Congenital Ankylosis of the Knee Treated with Van Nes Rotationplasty: A Case Report.

CASE: This is a case of a female patient born with thrombocytopenia-absent radius syndrome, with bilateral upper extremity phocomelia, bilateral hip dislocations, and congenital fusion of the right knee with progressively worsening flexion contracture. At age 3 years and 5 months, the patient was treated with excision of the knee ankylosis and Van Nes rotationplasty. This proved durable at age 20 years (final follow-up) without any need for further surgery and without complication. CONCLUSION: This is the first known report of Van Nes rotationplasty as a durable treatment option in the management of congenital knee ankylosis, which may avoid reoperation and eliminate risk of recurrence.

Choice selective inhibition drives stability and competition in decision circuits.

During perceptual decision-making, the firing rates of cortical neurons reflect upcoming choices. Recent work showed that excitatory and inhibitory neurons are equally selective for choice. However, the functional consequences of inhibitory choice selectivity in decision-making circuits are unknown. We developed a circuit model of decision-making which accounts for the specificity of inputs to and outputs from inhibitory neurons. We found that selective inhibition expands the space of circuits supporting decision-making, allowing for weaker or stronger recurrent excitation when connected in a competitive or feedback motif. The specificity of inhibitory outputs sets the trade-off between speed and accuracy of decisions by either stabilizing or destabilizing the saddle-point dynamics underlying decisions in the circuit. Recurrent neural networks trained to make decisions display the same dependence on inhibitory specificity and the strength of recurrent excitation. Our results reveal two concurrent roles for selective inhibition in decision-making circuits: stabilizing strongly connected excitatory populations and maximizing competition between oppositely selective populations.

A Randomised Phase I Study to Assess the Safety, Tolerability and Pharmacokinetics of Palovarotene Ophthalmic Solution.

BACKGROUND AND OBJECTIVE: Palovarotene, a selective retinoic acid receptor γ agonist, is under investigation for the treatment of dry eye disease. This study aimed to determine the ocular and systemic safety, tolerability and pharmacokinetics of palovarotene ophthalmic solution (PVO-OS) in healthy adults. METHODS: This was a randomised, vehicle-controlled phase I study (NCT04762355; retrospectively registered). Participants received either PVO-OS (at 0.025, 0.05 or 0.10 mg/mL) or a vehicle (placebo-to-match PVO-OS) once-daily or twice-daily for seven consecutive days. Safety was assessed by ocular and systemic assessments. Blood samples for pharmacokinetic assessments were collected before and after dose administration. RESULTS: Thirty-six participants were randomised to PVO-OS and 12 to the vehicle. Overall, 89 treatment-emergent ocular adverse events (TEOAEs) were reported by 22 participants (61.1%) receiving PVO-OS and ten TEOAEs were reported by five participants (41.7%) receiving the vehicle. Erythema, irritation and skin dryness of the eyelid were the most common TEOAEs in participants receiving PVO-OS. The incidence of TEOAEs and eyelid-related findings in the PVO-OS groups increased with ascending dose and frequency compared with participants treated with the vehicle. All TEOAEs were mild (96.6%) or moderate (3.4%) and resolved without sequelae. Plasma palovarotene concentrations were generally measurable for up to 3-4 h for 0.025 mg/mL and 0.05 mg/mL and up to 12 h for 0.10 mg/mL dose regimens, independent of the frequency of administration. CONCLUSIONS: PVO-OS was generally well tolerated at doses up to and including 0.10 mg/mL twice daily. Similar pharmacokinetic profiles were observed for the once-daily and twice-daily regimens following multiple ascending doses of PVO-OS.

Multi-institutional distributed data networks for real-world evidence about medical devices: building unique device identifiers into longitudinal data (BUILD).

Objectives: To support development of a robust postmarket device evaluation system using real-world data (RWD) from electronic health records (EHRs) and other sources, employing unique device identifiers (UDIs) to link to device information. Methods: To create consistent device-related EHR RWD across 3 institutions, we established a distributed data network and created UDI-enriched research databases (UDIRs) employing a common data model comprised of 24 tables and 472 fields. To test the system, patients receiving coronary stents between 2010 and 2019 were loaded into each institution's UDIR to support distributed queries without sharing identifiable patient information. The ability of the system to execute queries was tested with 3 quality assurance checks. To demonstrate face validity of the data, a retrospective survival study of patients receiving zotarolimus or everolimus stents from 2012 to 2017 was performed using distributed analysis. Propensity score matching was used to compare risk of 6 cardiovascular outcomes within 12 months postimplantation. Results: The test queries established network functionality. In the analysis, we identified 9141 patients (Mercy = 4905, Geisinger = 4109, Intermountain = 127); mean age 65 ± 12 years, 69% males, 23% zotarolimus. Separate matched analyses at the 3 institutions showed hazard ratio estimates (zotarolimus vs everolimus) of 0.85-1.59 for subsequent percutaneous coronary intervention (P = .14-.52), 1.06-2.03 for death (P = .16-.78) and 0.94-1.40 for the composite endpoint (P = .16-.62). Discussion: The analysis results are consistent with clinical studies comparing these devices. Conclusion: This project shows that multi-institutional data networks can provide clinically relevant real-world evidence via distributed analysis while maintaining data privacy.

Anatomic all-epiphyseal ACL reconstruction with "inside-out" femoral tunnel placement in immature patients yields high return to sport rates and functional outcome scores a minimum of 24 months after reconstruction.

PURPOSE: To understand if anatomic physeal-sparing ACL reconstruction in the immature host preserves range of motion, permits a return to sports, and avoids limb length discrepancy and accelerated intra-articular degeneration with a cross-sectional radiographic, physical examination and patient-reported outcomes analysis. METHODS: A cross-sectional recall study included 38 patients aged 7-15 who underwent all-epiphyseal ACL reconstruction with hamstring allograft performed by a single surgeon at a large academic medical center. All-epiphyseal reconstructions were performed using a modified Anderson physeal-sparing technique, with the femoral tunnel placed using an "inside-out" technique. Assessments consisted of a physical exam, long leg cassette radiographs, KT-1000 measurements, subjective patient metrics, and magnetic resonance imaging. RESULTS: Thirty-eight (56.7%) of 66 eligible patients returned for in-person clinical and radiographic exams. Patients were 11.4 ± 1.8 years at the time of surgery. Five patients were females (13.2%). Mean follow-up was 5.5 ± 2.4 years. ACL re-injuries occurred in four patients (10.5%), all of whom underwent revision reconstructions. Thirty-three of the remaining 34 (97.1%) patients returned to sports following their reconstruction, and 24 (70.6%) returned to their baseline level of competition. Mean limb length discrepancy (LLD) was 0.2 ± 1.4 cm. Nine patients had an LLD of > 1 cm (26.5%), which occurred at an equivalent age as those with < 1 cm LLD (10.8 ± 2.0 vs. 11.7 ± 1.7, n.s.). Pre-operative Marx scores (13.1 ± 3.5) were not significantly different from post-operative values (12.3 ± 5.1, n.s.). Patients who required ACL revisions had significantly lower Marx scores than those with intact primary grafts (8.3 ± 7.1 vs. 13.4 ± 4.5, p = 0.047). Cohort mean International Knee Documentation Committee (IKDC) score was 89.7 ± 12.7. CONCLUSION: Anatomic all-epiphyseal anatomic ACL reconstruction appears to be useful in patients with significant projected remaining growth, with good return-to-sport outcomes and minimal risk of clinically significant physeal complications. However, given the limited patient recall possible in the present study, further large sample size, high-quality works are necessary to validate our findings. LEVEL OF EVIDENCE: Level IV.

Biochemistry course-based undergraduate research experience: Purification, characterization, and identification of an unknown lactate dehydrogenase isoenzyme.

Enzyme purification, characterization, and identification are some of the best ways to introduce undergraduate students to many aspects of biochemistry, particularly as part of project-based learning (PBL). These kinds of multi-step laboratory experiments not only help students to better understand basic biochemistry concepts but also serve to introduce them to the scaffolded nature of the research environment. A 13-week enzyme-based laboratory project was designed as one of three components associated with the course titled Capstone Laboratory, which is delivered to second-year undergraduate students at Weill Cornell Medicine in Qatar (WCM-Q). The project incorporated several fundamental biochemical laboratory techniques, such as chromatography, centrifugation, spectrophotometry, electrophoresis, and kinetic assays, as well as enzyme inhibition and bioinformatic exercises. The aims of the project were to first purify, then to quantify, and finally to study a particular lactate dehydrogenase (LDH) isoenzyme extracted from different chicken organs. LDH was selected for investigation because its inhibition has potential as a therapeutic strategy for cancer treatment. Students enrolled in the Capstone Laboratory course were divided into three groups. Each group conducted experiments associated with one of the project's three aims over consecutive 3-week periods. Relevant data and materials were passed from one group to the next, with individual students writing reports describing the results from their respective collection of experiments. Students in the third and final group gave presentations summarizing the results of the overall project. In the associated bioinformatic exercises, students assessed the similarities and differences between chicken-sourced and human-sourced LDH as well as the interaction between the LDH enzyme and the inhibitors. This PBL in biochemistry is a successful addition to the WCM-Q premedical curriculum because (a) it affords the second-year premedical students opportunities to improve and develop content knowledge and technical and communication skills, and also (b) it provides an opportunity to engage many of the undergraduate students in research.

Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma.

BACKGROUND: Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0-1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety. RESULTS: One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95-11.96) for necuparanib arm and 9.99 months (95% CI: 7.85-12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66-1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%). CONCLUSION: The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243.

Intermediate-term annualized curve progression of adolescent idiopathic scoliosis curves measuring 40° or greater.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: The objective of this study was to examine intermediate-term progression for a large series of patients with adolescent idiopathic scoliosis (AIS) with curves 40° or greater. BACKGROUND: Curve progression in AIS has been well documented for smaller curves in adolescence up to skeletal maturity; however, the data on curve progression past 40° or into adulthood are limited. With many surgeons recommending surgical correction when patients reach this threshold, it is important to understand the radiographic progression of curves into adulthood. METHODS: A database of all patients seen by a single surgeon from 1984 through 2018 with AIS curves progressing to at least 40° entered prospectively was utilized for this study. This included a total of 738 patients. Curve progression was analyzed overall and stratified by length of follow-up, curve location, and Risser stage at the time of presentation among other variables. Curve magnitude and Risser stage designations in this study were validated by performing a separate inter- and intrarater agreement study using four independent reviewers reading 50 patients' Cobb angle and Risser stage blinded in triplicate to examine the reliability of the study measurements. RESULTS: Annualized curve progression (ACP) averaged 6.3 ± 10.4°. ACP varied with length of follow-up: patients with up to 1 year of follow-up had an average ACP of 11.5 ± 17.0°, while those with 1-2 years had 8.2 ± 8.8°, and 2-5 years had 3.7 ± 4.1°, tapering off further from there. Risser stage 0 or 1 was associated with the highest ACP as compared to Risser stage 2-3 or 4-5. Intraclass correlation (ICC) values for Cobb angle measurement and Risser stage designations from four raters measuring 50 patients' measures, blinded and in triplicate, were all > 0.80, signifying a high degree of reliability within and between readers. CONCLUSIONS: Annualized curve progression for 40° and greater curves was not linear over time; it was greatest immediately after a curve reaches 40° and tapered off over the next decade. Immature Risser stage at presentation was strongly associated with increasing ACP at all time frames. LEVEL OF EVIDENCE: Prognostic Level I.

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics.

AIMS: Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. METHODS: A 3-part, open-label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5-6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2-period randomized cross-over design. Itraconazole plasma and sputum concentrations were evaluated. RESULTS: None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration-time curve up to 24 h) 106- to 400-fold lower across doses tested (10-35 mg) than steady-state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70-fold higher and geometric mean plasma concentrations were 66-fold lower than with oral Sporanox. CONCLUSION: PUR1900 was safe and well-tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.

Acetylcholine Mediates Dynamic Switching Between Information Coding Schemes in Neuronal Networks.

Rate coding and phase coding are the two major coding modes seen in the brain. For these two modes, network dynamics must either have a wide distribution of frequencies for rate coding, or a narrow one to achieve stability in phase dynamics for phase coding. Acetylcholine (ACh) is a potent regulator of neural excitability. Acting through the muscarinic receptor, ACh reduces the magnitude of the potassium M-current, a hyperpolarizing current that builds up as neurons fire. The M-current contributes to several excitability features of neurons, becoming a major player in facilitating the transition between Type 1 (integrator) and Type 2 (resonator) excitability. In this paper we argue that this transition enables a dynamic switch between rate coding and phase coding as levels of ACh release change. When a network is in a high ACh state variations in synaptic inputs will lead to a wider distribution of firing rates across the network and this distribution will reflect the network structure or pattern of external input to the network. When ACh is low, network frequencies become narrowly distributed and the structure of a network or pattern of external inputs will be represented through phase relationships between firing neurons. This work provides insights into how modulation of neuronal features influences network dynamics and information processing across brain states.

How rhythms of the sleeping brain tune memory and synaptic plasticity.

Decades of neurobehavioral research has linked sleep-associated rhythms in various brain areas to improvements in cognitive performance. However, it remains unclear what synaptic changes might underlie sleep-dependent declarative memory consolidation and procedural task improvement, and why these same changes appear not to occur across a similar interval of wake. Here we describe recent research on how one specific feature of sleep-network rhythms characteristic of rapid eye movement and non-rapid eye movement-could drive synaptic strengthening or weakening in specific brain circuits. We provide an overview of how these rhythms could affect synaptic plasticity individually and in concert. We also present an overarching hypothesis for how all network rhythms occurring across the sleeping brain could aid in encoding new information in neural circuits.

Resonance with subthreshold oscillatory drive organizes activity and optimizes learning in neural networks.

Network oscillations across and within brain areas are critical for learning and performance of memory tasks. While a large amount of work has focused on the generation of neural oscillations, their effect on neuronal populations' spiking activity and information encoding is less known. Here, we use computational modeling to demonstrate that a shift in resonance responses can interact with oscillating input to ensure that networks of neurons properly encode new information represented in external inputs to the weights of recurrent synaptic connections. Using a neuronal network model, we find that due to an input current-dependent shift in their resonance response, individual neurons in a network will arrange their phases of firing to represent varying strengths of their respective inputs. As networks encode information, neurons fire more synchronously, and this effect limits the extent to which further "learning" (in the form of changes in synaptic strength) can occur. We also demonstrate that sequential patterns of neuronal firing can be accurately stored in the network; these sequences are later reproduced without external input (in the context of subthreshold oscillations) in both the forward and reverse directions (as has been observed following learning in vivo). To test whether a similar mechanism could act in vivo, we show that periodic stimulation of hippocampal neurons coordinates network activity and functional connectivity in a frequency-dependent manner. We conclude that resonance with subthreshold oscillations provides a plausible network-level mechanism to accurately encode and retrieve information without overstrengthening connections between neurons.

Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects.

The aims of this randomized, double-blind, three-arm, single-dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as "M923") to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration (Cmax ), area under the curve (AUC) from time 0 extrapolated to infinity (AUC0-inf ), and AUC from time 0 to 336 hours (AUC0-336 ). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40-mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as "US Humira"; or adalimumab EU Humira (n = 103), hereafter referred to as "EU Humira." PK equivalence was demonstrated for all primary PK endpoints. Geometric least squares means ratios (GMRs) for Cmax , AUC0-inf , and AUC0-336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%-125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates.

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Familial cerebral cavernous malformations type III (fCCM3) is a disease of the cerebrovascular system caused by loss-of-function mutations in ccm3 that result in dilated capillary beds that are susceptible to hemorrhage. Before hemorrhage, fCCM3 lesions are characterized by a hyperpermeable blood-brain barrier (BBB), the key pathologic feature of fCCM3. We demonstrate that connexin 43 (Cx43), a gap junction (GJ) protein that is incorporated into the BBB junction complex, is up-regulated in lesions of a murine model of fCCM3. Small interfering RNA-mediated ccm3 knockdown (CCM3KD) in brain endothelial cells in vitro increased Cx43 protein expression, GJ plaque size, GJ intracellular communication (GJIC), and barrier permeability. CCM3KD hyperpermeability was rescued by GAP27, a peptide gap junction and hemichannel inhibitor of Cx43 GJIC. Tight junction (TJ) protein, zonula occludens 1 (ZO-1), accumulated at Cx43 GJs in CCM3KD cells and displayed fragmented staining at TJs. The GAP27-mediated inhibition of Cx43 GJs in CCM3KD cells restored ZO-1 to TJ structures and reduced plaque accumulation at Cx43 GJs. The TJ protein, Claudin-5, was also fragmented at TJs in CCM3KD cells, and GAP27 treatment lengthened TJ-associated fragments and increased Claudin 5-Claudin 5 transinteraction. Overall, we demonstrate that Cx43 GJs are aberrantly increased in fCCM3 and regulate barrier permeability by a TJ-dependent mechanism.-Johnson, A. M., Roach, J. P., Hu, A., Stamatovic, S. M., Zochowski, M. R., Keep, R. F., Andjelkovic, A. V. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Constructing the informatics and information technology foundations of a medical device evaluation system: a report from the FDA unique device identifier demonstration.

Objective: The US Food and Drug Administration (FDA) has recognized the need to improve the tracking of medical device safety and performance, with implementation of Unique Device Identifiers (UDIs) in electronic health information as a key strategy. The FDA funded a demonstration by Mercy Health wherein prototype UDIs were incorporated into its electronic information systems. This report describes the demonstration's informatics architecture. Methods: Prototype UDIs for coronary stents were created and implemented across a series of information systems, resulting in UDI-associated data flow from manufacture through point of use to long-term follow-up, with barcode scanning linking clinical data with UDI-associated device attributes. A reference database containing device attributes and the UDI Research and Surveillance Database (UDIR) containing the linked clinical and device information were created, enabling longitudinal assessment of device performance. The demonstration included many stakeholders: multiple Mercy departments, manufacturers, health system partners, the FDA, professional societies, the National Cardiovascular Data Registry, and information system vendors. Results: The resulting system of systems is described in detail, including entities, functions, linkage between the UDIR and proprietary systems using UDIs as the index key, data flow, roles and responsibilities of actors, and the UDIR data model. Conclusion: The demonstration provided proof of concept that UDIs can be incorporated into provider and enterprise electronic information systems and used as the index key to combine device and clinical data in a database useful for device evaluation. Keys to success and challenges to achieving this goal were identified. Fundamental informatics principles were central to accomplishing the system of systems model.

Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results.

LESSONS LEARNED: Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling. BACKGROUND: Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab-paclitaxel in patients with metastatic pancreatic cancer. METHODS: Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined. RESULTS: Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab-paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II. CONCLUSION: Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated.

SRS-22r Scores in Nonoperated Adolescent Idiopathic Scoliosis Patients With Curves Greater Than Forty Degrees.

STUDY DESIGN: Case control comparative series. OBJECTIVE: Describe surgical range adolescent idiopathic scoliosis (AIS) patients electing to forgo surgery and compare health-related quality-of-life outcomes to a similar cohort of operated AIS patients by the same single surgeon. SUMMARY OF BACKGROUND DATA: No data have been published either documenting SRS-22r scores of nonoperated patients with curves ≥40° or comparing these scores to a demographically similar operated cohort. METHODS: Individuals with curves ≥40°, age ≥18 years, and electing to forgo surgery were identified. All patients completed an SRS-22r questionnaire. This nonoperated cohort's SRS-22r scores were compared to those of a large demographically similar cohort operated by the same surgeon. Group differences between the SRS-22r scores were evaluated by comparing these to published Minimal Clinically Important Differences (MCID) for the SRS-22r. RESULTS: One hundred ninety subjects with nonoperated curves were compared to 166 individuals who underwent surgery. The nonoperated cohort averaged 23.5 years of age, averaged 7.7 years since curve reached 40°, and had an average 50° Cobb angle at last follow-up. No statistical significant differences were found between the groups on the Pain, Function, or Mental Health domains of the SRS-22r. Statistically significant differences in favor of the operative cohort were found for self-image, satisfaction, and total score. The observed group differences did not meet the established thresholds for minimal clinically important differences in any of the domain scores, the average total score, or raw scores. CONCLUSION: There are no meaningful clinically significant differences in SRS-22r scores at average 8-year follow-up between AIS patients with curves ≥40° treated with or without surgery. These data in conjunction with an absence of long-term evidence of serious medical consequences with nonsurgical management of curves ≥40° should encourage surgeons to reevaluate the benefits of routine surgical care. LEVEL OF EVIDENCE: 3.

Outcomes of Pediatric Fractures Managed With Closed Reduction by Orthopaedic Residents in the Emergency Department.

BACKGROUND: Closed reduction of pediatric fractures is commonly performed by orthopaedic residents using conscious sedation in the emergency department (ED). The purpose of this study was to determine the rate of satisfactory reductions as performed by residents, and to determine the outcomes of these procedures. METHODS: A retrospective review was performed of all fractures that underwent closed reduction under conscious sedation in the ED of a level 1 pediatric trauma center between January 1, 2010 and November 30, 2014. Initial and subsequent radiographs were reviewed and a determination was made as to whether the initial reduction was satisfactory, based on predetermined criteria for angulation and displacement. If a second reduction attempt in the operating room was necessary, this was noted. Chart notes were reviewed until a documented endpoint was reached, such as uneventful healing, malunion, nonunion, or growth arrest. RESULTS: A total of 838 subjects were identified. The upper extremity was involved in 85% of the fractures. Of the initial 838 fracture reductions performed, 39 (4.7%) were unsatisfactory. Residents on their first pediatric orthopaedic rotation had a higher unsatisfactory reduction rate compared with more experienced residents (7.0% vs. 3.4%, P=0.01). A second reduction was performed for 94 of 749 (12.6%) fractures. Of these, 35 (37.2%) required an open procedure to accomplish a satisfactory reduction. Fractures with initially satisfactory reductions were significantly less likely to require a second reduction attempt than those with initially unsatisfactory reductions (9.2% vs. 80.0%, P<0.01). The likelihood of a satisfactory reduction was significantly higher in the upper extremity than in the lower extremity. Overall, the vast majority (99.2%) of fractures had a satisfactory final outcome. CONCLUSIONS: Most attempts at closed reduction of pediatric fractures in the ED by orthopaedic residents are successful, and the likelihood of a satisfactory reduction was associated with increased levels of resident experience. Fractures with an initially successful reduction were far less likely to require remanipulation. LEVEL OF EVIDENCE: Level IV-this is a therapeutic case series.