Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia.

The orphan G-protein-coupled receptor GPR139 is highly expressed in the habenula, a small brain nucleus that has been linked to depression, schizophrenia (SCZ), and substance-use disorder. High-throughput screening and a medicinal chemistry structure-activity relationship strategy identified a novel series of potent and selective benzotriazinone-based GPR139 agonists. Herein, we describe the chemistry optimization that led to the discovery and validation of multiple potent and selective in vivo GPR139 agonist tool compounds, including our clinical candidate TAK-041, also known as NBI-1065846 (compound 56). The pharmacological characterization of these GPR139 agonists in vivo demonstrated GPR139-agonist-dependent modulation of habenula cell activity and revealed consistent in vivo efficacy to rescue social interaction deficits in the BALB/c mouse strain. The clinical GPR139 agonist TAK-041 is being explored as a novel drug to treat negative symptoms in SCZ.

Utilization and Yield of CT Urography: Are the American Urological Association Guidelines for Imaging of Patients With Asymptomatic Microscopic Hematuria Being Followed?

OBJECTIVE: The purposes of this study were to determine whether patients with asymptomatic microscopic hematuria undergoing CT urography (CTU) meet the American Urological Association criteria for radiologic evaluation and to determine the yield of CTU for upper tract malignancy. MATERIALS AND METHODS: A retrospective review was conducted of consecutive CTU examinations performed for asymptomatic microscopic hematuria in adult patients. Patients with clinical evidence suggestive of a benign cause of hematuria (stone, urinary tract infection, trauma) or prior urologic malignancy were excluded. The study group included 419 patients (173 men, 246 women). CT reports were reviewed to identify causes of hematuria in all cases. Evaluate for appropriateness was conducted with 200 randomly allocated patients. Urinalysis results were reviewed, and appropriate use of CTU was defined as more than 3 RBCs per high-power field in the absence of urinary tract infection. Cystoscopy results after CTU were noted. RESULTS: In total, 58 of 200 patients (29.0%; 95% CI, 23.2-35.6%) did not meet American Urological Association criteria for radiologic evaluation. Fifteen (7.5%) received dipstick analysis only. Thirty-eight (19.0%) had urinalysis results showing 0-2 RBCs per high-power field. Five patients (2.5%) were found to have urinary tract infections. No upper tract urothelial neoplasms were identified (0/419; 95% CI, 0.0-0.9%). One solid renal mass was identified without pathologic confirmation. One possible bladder mass was seen at CTU but not visualized at subsequent cystoscopy. CONCLUSION: In 29.0% of examinations, CTU is performed for patients who do not meet the criteria for radiologic evaluation. The yield of CTU for upper urinary tract malignancy is low.

Incidentally detected biliary ductal dilatation on contrast-enhanced CT: what is the incidence of occult obstructing malignancy?

PURPOSE: The purpose of this study was to determine the incidence of occult obstructing malignancy in the setting of asymptomatic biliary ductal dilatation incidentally detected and without identifiable cause on contrast-enhanced CT. METHODS: A retrospective search identified patients with biliary ductal dilatation on contrast-enhanced CT from March 30, 2007 to November 1, 2017. Patients with biliary symptomatology or clinical concern for an obstructing process, an explanation for biliary ductal dilatation on index CT, intrahepatic without extrahepatic biliary ductal dilatation, concurrent pancreatic ductal dilatation, and inadequate follow-up were excluded. A reference standard of at least 1 year of imaging follow-up or 2 years of clinical follow-up was used to exclude occult obstructing malignancy. RESULTS: 156 patients were included; 120 patients met imaging follow-up criteria and 36 patients met clinical follow-up criteria. No cases of occult malignancy were identified as the source of biliary ductal dilatation (95% CI 0.0-1.9%). LFTs were available for 131 patients, of which 36 were elevated (27%). One case demonstrated a 1.2-cm ampullary adenoma on endoscopic retrograde cholangiopancreatography (occult on follow-up MRI, normal LFTs at the time of the index CT). CONCLUSION: Asymptomatic biliary ductal dilatation incidentally detected and without identifiable cause on contrast-enhanced CT is likely benign in patients with normal LFTs, and further workup may not be warranted.

Bilateral Destructive Hip Disease from Untreated Juvenile Idiopathic Arthritis.

We report a novel case of a pediatric patient with bilateral hip destruction from untreated Juvenile idiopathic arthritis (JIA). She was presented at the age of 9 with hip pain associated with bilateral acetabular dysplasia and a dislocated left femoral head. Only 1.5 years later, the patient developed complete destruction of the left femoral head and dislocated right femoral head. The authors have not identified literature describing a similar case report of bilateral femoral head destruction resulting from Persistent Oligoarticular JIA. Pediatric patients presenting with rapidly evolving destructive process should be evaluated for rheumatologic, infectious, and spinal etiologies.

The medial epicondyle of the distal femur is the optimal location for MRI measurement of semitendinosus and gracilis tendon cross-sectional area.

PURPOSE: Graft diameter ≥ 8 mm reduces the risk of failure after anterior cruciate ligament reconstruction (ALCR) with hamstring tendon autograft. Pre-operative measurement of gracilis (GT) and semitendinosus (ST) cross-sectional area using MRI has been utilized but the optimal location for measurement is unknown. The main purpose of this study was to examine the cross-sectional areas of GT + ST at different locations and develop a model to predict whether a doubled hamstring graft of GT + ST will be of sufficient cross-sectional area for ACLR. METHODS: A retrospective review was performed of 154 patients who underwent primary ACLR using doubled hamstring autograft. Cross-sectional area measurements of GT + ST on pre-operative MRI axial images were made at three locations: medial epicondyle (ME), tibiofemoral joint line (TJL), and tibial physeal scar (TPS) and calculated the correlation of intra-operative graft size for each location using the Pearson's correlation coefficient. A receiver operating characteristic (ROC) established a threshold that would predict graft diameter ≥ 8 mm. RESULTS: Measurement of GT + ST at the ME had a stronger correlation (r = 0.389) to intra-operative graft diameter than measurements at the TJL (r = 0.256) or TPS (r = 0.240). The ROC indicated good predictive value for hamstring graft diameter ≥ 8 mm based on MRI measurement at the ME with the optimal threshold with the highest sensitivity and specificity as 18 mm2. CONCLUSION: Cross-sectional area measurement of GT + ST at the ME correlated most closely to intra-operative diameter of a doubled hamstring autograft compared to measurements at the TJL or the TPS. As graft diameter < 8 mm is correlated with higher failure rates of ACL surgery, the ability to pre-operatively predict graft diameter is clinically useful. LEVEL OF EVIDENCE: Level III, prognostic study.

Self-Resolution of a Draining Sinus Tract in a Patient with Chronic Periprosthetic Hip Infection.

We report a novel case of a patient who had a draining sinus soon after a total hip arthroplasty that spontaneously resolved. The patient voluntarily discontinued antibiotic suppressive therapy (AST) after 10 years of treatment and paradoxically experienced full resolution of signs of chronic prosthetic joint infection (PJI), including recovery of his left-sided draining sinus tract. Now 8 years after discontinuing AST, the patient has no pain, good function, and no major or minor criteria of joint infection according to the Musculoskeletal Infection Society (MSIS) workgroup. The authors have not identified literature describing a similar resolution of draining sinus tracts from around a prosthetic joint after discontinuing AST. Despite the resolution of this patient's sinus tract, the authors do not advocate for discontinuing AST in patients with a draining sinus tract. However, in spite of the fact that the MSIS consensus statement suggests that a draining sinus is a sure sign of PJI and that the assumption is that the infection will not go away until explant, this case was different.