and the risk of instability increased by 20% for every 1-mm increase in coracohumeral distance.

Posterior chondrolabral cleft: clinical significance and associations with shoulder instability.

BACKGROUND: A high signal intensity cleft between the labrum and articular cartilage of the posterior glenoid is commonly visible on MRI and has been suggested to be anatomic variation [3, 10, 23]. The association of a posterior cleft with variations in glenoid morphology or with shoulder instability is unknown. QUESTIONS/PURPOSES: The purposes of this study were to determine if posterior chondrolabral clefts are associated with variations in glenoid morphology, and to determine if they are associated with shoulder instability. PATIENTS AND METHODS: Shoulder MRI was performed in 1,264 shoulders, 1,135 male (89.8%), and 129 female (10.2%). A musculoskeletal radiologist blinded to history and outcomes evaluated the MR images for linear high signal intensity at the posterior chondrolabral junction and a rounded or truncated contour of the posterior glenoid. Glenoid version and depth were measured. Patients were followed prospectively for shoulder instability for 4 years. Univariate and multivariate statistical analysis were performed. RESULTS: Posterior chondrolabral cleft was present in 114/1,264. Posterior chondrolabral cleft was associated with a rounded or truncated posterior glenoid. There were 9.5° retroversion in shoulders with a posterior cleft, and 7.7° retroversion in shoulders without a cleft. Shoulders with a posterior chondrolabral cleft were more likely to develop shoulder instability. CONCLUSIONS: Posterior chondrolabral clefts are not uncommon on MRI. They are associated with a rounded or truncated posterior glenoid and a small but significant increase in glenoid retroversion. They are associated with shoulder instability.

Hepatitis C virus serine protease: synthesis of radioactive and stable isotope-labeled potent inhibitors.

Drug candidates labeled with radioactive and stable isotopes are required for absorption, distribution, metabolism, and excretion (ADME) studies, pharmacokinetics, autoradiography, bioanalytical, and other research activities. The findings from these studies are crucial in the development of a drug candidate and its approval for human use. Herein, we report the synthesis of potent and selective hepatitis C virus serine protease inhibitors related to BILN 2061 and BI 201335 labeled with radioactive and stable isotopes. Synthetic efforts were focused on the common substituted thiazole moiety, which is easily accessible via a Hantzsch's reaction of α-bromoketones and mono-substituted thioureas. In the radioactive synthesis, commercially available carbon-14 thiourea was utilized to prepare mono-substituted thioureas, which upon condensation with α-bromoketones in isopropanol followed by ester hydrolysis gave the desired carbon-14-labeled protease inhibitors. The same strategy was used to prepare these inhibitors labeled with stable isotopes. Mono-substituted thioureas were obtained from commercially available deuterium-labeled intermediates and then condensed with α-bromoketones followed by ester hydrolysis to give the deuterium-labeled inhibitors.

A scalable and regioselective synthesis of 2-difluoromethyl pyridines from commodity chemicals.

A scalable de novo synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group.

Risk factors for posterior shoulder instability in young athletes.

BACKGROUND: While posterior glenohumeral instability is becoming increasingly common among young athletes, little is known of the risk factors for injury. PURPOSE: To determine the modifiable and nonmodifiable risk factors for posterior shoulder instability in a high-risk cohort. STUDY DESIGN: Case-control study (prognosis); Level of evidence, 2. METHODS: A prospective cohort study in which 714 young athletes were followed from June 2006 through May 2010 was conducted. Baseline testing included a subjective history of instability, instability testing by a sports medicine fellowship-trained orthopaedic surgeon, range of motion, strength measurement with a handheld dynamometer, and bilateral noncontrast magnetic resonance imaging of the shoulder. A musculoskeletal radiologist measured glenoid version, height, depth, rotator interval (RI) height, RI width, RI area, and RI index. Participants were followed to document all acute posterior shoulder instability events during the 4-year follow-up period. The time to the posterior shoulder instability event during the follow-up period was the primary outcome of interest. Univariate and multivariable Cox proportional hazards regression models were used to analyze the data. RESULTS: Complete data on 714 participants were obtained. During the 4-year surveillance period, 46 shoulders sustained documented glenohumeral instability events, of which only 7 were posterior in direction. The baseline factors that were associated with subsequent posterior instability during follow-up were increased glenoid retroversion (P < .0001), increased external rotation strength in adduction (P = .029) and at 45° of abduction (P = .015), and increased internal rotation strength in adduction (P = .038). CONCLUSION: This is the largest known prospective study to follow healthy participants in the development of posterior shoulder instability. Posterior instability represents 10% of all instability events. The most significant risk factor was increased glenoid retroversion. While increased internal/external strength was also associated with subsequent instability, it is unclear whether these strength differences are causative or reactive to the difference in glenoid anatomy. This work confirms that increased glenoid retroversion is a significant prospective risk factor for posterior instability.

Carbamoyl anion addition to N-sulfinyl imines: highly diastereoselective synthesis of α-amino amides.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

A highly convergent and efficient synthesis of a macrocyclic hepatitis C virus protease inhibitor BI 201302.

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1-0.2 M concentration) and the efficient sulfone-mediated SNAr reaction.

Simple method of glenoid bone loss calculation using ipsilateral magnetic resonance imaging.

BACKGROUND: Current methods for estimating glenoid bone loss in patients with chronic shoulder instability include computed tomography imaging with 3-dimensional reconstruction, specialized computer software, and imaging of the contralateral shoulder. An ideal method of glenoid measurement would require only magnetic resonance imaging (MRI) of the injured shoulder. PURPOSE: To determine whether MRI measurement of glenoid height, as well as sex, could be used to estimate glenoid width in healthy subjects with no history of shoulder instability. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Bilateral shoulder MRIs were obtained in a healthy cohort of young athletes as part of the baseline assessment in a prospective cohort study. A musculoskeletal radiologist measured glenoid height and width using the sagittal MRI cuts. Univariate and multivariate regression analyses were performed to determine whether demographic and MRI measurements of the glenoid could be used to estimate glenoid width. RESULTS: Of the 1264 shoulder MRIs evaluated, the mean glenoid width was 26.67 mm (±2.49 mm), and the mean glenoid height was 42.15 mm (±3.00 mm). There were significant differences between the 129 female glenoids and the 1035 male glenoids for both width (23.1 mm, 27.1 mm, respectively, P < .0001) and height (37.9 mm, 42.7 mm, respectively, P < .0001); however, the relationship between glenoid height and width was similar for both men and women. The glenoid width was found to correlate with the height measurement (r = 0.56) for the entire cohort. Based on the results of linear regression analysis, controlling for the influence of sex, a formula was created that represents the relationship between these variables for male subjects: Glenoid Width = (1/3 Height) + 15 mm. Female patients are estimated with a formula that represents the same slope but a different intercept: W = 1/3 H + 13 mm. CONCLUSION: Significant differences in glenoid height and width were found by sex; however, the relationship between height and width was similar. These variables are correlated, and the resultant formula can be used to estimate the expected glenoid width in a patient with bone loss. This formula allows for easy calculation of the amount of glenoid bone loss with only a ruler and an MRI of the injured shoulder.