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Perceptual decision-making involves multiple cognitive processes, including accumulation of sensory evidence, planning, and executing a motor action. How these processes are intertwined is unclear; some models assume that decision-related processes precede motor execution, whereas others propose that movements reflecting on-going decision processes occur before commitment to a choice. Here we combine and apply two complementary methods to study the relationship between decision processes and the movements leading up to a choice. The first is a free response pulse-based evidence accumulation task, in which stimuli continue until choice is reported and the second is a motion-based drift diffusion model (mDDM), in which movement variables from video pose estimation constrain decision parameters on a trial-by-trial basis. We find the mDDM provides a better model fit to rats' decisions in the free response accumulation task than traditional DDM models. Interestingly, on each trial we observed a period of time, prior to choice, that was characterized by head immobility. The length of this period was positively correlated with the rats' decision bounds and stimuli presented during this period had the greatest impact on choice. Together these results support a model in which internal decision dynamics are reflected in movements and demonstrate that inclusion of movement parameters improves the performance of diffusion-to-bound decision models.

Photochemical sealing of a nerve wrap over the repair site isolates and optimizes the regenerating nerve microenvironment. To facilitate clinical adoption of the technology, we investigated photosealed autologous tissue in a rodent sciatic nerve transection and repair model. Rats underwent transection of the sciatic nerve with repair performed in three groups: standard microsurgical neurorrhaphy (SN) and photochemical sealing with a crosslinked human amnion (xHAM) or autologous vein. Functional recovery was assessed at four-week intervals using footprint analysis. Gastrocnemius muscle mass preservation, histology, and nerve histomorphometry were evaluated at 120 days. Nerves treated with a PTB-sealed autologous vein improved functional recovery at 120 days although the comparison between groups was not significantly different (SN: -58.4 +/- 10.9; XHAM: -57.9 +/- 8.7; Vein: -52.4 +/- 17.1). Good muscle mass preservation was observed in all groups, with no statistical differences between groups (SN: 69 +/- 7%; XHAM: 70 +/- 7%; Vein: 70 +/- 7%). Histomorphometry showed good axonal regeneration in all repair techniques. These results demonstrate that peripheral nerve repair using photosealed autologous veins produced regeneration at least equivalent to current gold-standard microsurgery. The use of autologous veins removes costs and foreign body concerns and would be readily available during surgery. This study illustrates a new repair method that could restore normal endoneurial homeostasis with minimal trauma following severe nerve injury.

The precise neural mechanisms within the brain that contribute to the remarkable lifetime persistence of memory are not fully understood. Two-photon calcium imaging allows the activity of individual cells to be followed across long periods, but conventional approaches require head-fixation, which limits the type of behavior that can be studied. We present a magnetic voluntary head-fixation system that provides stable optical access to the brain during complex behavior. Compared to previous systems that used mechanical restraint, there are no moving parts and animals can engage and disengage entirely at will. This system is failsafe, easy for animals to use and reliable enough to allow long-term experiments to be routinely performed. Animals completed hundreds of trials per session of an odor discrimination task that required 2-4 s fixations. Together with a reflectance fluorescence collection scheme that increases two-photon signal and a transgenic Thy1-GCaMP6f rat line, we are able to reliably image the cellular activity in the hippocampus during behavior over long periods (median 6 months), allowing us track the same neurons over a large fraction of animals' lives (up to 19 months)., (© 2024. The Author(s).)

Background and Objectives: Toxic stress and trauma are prevalent in the pediatric population. The sequela can be significant, leading to disruptive behaviors in early childhood to chronic medical conditions in adulthood. Two factors that can mitigate negative outcomes of developmental traumatic stress include relational health care and healthy parental relationships. Family physicians are poised to play a significant role in both attenuating factors. Therefore, focused pediatric trauma-informed knowledge and skills training for family medicine residents is important., Methods: One family medicine residency program added a training module for residents, with two objectives: increase in-exam room trauma-informed interaction skills, and increase knowledge and skills for physicians to coach parents on strengthening the parent-child relationship. The training included didactics and skills training. Knowledge and skills were measured pre- and posttraining., Results: A total of 39 residents participated in the study over 3 years. The knowledge score increased by 4.49 points from pre- to posttraining. The number of trauma-informed interactional skills the residents demonstrated at posttraining had increased significantly. During the pilot, all participants moved from below mastery of skills to full mastery., Conclusions: After being instructed in best practices in trauma-informed pediatric interactions, residents demonstrated an increased number of behaviors that cultivate pediatric relational health care. Residents demonstrated knowledge and skills gains that denoted their ability to interact with patients and coach parents in evidence-based ways that can mitigate the impact of childhood trauma exposure.

Neuron migration is a key phase of neurogenesis, critical for the assembly and function of neuronal circuits. In songbirds, this process continues throughout life, but how these newborn neurons disperse through the adult brain is unclear. We address this question using in vivo two-photon imaging in transgenic zebra finches that express GFP in young neurons and other cell types. In juvenile and adult birds, migratory cells are present at a high density, travel in all directions, and make frequent course changes. Notably, these dynamic migration patterns are well fit by a superdiffusive model. Simulations reveal that these superdiffusive dynamics are sufficient to disperse new neurons throughout the song nucleus HVC. These results suggest that superdiffusive migration may underlie the formation and maintenance of nuclear brain structures in the postnatal brain and indicate that transgenic songbirds are a useful resource for future studies into the mechanisms of adult neurogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rats are used in neuroscience research because of their physiological similarities with humans and accessibility as model organisms, trainability, and behavioral repertoire. In particular, rats perform a wide range of sophisticated social, cognitive, motor, and learning behaviors within the contexts of both naturalistic and laboratory environments. Further progress in neuroscience can be facilitated by using advanced imaging methods to measure the complex neural and physiological processes during behavior in rats. However, compared with the mouse, the rat nervous system offers a set of challenges, such as larger brain size, decreased neuron density, and difficulty with head restraint. Here, we review recent advances in in vivo imaging techniques in rats with a special focus on open-source solutions for calcium imaging. Finally, we provide suggestions for both users and developers of in vivo imaging systems for rats., (© 2023 The Authors.)

Background: Surgical risk prediction models traditionally use patient attributes and measures of physiology to generate predictions about postoperative outcomes. However, the surgeon's assessment of the patient may be a valuable predictor, given the surgeon's ability to detect and incorporate factors that existing models cannot capture. We compare the predictive utility of surgeon intuition and a risk calculator derived from the American College of Surgeons (ACS) NSQIP., Study Design: From January 10, 2021 to January 9, 2022, surgeons were surveyed immediately before performing surgery to assess their perception of a patient's risk of developing any postoperative complication. Clinical data were abstracted from ACS NSQIP. Both sources of data were independently used to build models to predict the likelihood of a patient experiencing any 30-day postoperative complication as defined by ACS NSQIP., Results: Preoperative surgeon assessment was obtained for 216 patients. NSQIP data were available for 9,182 patients who underwent general surgery (January 1, 2017 to January 9, 2022). A binomial regression model trained on clinical data alone had an area under the receiver operating characteristic curve (AUC) of 0.83 (95% CI 0.80 to 0.85) in predicting any complication. A model trained on only preoperative surgeon intuition had an AUC of 0.70 (95% CI 0.63 to 0.78). A model trained on surgeon intuition and a subset of clinical predictors had an AUC of 0.83 (95% CI 0.77 to 0.89)., Conclusions: Preoperative surgeon intuition alone is an independent predictor of patient outcomes; however, a risk calculator derived from ACS NSQIP is a more robust predictor of postoperative complication. Combining intuition and clinical data did not strengthen prediction., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background . There have been few advances in technique since vascular anastomosis was performed with silk suture on a curved needle in 1902. This technique results in disruption of the endothelium with exposed intraluminal suture, both of which may lead to thrombocyte aggregation, intimal hyperplasia, and vascular stenosis. A variety of alternative techniques have been explored, with limited success. Photochemical tissue bonding (PTB) is a light-activated methodology of rapidly cross-linking tissue interfaces at the molecular level. Herein, we describe a new technique for anastomosis of venous interposition graft in an ovine model of femoral artery bypass utilizing PTB. Methods . Polypay specific pathogen free sheep (n = 5; 40-45 kg) underwent femoral artery bypass utilizing saphenous vein. The femoral artery was transected and reversed saphenous vein was implanted as an interposition graft. The proximal anastomosis was created as a vein-over-artery cuff utilizing PTB, and the distal anastomosis was created with standard interrupted 8-0 polypropylene suture. Four weeks post-index operation, femoral angiogram was performed to evaluate patency, tortuosity, and luminal diameter. All bypass grafts were harvested and longitudinal and transverse histological sections from the proximal anastomosis were analyzed. Results . The PTB anastomoses (n = 5) were immediately watertight and patent. All animals survived the 28-day study duration. Angiography revealed patent grafts with no aneurysm or stenosis (n = 5). Histologic examination revealed integration of the venous endothelium with the arterial adventitia. Conclusion . Photochemical tissue bonding creates an immediate strong, watertight vascular anastomosis that can withstand physiologic arterial pressure and remains patent at 28 days without the need for intraluminal suture.

Evidence accumulation, an essential component of perception and decision making, is frequently studied with psychophysical tasks involving noisy or ambiguous stimuli. In these tasks, participants typically receive verbal or written instructions that describe the strategy that should be used to guide decisions. Although convenient and effective, explicit instructions can influence learning and decision making strategies and can limit comparisons with animal models, in which behaviors are reinforced through feedback. Here, we developed an online video game and nonverbal training pipeline, inspired by pulse-based tasks for rodents, as an alternative to traditional psychophysical tasks used to study evidence accumulation. Using this game, we collected behavioral data from hundreds of participants trained with an explicit description of the decision rule or with experiential feedback. Participants trained with feedback alone learned the game rules rapidly and used strategies and displayed biases similar to those who received explicit instructions. Finally, by leveraging data across hundreds of participants, we show that perceptual judgments were well described by an accumulation process in which noise scaled nonlinearly with evidence, consistent with previous animal studies but inconsistent with diffusion models widely used to describe perceptual decisions in humans. These results challenge the conventional description of the accumulation process and suggest that online games provide a valuable platform to examine perceptual decision making and learning in humans. In addition, the feedback-based training pipeline developed for this game may be useful for evaluating perceptual decision making in human populations with difficulty following verbal instructions. NEW & NOTEWORTHY Perceptual uncertainty sets critical constraints on our ability to accumulate evidence and make decisions; however, its sources remain unclear. We developed a video game, and feedback-based training pipeline, to study uncertainty during decision making. Leveraging choices from hundreds of subjects, we demonstrate that human choices are inconsistent with popular diffusion models of human decision making and instead are best fit by models in which perceptual uncertainty scales nonlinearly with the strength of sensory evidence.

In this issue of Neuron, Tseng and colleagues reveal functional gradients in the mouse posterior cortex that reconcile specialized and distributed processing during flexible, goal-directed navigation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Painful neuroma is a frequent sequela of peripheral nerve injury which can result in pain and decreased quality of life for the patient, often necessitating surgical intervention. End neuromas are benign neural tumors that commonly form after nerve transection, when axons from the proximal nerve stump regenerate in a disorganized manner in an attempt to recreate nerve continuity. Inflammation and collagen remodeling leads to a bulbous end neuroma which can become symptomatic and result in decreased quality of life. This review covers surgical prophylaxis of end neuroma formation at time of injury, rather than treatment of existing neuroma and prevention of recurrence. The current accepted methods to prevent end neuroma formation at time of injury include different mechanisms to inhibit the regenerative response or provide a conduit for organized regrowth, with mixed results. Approaches include proximal nerve stump capping, nerve implantation into bone, muscle and vein, various pharmacologic methods to inhibit axonal growth, and mechanisms to guide axonal growth after injury. This article reviews historical treatments that aimed to prevent end neuroma formation as well as current and experimental treatments, and seeks to provide a concise, comprehensive resource for current and future therapies aimed at preventing neuroma formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scott, Winograd and Redmond.)

Introduction: Libraries have provided mediated search services for more than forty years without a practice standard to guide the execution of searches, training of searchers, or evaluation of search performance. A pan-Canadian group of librarians completed a study of the literature on mediated search practices from 2014-2017 as a first step in addressing this deficit., Methods: We used a three-phase, six-part content analysis process to examine and analyze published guidance on literature searching. Card sorting, Delphi methods, and an online questionnaire were then used to validate our findings and build a code of practice., Results: Our code of practice for mediated searching lists eighty-five search tasks arranged in performance order, within five progressive levels of search complexity. A glossary of 150 search terms supports the code of practice., Discussion: The research literature on mediated search methods is sparse and fragmented, lacking currency and a shared vocabulary. A code of practice for mediated searching will provide clarity in terminology, approach, and methods. This code of practice will provide a unified and convenient reference for training a new hire, upholding standards of search service delivery, or educating the next wave of health library professionals., Competing Interests: The authors have no conflicts of interest to declare., (© Ballantyne Scott, Baer, Farrell, Lee, MacDonald, Rabb, and Vaska.)

Neuroma is a common sequela of traumatic peripheral nerve injury that can result in pain and decreased quality of life for patients. Neuromas result from axonal outgrowth in an attempt to reestablish continuity with the disrupted distal nerve end. Photosealing is a light-activated technique whereby tissues can be securely isolated in a strong and secure manner. This study investigated whether photosealing of autologous vein and crosslinked human amniotic membrane (xHAM) to cap the proximal stump of transected sciatic nerve would prevent disorganized axonal regeneration and neuroma in a rat model., Methods: The right sciatic nerve of Lewis rats (n = 27, 300-350 g) was transected 1 cm proximal to the trifurcation. Animals were randomized to one of three groups (n = 9): no further intervention (Group 1), photosealing with xHAM (Group 2), or photosealing with vein (Group 3). After 60 days, rats were euthanized and their right hindlimbs were re-explored for evidence of disorganized axonal regeneration and/or bulbous neuroma., Results: All untreated control animals were found to have protruding nerve fibers, often invading the adjacent muscle, and 33% of these control animals exhibited a bulbous neuroma. Photosealing with xHAM successfully capped 100% of nerves, with no observable axonal outgrowth. Photosealing with vein prevented axonal outgrowth in eight of nine nerves. No bulbous neuroma was found in any photosealed nerves., Conclusion: Nerve capping with photosealed xHAM or autologous vein can prevent axonal outgrowth in transected nerves, therefore decreasing the likelihood of symptomatic neuroma formation following nerve transection injury or surgical intervention., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Extradomain-B Fibronectin (EDB-FN) is an oncomarker that can be visualized with magnetic resonance molecular imaging (MRMI) to detect pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we sought to assess the expression of EDB-FN in clinical samples of PDAC and to evaluate MRMI of PDAC metastasis with an EDB-FN-specific gadolinium-based contrast agent (MT218) in an orthotopic KPC-GFP-Luc mouse model. EDB-FN expression was evaluated in PDAC tissue samples through immunohistochemistry. RNA-Seq data obtained from the GEPIA2 project was evaluated to demonstrate EDB-FN expression in large patient cohorts. FLASH-3D MRI at 3 T of the KPC-GFP-Luc metastasis model was performed following injection of MT218. Tumor enhancement in MR images was correlated to postmortem distribution of KPC-GFP-Luc tumors using fluorescent and bright-field cryo-imaging and anatomical landmarks. EDB-FN immunohistochemical staining scores of human metastatic tumor stroma, (2.17 ± 0.271), metastatic tumor parenchyma (2.08 ± 0.229), primary tumor stroma (1.61 ± 0.26), and primary tumor parenchyma (1.61 ± 0.12) were significantly (p < 0.0001) higher than normal pancreas stroma (0.14 ± 0.10) and normal pancreas parenchyma (0.14 ± 0.14). EDB-FN mRNA expression in tumors is 4.98 log 2 (TPM + 1) and 0.18 log 2 (TPM + 1) in normal tissue (p < 0.01). A mouse model of EDB-FN rich PDAC metastasis exhibited T 1 -weighted contrast to noise (CNR) changes of 21.80 ± 4.34 in perimetastatic regions and 8.38 ± 0.79 in metastatic regions identified through cryo-imaging, significantly higher (p < 0.05) than CNR changes found in normal liver (-6.43 ± 0.92), mesentery (2.24 ± 0.92), spleen (-3.06 ± 2.38) and intestine (1.08 ± 2.15). We conclude that EDB-FN is overexpressed in metastatic and primary PDAC tumors and MRMI with MT218 enables the detection of metastatic and perimetastatic tissues., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Optical imaging of calcium signals in the brain has enabled researchers to observe the activity of hundreds-to-thousands of individual neurons simultaneously. Current methods predominantly use morphological information, typically focusing on expected shapes of cell bodies, to better identify neurons in the field-of-view. The explicit shape constraints limit the applicability of automated cell identification to other important imaging scales with more complex morphologies, e.g., dendritic or widefield imaging. Specifically, fluorescing components may be broken up, incompletely found, or merged in ways that do not accurately describe the underlying neural activity. Here we present Graph Filtered Temporal Dictionary (GraFT), a new approach that frames the problem of isolating independent fluorescing components as a dictionary learning problem. Specifically, we focus on the time-traces-the main quantity used in scientific discovery-and learn a time trace dictionary with the spatial maps acting as the presence coefficients encoding which pixels the time-traces are active in. Furthermore, we present a novel graph filtering model which redefines connectivity between pixels in terms of their shared temporal activity, rather than spatial proximity. This model greatly eases the ability of our method to handle data with complex non-local spatial structure. We demonstrate important properties of our method, such as robustness to morphology, simultaneously detecting different neuronal types, and implicitly inferring number of neurons, on both synthetic data and real data examples. Specifically, we demonstrate applications of our method to calcium imaging both at the dendritic, somatic, and widefield scales.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal., Introduction: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation., Methods: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88)., Results: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04)., Conclusion: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development., Introduction: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis., Methods: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D 3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo., Results: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups., Conclusion: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial., Trial Registration: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Background: Patients commonly use online materials as a source of health information. Since poor health literacy has been shown to correlate with negative outcomes, it is recommended that patient-directed materials be written at a sixth-grade reading level. This study evaluates the readability and understandability of commonly accessed online materials pertaining to both endovascular and open repair of abdominal aortic aneurysm., Methods: Searches for "endovascular repair abdominal aortic aneurysm" and "open repair abdominal aortic aneurysm" were performed on both Google and Bing, and the top 10 websites from each search engine were identified. Relevant websites (total N = 28, endovascular n = 15, open n = 15, and 2 redundant sites) with patient-directed content were analyzed. Readability was assessed using 9 established methods, and understandability was assessed using the Patient Education Materials Assessment Tool scoring system., Results: The average reading grade level for all sites was 12.8. Endovascular sites averaged a reading grade level of 13.6 with a range from 11.5 to 15.6. Open-repair websites had a grade-level average of 12.1 with a range from 9.9 to 14.1. Readability was found to be inversely related to understandability, with a Pearson correlation coefficient of -0.551 ( P = .003). No website was written at or below the recommended sixth-grade reading level., Conclusions: Patient-directed online health information pertaining to open and endovascular repair of abdominal aortic aneurysm exceeds the recommended sixth-grade reading level. Increasing complexity of health literature correlates with poor understandability. Modifications such as shorter sentences, fewer words with more than 6 letters, and increasing usage of clear visual aids can increase readability and understandability.

Objective: Minimally invasive (video-assisted thoracoscopic surgery) mediastinal parathyroidectomy has been described as a technique for surgical management of primary hyperparathyroidism due to ectopic parathyroid adenoma. Herein, we present the largest cohort of patients ( n  = 8) treated with robot-assisted mediastinal parathyroidectomy and describe our technique for this procedure, pre- and intraoperative variables, and postoperative outcomes. Materials and Methods: A single surgeon, single institution case series of eight consecutive robot-assisted mediastinal parathyroidectomies performed from April 2013 to March 2018. Preoperative workup, intraoperative variables, and postoperative outcomes were evaluated. Results: Of the eight patients, seven were women. Average age was 54 years (range: 28-69) and average body mass index 33.6 (range: 24.8-42.9). Seven patients had a preoperative diagnosis of primary hyperparathyroidism with preoperative parathyroid hormone (PTH) and calcium levels (PTH: 137 (70-192); Ca 2+ : 10.9 (10.2-12), and one patient had preoperative diagnosis of thymoma. Preoperative imaging studies included computed tomography (CT)-sestamibi ( n  = 3), CT neck ( n  = 4), CT chest ( n  = 6), and neck ultrasound ( n  = 6). Intraoperative PTH measurements found >50% reduction in all cases. Average length of surgery was 108.6 minutes (range: 76-186); average blood loss 26 cc. All specimens were parathyroid adenomas, with an average size of 16 mm (range: 7-35 mm). Seven of eight patients were discharged on postoperative day 1. No complications or recurrences occurred at a median follow-up of 18.5 days (range: 15-1,066 days). Conclusions: Robot-assisted thoracoscopic parathyroidectomy is a safe and effective technique, with immediate improvement in PTH levels. Thorough clinical, biochemical, and radiologic preoperative workup assists in operative planning and may improve diagnostic accuracy of anterior mediastinal masses.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis., Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66)., Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051)., Interpretation: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis., Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose of Review: Opioid misuse and abuse in the USA has evolved into an epidemic of tragic pain and suffering, resulting in the estimated death of over 64,000 people in 2016. Governmental regulation has escalated alongside growing awareness of the epidemic's severity, both on the state and federal levels., Recent Findings: This article reviews the timeline of government interventions from the late 1990s to today, including the declaration of the opioid crisis as a national public health emergency and the resultant changes in funding and policy across myriad agencies. Aspects of the cultural climate that fuel the epidemic, and foundational change that may promote sustained success against it, are detailed within as well. As a consequence of misuse and abuse of opioids, governmental regulation has attempted to safeguard society, and clinicians should appreciate changes and expectations of prescribers.

Background: Autologous fat transfer is common in breast reconstruction because of its versatility for use in contour deformities. The authors examined three different fat grafting processing techniques for complications and safety profile using their institutional database., Methods: Retrospective review was performed of patients from a single institution who had undergone autologous fat transfer following breast reconstruction from 2012 to 2016. Individuals were separated into three cohorts according to fat harvest technique: (1) centrifugation, (2) Telfa gauze, or (3) Revolve. Complications between the groups were assessed., Results: A total of 267 cases of autologous fat transfer were identified (centrifugation, n = 168; Telfa, n = 44; and Revolve, n = 55). Grafting by means of centrifugation was associated with the greatest incidence of oil cysts (12.5 percent; p = 0.034), postoperative adverse events observed in the clinic (13.7 percent; p = 0.002), and total complications (25.6 percent; p = 0.001). The use of Telfa resulted in the lowest rates of oil cyst formation (0 percent; p = 0.002) and total complications (2.3 percent; p = 0.001). Grafting by means of centrifugation was also associated with the highest frequency of repeated injections among the three techniques after initial grafting (19.6 percent; p = 0.029). In contrast, Revolve demonstrated a repeated injection rate of just 5.45 percent, significantly lower when independently compared with centrifugation (p = 0.011). Multivariate analysis demonstrated that higher total graft volume (p = 0.002) and the use of centrifugation (p = 0.002) were significant risk factors for adverse events seen in the clinic postoperatively., Conclusions: Significant differences in postoperative outcomes exist between varying fat transfer techniques. Autologous fat transfer by means of centrifugation harbored the highest rates of complication, whereas Telfa and Revolve exhibited similar safety profiles., Clinical Question/level of Evidence: Therapeutic, III.

Widefield imaging of calcium dynamics is an emerging method for mapping regional neural activity but is currently limited to restrained animals. Here we describe cScope, a head-mounted widefield macroscope developed to image large-scale cortical dynamics in rats during natural behavior. cScope provides a 7.8 × 4 mm field of view and dual illumination paths for both fluorescence and hemodynamic correction and can be fabricated at low cost using readily attainable components. We also report the development of Thy-1 transgenic rat strains with widespread neuronal expression of the calcium indicator GCaMP6f. We combined these two technologies to image large-scale calcium dynamics in the dorsal neocortex during a visual evidence accumulation task. Quantitative analysis of task-related dynamics revealed multiple regions having neural signals that encode behavioral choice and sensory evidence. Our results provide a new transgenic resource for calcium imaging in rats and extend the domain of head-mounted microscopes to larger-scale cortical dynamics. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Localized and unresectable pancreatic ductal adenocarcinoma (PDA) comprises one third of new diagnoses and includes borderline resectable (BR) and locally advanced (LA) unresectable disease. In a cohort of patients who were treated and followed at a single institution, we assessed clinical and radiographic predictors of outcome., Methods: The study included 69 consecutive patients with BR or LA PDA. Serial imaging studies were reviewed by both a pancreatic surgeon and a radiologist for vascular abutment or encasement by cancer, and they were recorded., Results: The cohort included 25 patients with BR and 44 patients with LA PDA, with median overall survivals (OS) of 15 and 14 months, respectively (p = 0.802). Fifteen patients were resected (22%), with a median OS of 21 months from diagnosis (HR 2.50, p = 0.006) and 13 months from resection. Median OS from diagnosis was 33 months in patients without lymph node metastases at resection (n = 10), but just 17 months with lymph node metastases (n = 5, HR = 8.95, p = 0.011). There were 12 two-year survivors in the total cohort (17%), and seven of them never underwent resection. First-line treatments consisted of gemcitabine (n = 13), modern first-line combinations (FOLFIRNOX or gemcitabine/nab-paclitaxel, n = 24), or alternative multi-agent therapies (n = 32); there were no statistical differences between treatment subgroups (OS of 10, 13, and 16 months, respectively). Common hepatic artery (CHA) abutment or encasement at diagnosis was associated with poor survival (adjusted hazard ratio, CHA abutment = 2.47 (p = 0.015) and CHA encasement = 2.16 (p = 0.036))., Conclusion: In this cohort, common hepatic arterial abutment or encasement and residual lymph node disease at resection portended a particularly poor outcome in patients with localized, unresectable PDA.

Decision-making in dynamic environments often involves accumulation of evidence, in which new information is used to update beliefs and select future actions. Using in vivo cellular resolution imaging in voluntarily head-restrained rats, we examined the responses of neurons in frontal and parietal cortices during a pulse-based accumulation of evidence task. Neurons exhibited activity that predicted the animal's upcoming choice, previous choice, and graded responses that reflected the strength of the accumulated evidence. The pulsatile nature of the stimuli enabled characterization of the responses of neurons to a single quantum (pulse) of evidence. Across the population, individual neurons displayed extensive heterogeneity in the dynamics of responses to pulses. The diversity of responses was sufficiently rich to form a temporal basis for accumulated evidence estimated from a latent variable model. These results suggest that heterogeneous, often transient sensory responses distributed across the fronto-parietal cortex may support working memory on behavioral timescales. VIDEO ABSTRACT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Decision-making behavior is often characterized by substantial variability, but its source remains unclear. We developed a visual accumulation of evidence task designed to quantify sources of noise and to be performed during voluntary head restraint, enabling cellular resolution imaging in future studies. Rats accumulated discrete numbers of flashes presented to the left and right visual hemifields and indicated the side that had the greater number of flashes. Using a signal-detection theory-based model, we found that the standard deviation in their internal estimate of flash number scaled linearly with the number of flashes. This indicates a major source of noise that, surprisingly, is not consistent with the widely used 'drift-diffusion modeling' (DDM) approach but is instead closely related to proposed models of numerical cognition and counting. We speculate that this form of noise could be important in accumulation of evidence tasks generally.

Objective: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA., Methods: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score)., Results: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups., Conclusion: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile., (© 2015 Merck Sharp & Dohme Corp. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Background & Aims: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for ulcerative colitis (UC) have not been evaluated previously., Methods: This randomized, double-blind trial evaluated the efficacy and safety of 16 weeks of treatment with infliximab monotherapy, azathioprine monotherapy, or the 2 drugs combined in tumor necrosis factor-a antagonist-naive adults with moderate to severe UC. Patients were assigned randomly to receive intravenous infusions of infliximab 5 mg/kg at weeks 0, 2, 6, and 14 plus daily oral placebo capsules; oral azathioprine 2.5 mg/kg daily plus placebo infusions on the infliximab schedule; or combination therapy with the 2 drugs. Corticosteroid-free clinical remission (primary end point, week 16) was evaluated at weeks 8 and 16. The study was terminated before the enrollment target was reached., Results: A total of 239 patients were included in efficacy analyses. Baseline characteristics were similar between treatment groups. Corticosteroid-free remission at week 16 was achieved by 39.7% (31 of 78) of patients receiving infliximab/azathioprine,compared with 22.1% (17 of 77) receiving infliximab alone(P =.017) and 23.7% (18 of 76) receiving azathioprine alone(P =.032). Mucosal healing at week 16 occurred in 62.8% (49 of 78) of patients receiving infliximab/azathioprine, compared with 54.6% (42 of 77) receiving infliximab (P = .295) and 36.8% (28 of 76) receiving azathioprine (P =.001). Serious infections occurred in 2 patients (1 patient receiving infliximab,and 1 patient receiving azathioprine)., Conclusions: Anti–tumor necrosis factor-a–naive patients with moderate to severe UC treated with infliximab plus azathioprine were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy. Combination therapy led to significantly better mucosal healing than azathioprine monotherapy. ClinicalTrials.gov number, NCT00537316.

Context: Odanacatib (ODN) is a selective cathepsin K inhibitor being developed to treat osteoporosis., Objective: The effects of ODN were evaluated on bone mineral density (BMD), biochemical markers of bone turnover, and safety in patients previously treated with alendronate., Design: This was a randomized, double-blind, placebo-controlled, 24-month study., Setting: The study was conducted at private or institutional practices., Participants: Postmenopausal women (n = 243) ≥ 60 years of age with low BMD at the total hip, femoral neck, or trochanter (T-score ≤-2.5 but >-3.5 without prior fracture or ≤-1.5 but >-3.5 with prior fracture) on alendronate for ≥ 3 years., Intervention: The intervention included ODN 50 mg or placebo weekly., Main Outcome Measures: The primary end point was percentage change from baseline of femoral neck BMD at month 24. BMD was assessed by dual-energy x-ray absorptiometry at baseline and 6, 12, and 24 months. Biochemical markers of bone turnover (serum C-telopeptides of type 1 collagen, urinary N-telopeptides of type 1 collagen, serum bone specific alkaline phosphatase, and serum N-terminal propeptide of type 1 collagen) were measured at baseline and 3, 6, 12, 18, and 24 months., Results: In the ODN group, BMD changes from baseline at the femoral neck, trochanter, total hip, and lumbar spine at 24 months (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. ODN significantly decreased urinary N-telopeptides of type 1 collagen to creatinine ratio and significantly increased serum N-terminal propeptide of type 1 collagen compared with placebo. Serum C-telopeptides of type 1 collagen was unexpectedly increased with ODN treatment. The safety profile appeared similar between groups., Conclusions: ODN provided incremental BMD gains in osteoporotic women after alendronate treatment.

High-throughput operant conditioning systems for rodents provide efficient training on sophisticated behavioral tasks. Combining these systems with technologies for cellular resolution functional imaging would provide a powerful approach to study neural dynamics during behavior. Here we describe an integrated two-photon microscope and behavioral apparatus that allows cellular resolution functional imaging of cortical regions during epochs of voluntary head restraint. Rats were trained to initiate periods of restraint up to 8 s in duration, which provided the mechanical stability necessary for in vivo imaging while allowing free movement between behavioral trials. A mechanical registration system repositioned the head to within a few microns, allowing the same neuronal populations to be imaged on each trial. In proof-of-principle experiments, calcium-dependent fluorescence transients were recorded from GCaMP-labeled cortical neurons. In contrast to previous methods for head restraint, this system can be incorporated into high-throughput operant conditioning systems., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 μg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p<0.001), spine trabecular vBMD (13.7%, p<0.001), femoral neck (FN) integral (int) vBMD (9.0%, p<0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p<0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p<0.001) and 21.8% (p<0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p<0.001) and 11.3% (p<0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p<0.05), and SubTrPF Ct.Th by 7.6% (p<0.05) and Ct.BMC by 6.2% (p<0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX-monkeys had comparable efficacy to ALN in DXA-based aBMD and QCT-based vBMD. However, FN cortical mineral content clearly demonstrated superior efficacy of ODN versus ALN in this model of estrogen-deficient non-human primates., (© 2013 Elsevier Inc. All rights reserved.)

Translational evaluation of disease progression and treatment response is critical to the development of therapies for osteoporosis. In this study, longitudinal in-vivo monitoring of odanacatib (ODN) treatment efficacy was compared to alendronate (ALN) in ovariectomized (OVX) non-human primates (NHPs) using high-resolution peripheral computed tomography (HR-pQCT). Treatment effects were evaluated using several determinants of bone strength, density and quality, including volumetric bone mineral density (vBMD), three-dimensional structure, finite element analysis (FEA) estimated peak force and biomechanical properties at the ultradistal (UD) radius at baseline, 3, 6, 9, 12, and 18 months of dosing in three treatment groups: vehicle (VEH), low ODN (2 mg/kg/day, L-ODN), and ALN (30 μg/kg/week). Biomechanical axial compression tests were performed at the end of the study. Bone strength estimates using FEA were validated by ex-vivo mechanical compression testing experiments. After 18months of dosing, L-ODN demonstrated significant increases from baseline in integral vBMD (13.5%), cortical thickness (24.4%), total bone volume fraction BV/TV (13.5%), FEA-estimated peak force (26.6%) and peak stress (17.1%), respectively. Increases from baseline for L-ODN at 18 months were significantly higher than that for ALN in DXA-based aBMD (7.6%), cortical thickness (22.9%), integral vBMD (12.2%), total BV/TV (10.1%), FEA peak force (17.7%) and FEA peak stress (11.5%), respectively. These results demonstrate a superior efficacy of ODN treatment compared to ALN at the UD radii in ovariectomized NHPs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans., Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women)., Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction., Conclusions: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing., (© 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Background: Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus., Patients and Methods: Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined., Results: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0-∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30-60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma., Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies. ClinicalTrials.gov Identifier NCT00112372.

Background: Sarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues., Objectives: The primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo., Design: This was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation., Setting: General community., Participants: 170 Women aged ≥65 with sarcopenia and moderate physical dysfunction., Measurements: Dual energy X-ray absorptiometry, muscle strength and power, physical performance measures., Results: Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well-tolerated with no evidence of androgenization., Conclusions: The MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation.

This study aimed to validate finite element analysis (FEA) estimation of strength, identify high-resolution peripheral quantitative computed tomography (HR-pQCT) measures correlating with strength, and evaluate the precision of HR-pQCT measurements to longitudinally monitor effects of osteoporosis treatment in ovariectomized (OVX) non-human primates (NHPs). HR-pQCT images were acquired in three groups of NHPs: Intact (n=10), OVX-odanacatib treated (OVX-ODN 30 mg/kg, n=10) and OVX-vehicle treated (OVX-Veh, n=10) at the ultradistal (UD) and distal 1/3 radii and tibia at 12, 16 and 20 months. FEA estimates of bone strength using the Pistoia criterion were validated by ex-vivo mechanical compression (r(2)=0.95) of the UD radius. Single linear regressions of FEA-determined ultimate stress showed high correlation with HR-pQCT derived parameters: integral vBMD (r(2)=0.86), bone volume fraction (r(2)=0.84) and cortical thickness (r(2)=0.79). Precision of HR-pQCT measurements, obtained from an excised radius and tibia, showed low variation (CV=0.005%-5.6%) and helped identify possible sources of error. Comparison of OVX-Veh and Intact groups showed decreases in bone parameters demonstrating trends consistent with bone loss. Comparison of OVX-ODN and OVX-Veh groups showed a treatment effect with increases in bone parameters: integral vBMD (477±27 vs. 364±22 mgHA/cm(3)) and cortical thickness (Ct.Th) (0.90±0.07 vs. 0.64±0.04 mm) at the UD radius, Ct.Th (2.15±0.28 vs. 1.56±0.08 mm) at the distal 1/3 radius. Axial compression peak stress calculated and obtained experimentally showed the OVX-ODN group was 33% stronger than the OVX-Veh group. We conclude that HR-pQCT and FEA serve as robust techniques to longitudinally monitor bone parameters and strength in NHP's., (Copyright © 2012 Elsevier Inc. All rights reserved.)