Search

Sarah E Ray,1 Vanessa Boudewyns,1 Christine Davis,1 Janice P Tzeng,1 Ila Srivastava,2 Oluwamurewa Oguntimein,3 Denise S Conti,4 Karen B Feibus2 1Center for Communication Science, RTI International, Research Triangle Park, NC, USA; 2Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA; 3Office of Medication Error Prevention and Risk Management, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA; 4Office of Safety and Clinical Evaluation, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USACorrespondence: Sarah E Ray, Center for Communication Science, RTI International, Research Triangle Park, NC, USA, Tel +1 770-407-4934, Email sray@rti.orgPurpose: This qualitative study explored patients’ attitudes about and perceptions of generic dry powder inhaler (DPI) substitution for the brand product and patients’ views of generic product quality, efficacy, design, and usability.Methods: Forty COPD and asthma patients (36 adults, four adolescents), who were actively using a brand DPI product, participated in one of six focus groups. Participants completed a journey mapping exercise to assess attitudes and opinions about a scenario where they refill their prescription and unexpectedly receive a generic DPI instead of their brand DPI. The focus groups were audio recorded, transcribed, and analyzed thematically.Results: The hypothetical scenario of unexpectedly receiving a generic DPI elicited mixed feelings including: happiness and relief about potential cost savings, confusion, disappointment, anger, and/or frustration with the unexpected switch. Participants in most groups anticipated anxiety or hesitation in using the generic DPI due to concerns about potential differences in usability, uncertainty about correct use, and questions about efficacy. Participants across all groups said they would ask a pharmacist or healthcare provider for information or answers to their questions, and some participants said they would use online resources. When participants held the brand and generic DPI devices, most preferred the brand DPI device and found it easier, less cumbersome, or more convenient to use (due to size and weight). However, many participants reiterated that the potential reduced cost of the generic DPI would be a primary factor in their decision-making related to generic DPI substitution for their brand DPI.Conclusion: Patients experienced a mixture of positive and negative feelings when faced with an unexpected generic DPI substitution. Some patients have doubts about their ability to successfully navigate differences in generic device design, and most expressed the desire to participate in discussions and decision-making with their HCP about generic DPI sameness and substitution.Keywords: COPD, asthma, medical devices, generic drugs, drug-device combination products, focus groups

Funding Acknowledgements Type of funding sources: None. Background The new Ensite X Cardiac Mapping (Abbott) system, with the introduction of Omnipolar technology (OT), provides three-dimensional information on voltage, direction of activation and conduction velocity of endocardial potentials, regardless of catheter orientation. OT thus enables the creation of more defined voltage maps and a wave speed map, a color map encoded by the numerical value of conduction velocity. Purpose We aimed to evaluate the feasibility and reliability of left atrium (LA) substrate and wave speed mapsperformed with OT in patients undergoing pulmonary vein isolation of paroxysmal atrial fibrillation (AF). Methods We included 39 patients undergoing catheter ablation for paroxysmal AF with the new Ensite X Cardiac Mapping System at five Italian Institution. In all patients the left atrium (LA) was mapped with the Advisor HD Grid catheter (Abbott). A sinus rhythm high-density voltage map and wave speed map were obtained and analyzed to compare low-voltage areas and to identify high conduction velocity areas. Results Thirty-nine pts were included in this analysis (61±10 years, 64% male, 68% with paroxysmal AF, CHA2DS2-VASc = 1.6±1.1, left atrial diameter = 46±9 mm, left ventricle ejection fraction 63±4%). The voltage maps were obtained by acquiring and, after point validation, analyzing significantly more points in the OT analysis than in the bipolar analysis (11455±8833 vs 8186±5826 and 2611±1728 vs 1753±1324, respectively; p < 0.001). Low-voltage area (< 0.05 mV) was significantly less extensive using OT (low-voltage OT area 8.9 cm2 [5.8; 24.2] vs low-voltage bipolar area 10.8 [6.4; 31.4]; p < 0.05), Fig 1. Considering wave speed maps, the pulmonary veins showed significantly higher values than the atrial values (LSPV: 2.89 ms/s ± 1.99; LIPV 2.86 ms/s ± 1.78; RSPV 3.31 ms/s ± 2.07; RIPV 2.86 ms/s ± 1.96; LA 1.67 ms/s ± 0.80; p< 0.001) while, in the atrium, the area of greatest speed was located on the roof (2.35 ms/s ± 1.53; p 0.02) almost drawing a bundle from the RSPV to the LA appendage that could coincide with the anatomical Bachmann’s bundle location, Fig 2. Conclusion OT makes it possible to obtain voltage maps by analyzing a larger number of points and providing a better substrate definition. Wave speed mapping is a promising new map type, allowing characterization and identification of high velocity areas. Further studies are needed to assess the impact of this new technology on procedural workflow and clinical outcome.

Background: Previous studies have demonstrated that preoperative patient-reported outcome measures are associated with postoperative outcomes in foot and ankle surgery, and also in specific procedures such as bunionectomy, flatfoot reconstruction, and total ankle replacement. The primary purpose of this study was to determine if preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) physical function, pain interference, pain intensity, and depression scores were associated with the ability of patients undergoing cheilectomy for hallux rigidus to achieve a minimal clinically important difference (MCID) of improvement. Methods: This retrospective study included preoperative and ≥2-year postoperative PROMIS physical function, pain interference, pain intensity, and depression scores for 125 feet in 118 patients undergoing cheilectomy collected from an institutional review board (IRB)–approved foot and ankle registry database. MCIDs were established using distribution-based methods to determine clinical significance of improvements in PROMIS scores. Receiver operating characteristic (ROC) curves and area under the curve analyses were used to determine which preoperative PROMIS scores were associated with patients meeting the MCID. Results: ROC analysis found statistically significant areas under the curve (AUCs) for the physical function domain (AUC 0.71), pain intensity (AUC 0.70), and depression (AUC 0.79) PROMIS domains. Subsequent analyses were unable to identify clinically useful 95% sensitivity and specificity preoperative thresholds, with the exception of the 95% sensitivity PROMIS physical function threshold. A preoperative physical function score of greater than 53.2 resulted in a 63% probability of achieving the MCID. The pain interference PROMIS domain did not demonstrate a statistically significant AUC. Conclusion: Preoperative PROMIS physical function, pain interference, pain intensity, and depression scores are minimally associated with preoperative to 2-year postoperative improvement in patients undergoing cheilectomy. It may be difficult to determine which patients improve from a cheilectomy based on the severity of symptoms they exhibit preoperatively. Level of Evidence: Level IV, retrospective case series.

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV

PDF file - 121K

PDF file - 62K, Table S1. Humanized MAb159 Pharmacokinetics in mouse. Table S2. Toxicology study of humanized MAb159 in mouse.

PDF file - 736K, Fig. S1. Generation and characterization of MAb159. Fig. S2. MAb159 induces GRP78 endocytosis through clathrin mediated pathway. Fig. S3. MAb159 induces apoptosis of tumor cells in vitro. Fig. S4. Surface GRP78 Forms Complex with PI3K. Fig. S5. Surface GRP78 level in cancer cell lines. Fig. S6. MAb159 treatment of xenograft tumor leads to reduced vessel density and mTOR signaling. Fig. S7. MAb159 shows no toxicity to normal organs in tumor xenograft study. Fig. S8. Inhibition of primary tumor growth and metastasis by MAb159 in 4T1 orthotopic model. Fig. S9. MAb159 inhibits the growth of hormone refractory mouse prostate cancer cell CE1 in vivo.

Purpose: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis.Experimental Design: MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application.Results: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN–loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics.Conclusions: GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly. Clin Cancer Res; 19(24); 6802–11. ©2013 AACR.

Supplementary Table 1 from Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of ApcMin/+ Mice

Colorectal cancer, one of the most common human malignancies in the Western world, is often subdivided based on tumor location in either the distal or proximal colon. Several mouse models have been developed to study human colorectal cancer, but few display this clear distinction between the two colonic locations. By crossing ApcMin/+ and Smad3 mutant mice, we showed that combined activation of the Wnt pathway and attenuation of the transforming growth factor-β (TGF-β) pathway causes high multiplicity and rapid onset of invasive tumorigenesis almost exclusively in the distal colon, closely mimicking the familial adenomatous polyposis (FAP) disease and consisting with distinct colorectal cancer etiologies based on tumor location. Transcriptional profiling revealed higher expression of several TGF-β activators in the normal distal mucosa than in proximal mucosa, suggesting a stronger reliance on TGF-β-mediated growth control in the distal than in the proximal colon. ApcMin/+Smad3−/− mice provide an alternative model to ApcMin/+ mice to study FAP and distal sporadic colorectal cancer. This model will be useful in dissecting mechanistic and etiologic differences between proximal and distal colonic cancer, whereas the confinement of tumorigenesis to the distal colon offers unique advantages in monitoring tumor progression by in vivo imaging. (Cancer Res 2006; 66(17): 8430-8)

Background: As total ankle arthroplasty (TAA) becomes more common, chronic periprosthetic joint infections (PJIs) will be encountered more frequently. No studies have reported on patient-reported outcomes following a 2-stage revision procedure for a chronic PJI after a TAA. The primary purpose of this study was to investigate postoperative clinical outcomes at a minimum of 2 years following a 2-stage revision TAA for chronic PJI. Methods: Patients who underwent a 2-stage revision TAA for a chronic PJI (>4 weeks after a primary TAA) between January 2010 and December 2019 were eligible to be included in this study. Chronic PJI was defined as a sinus tract that directly communicated with the prosthesis or the same organism identified in ≥2 synovial fluid samples. Twelve patients were eligible to be included in this case series. One patient died prior to 2-year follow-up, which left 11 patients available for analysis. All 11 patients underwent reimplantation. The data were found not to be normally distributed; therefore, medians and interquartile ranges (IQRs) were reported. Results: At a median of 3.0 years (IQR 2.0-4.0 years) following the second stage of their revision arthroplasty, the median Foot and Ankle Ability Measure (FAAM) Activities of Daily Living and Sports scores were 60.7 (IQR 52.4, 79.8) and 31.3 (IQR 9.4, 40.6), respectively. At final follow-up, 10 patients (90.9%) were ambulating with a TAA in place. Seven patients (63.6%) required a reoperation including 1 patient who underwent a below-knee amputation. Conclusion: Our study suggests that a 2-stage revision TAA may be an option for patients with a chronic PJI. However, patients who undergo a 2-stage revision TAA for a chronic PJI have lower than previously published 2-year FAAM scores and a high rate of reoperation. Level of Evidence: Level IV, case series.

Cytomegalovirus (CMV) infection is asymptomatic in the majority of immunocompetent patients. However, it can cause severe presentations, particularly in patients who are immunocompromised. We are reporting a rare association between respiratory failure secondary to cavitary pneumonia and a large pericardial effusion due to CMV infection in a patient with human immunodeficiency virus. The patient presented with hypoxic respiratory failure and a large pericardial effusion at risk of tamponade. After extensive investigation, the sole pathogen identified in the patient’s bronchoalveolar lavage and pericardial fluid was CMV.

Particle size characterization for active pharmaceutical ingredients (APIs) in nasal spray suspension products presents unique challenges because both the API and excipient particles are present in the final dosage form. Currently, an established method is lacking because traditional particle sizing technologies do not distinguish the chemical identity of the particles. In this study, a non-destructive, ingredient-specific particle sizing method was developed for characterization of mometasone furoate (MF) nasal spray suspensions using Morphology Directed Raman Spectroscopy (MDRS). A five-step method development procedure was used in this study: sample preparation, particle imaging and morphology analysis, particle Raman measurements and classification, morphology filter selection, and minimum number of particles determination. Wet dispersion sample preparation method was selected to ensure that the particles were measured in their original suspended state. A training set containing over 10,000 randomly-selected particles, including both the API and excipient particles, was used to gain a comprehensive understanding of particle size, shape, and chemical ID for the nasal spray suspension. Morphology and Raman measurements were performed on each particle in the training set. The measurement results suggested that the aspect ratio and intensity mean filter combination was an appropriate morphology filter setting to selectively target API particles and exclude most of excipient particles. With further optimization of the morphology filter cutoff values and determination of minimal number of particles to be measured, the total measurement time was reduced from 90 hours to 8 hours. The morphologically screening strategy ultimately allowed us to create a time-efficient practical API-specific particle size distribution (PSD) methods for nasal spray suspensions. This study shows that MDRS is a fit for purpose analytical technique for determining ingredient-specific PSDs of the pharmaceutical formulation studied in this work.

Background: The Lapidus procedure and scarf osteotomy are indicated for the operative treatment of hallux valgus; however, no prior studies have compared outcomes between the procedures. The aim of this study was to compare clinical and radiographic outcomes between patients with symptomatic hallux valgus treated with the modified Lapidus procedure versus scarf osteotomy. Methods: This retrospective cohort study included patients treated by 1 of 7 fellowship-trained foot and ankle surgeons. Inclusion criteria were age older than 18 years, primary modified Lapidus procedure or scarf osteotomy for hallux valgus, minimum 1-year postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores, and minimum 3-month postoperative radiographs. Revision cases were excluded. Clinical outcomes were assessed using 6 PROMIS domains. Pre- and postoperative radiographic parameters were measured on anteroposterior (AP) and lateral weightbearing radiographs. Statistical analysis utilized targeted minimum-loss estimation (TMLE) to control for confounders. Results: A total of 136 patients (73 Lapidus, 63 scarf) with an average of 17.8 months of follow-up were included in this study. There was significant improvement in PROMIS physical function scores in the modified Lapidus (mean change, 5.25; P < .01) and scarf osteotomy (mean change, 5.50; P < .01) cohorts, with no significant differences between the 2 groups ( P = .85). After controlling for bunion severity, the probability of having a normal postoperative intermetatarsal angle (IMA; Conclusion: Although the modified Lapidus procedure led to a higher probability of achieving a normal IMA, both procedures yielded similar improvements in 1-year patient-reported outcome measures. Level of Evidence: Level III, retrospective cohort.

[Image: see text] Thymidine analogues, 5-substituted 2′-deoxy-2′-[(18)F]fluoro-arabinofuranosyluracil derivatives, are promising positron emission tomography (PET) tracers being evaluated for noninvasive imaging of cancer cell proliferation and/or reporter gene expression. We report the radiosynthesis of 2′-deoxy-2′-[(18)F]fluoro-5-methyl-1-β-d-arabinofuranosyluracil ([(18)F]FMAU) and other 2′-deoxy-2′-[(18)F]fluoro-5-substituted-1-β-d-arabinofuranosyluracil analogues using 1,4-dioxane to replace the currently used 1,2-dichloroethane. Compared to 1,2-dichloroethane, 1,4-dioxane is analyzed as a better solvent in terms of radiochemical yield and toxicity concern. The use of a less toxic solvent allows for the translation of the improved approach to clinical production. The new radiolabeling method can be applied to an extensive range of uses for (18)F-labeling of other nucleoside analogues.

Background: Previous studies have demonstrated that procedure-specific thresholds using preoperative patient-reported outcome scores may be used to predict postoperative outcomes. The primary purpose of this study was to determine if preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) thresholds could be used to predict which patients would clinically improve at 2 years postoperatively following reconstruction of their flexible adult-acquired flatfoot deformity (AAFD). Methods: PROMIS physical function, pain interference, and depression scores were prospectively collected preoperatively and at a minimum of 2 years postoperatively for 75 feet with flexible AAFD. Minimal clinically important differences (MCIDs) were calculated to establish significant postoperative improvement. Receiver operating characteristic curves and area under the curve analyses were employed to determine whether preoperative PROMIS scores could be used to predict postoperative outcomes. Results: The PROMIS physical function receiver operating characteristic curve analysis (area under the curve = 0.913, P < .001) found that a preoperative PROMIS physical function score greater than 45.7 resulted in a 14.3% probability of achieving the MCID, whereas a preoperative score of less than 40.8 had a 97.7% probability of achieving the MCID. A preoperative PROMIS pain interference score (area under the curve = 0.799, P < .001) less than 54.1 had only a 23.1% probability of achieving the MCID at 2 years postoperatively. Conclusions: Preoperative PROMIS physical function and pain interference scores could be used to predict postoperative improvement in patients with flexible AAFD. These results may help surgeons counsel patients regarding the anticipated benefit of surgery. Level of Evidence: Level III, retrospective comparative series.

Tau pathology and vascular dysfunction are important contributors to Alzheimer's disease (AD), but vascular–tau associations and their effects on cognition are poorly understood. We investigated these associations in male and female humans by conducting voxelwise comparisons between cerebral blood flow (CBF) and tau positron emission tomography (PET) images in independent discovery [cognitively normal (CN), 19; mild cognitive impairment (MCI) risk, 43; MCI, 6] and replication (CN,73; MCI, 45; AD, 20) cohorts. In a subgroup, we assessed relationships between tau and soluble platelet-derived growth factor β (sPDGFRβ), a CSF marker of pericyte injury. We tested whether CBF/sPDGFRβ–tau relationships differed based on Montreal Cognitive Assessment (MoCA) global cognition performance, or based on amyloid burden. Mediation analyses assessed relationships among CBF/sPDGFRβ, tau, and cognition. Negative CBF–tau correlations were observed predominantly in temporal-parietal regions. In the replication cohort, early negative CBF–tau correlations increased in spatial extent and in strength of correlation with increased disease severity. Stronger CBF–tau and sPDGFRβ–tau correlations were observed in participants with greater amyloid burden and lower MoCA scores. Importantly, when stratifying by amyloid status, stronger CBF–tau relationships in individuals with lower MoCA scores were driven by amyloid+participants. Tau PET was a significant mediator CBF/sPDGFRβ–MoCA relationships in numerous regions. Our results demonstrate vascular–tau associations across the AD spectrum and suggest that early vascular–tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of AD on cognition. Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.SIGNIFICANCE STATEMENTEmerging evidence demonstrates a role for vascular dysfunction as a significant contributor to Alzheimer's pathophysiology. However, associations between vascular dysfunction and tau pathology, and their effects on cognition remain poorly understood. Multimodal neuroimaging data from two independent cohorts were analyzed to provide novelin vivoevidence of associations between cerebral blood flow (CBF), an MRI measure of vascular health, and tau pathology using PET. CBF–tau associations were related to cognition and driven in part by amyloid burden. Soluble platelet-derived growth factor β, an independent CSF vascular biomarker, confirmed vascular–tau associations in a subgroup analysis. These results suggest that combination treatments targeting vascular health, amyloid-β, and tau levels may more effectively preserve cognitive function than single-target therapies.

Due to rising demands on productivity and flexibility, assembly processes are currently experiencing a substantial transformation. Workstations where humans and robots work closely together are becoming increasingly popular, as they provide major advantages compared to manual assembly and full automation. Yet, human-robot collaboration (HRC) can only be successful if the workforce is willing to accept it. How assembly workers perceive HRC still has to be properly investigated. An exploratory investigation using a Grounded Theory approach was conducted to identify factors that are likely to influence workers’ acceptance of introducing HRC at work. Seventeen workers with various levels of HRC experience from four different manufacturing companies were interviewed. Findings reveal that some workers perceive HRC as a threat, while others regard it as an opportunity. This perception seems to depend both on their thoughts and feelings about the technology, i.e., collaborative robots, and the organizational change associated with the introduction of this technology. Several factors related to the robot (object-related factors), the individual background of the workers (subject-related factors), and the organizational environment (context-related factors) are found to influence workers’ thoughts and feelings. Implications for researchers and manufacturing companies are outlined.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Background: The posteromedial ankle structures are at risk during total ankle replacement (TAR). The purpose of our study was to investigate the distance of these structures from the posterior cortex of the tibia and talus in order to determine their anatomy at different levels of bone resection during a TAR and whether plantarflexion of the ankle reliably moved these structures posteriorly. Methods: Ten feet in 10 patients with end-stage tibiotalar arthritis indicated for a TAR were included. Preoperative magnetic resonance images were obtained with the foot in a neutral position as well as in maximum plantarflexion to measure the distance of posteromedial ankle structures to the closest part of the posterior cortex of the tibia or talus. Wilcoxon signed-rank rests were used to investigate differences in these distances. Results: The mean distance from the posterior tibial cortex to the tibial nerve at 14 and 7 mm above the tibial plafond was 8.7 mm (range 5.0-11.8 mm) and 6.7 mm (range 2.7-10.6 mm), respectively, which represented a statistically significant movement anteriorly ( P = .021). The posterior tibial artery was, on average, 8.0 mm (range 3.6-13.9 mm) and 7.2 mm (range 3.1-9.4 mm) from the posterior tibial cortex at 14 and 7 mm above the tibial plafond, respectively. Distal to the tibial plafond, the posterior tibial artery and flexor digitorum longus tendons moved posteriorly by less than 1 mm in plantarflexion (all P < .05); otherwise, plantarflexion of the ankle did not affect the position of the tibial nerve, posterior tibial tendon, or flexor hallucis longus. Conclusion: In patients with end-stage ankle arthritis, the tibial nerve and posterior tibial artery lie, on average, between 6.5 and 10 mm from the posterior tibial and talar cortices. Plantarflexion of the ankle did not reliably move the posteromedial ankle structures posteriorly. Level of Evidence: Level IV, case series, therapeutic

Category: Bunion Introduction/Purpose: Hallux valgus (HV) is a triplanar deformity of the first metatarsal in which the first metatarsal adducts, dorsiflexes, and pronates with an average increase in pronation between 2° and 8° compared with normal patients (Kimura JBJS, Campbell FAI). Despite these radiographic changes of the first metatarsal in patients with HV, no correlation between postoperative two-dimensional radiographic parameters and patient-reported outcomes has been reported (Thordarson FAI). The purpose of this study was to determine if a postoperative decrease in first metatarsal pronation (1MTPronation) was associated with changes in patient-reported outcomes as measured by the PROMIS physical function, pain interference, and pain intensity domains or recurrence rates in patients with HV who undergo a first tarsometatarsal fusion (modified Lapidus procedure). Methods: This study included thirty-nine consecutive HV patients who underwent a modified Lapidus procedure, had preoperative and >=2-year postoperative PROMIS scores, and had 1MTPronation measured using the previously described triplanar angle of pronation (FAI, in press) on preoperative and at least 5-month postoperative weightbearing CT scans. Multivariable regression analyses were used to investigate differences in the change in PROMIS domains preoperatively and 2-years postoperatively between patients with 'no change/increased 1MTPronation' and 'decreased 1MTPronation.' No differences in preoperative radiographic parameters or patient characteristics found between two groups. A secondary analysis using multivariable regression modeling was performed to determine if patients with a decrease in 1MTPronation between 2°-8° ('moderate pronation change') had greater improvements in PROMIS scores compared with 'minimal pronation change' (8°) groups. A log-binomal regression analysis was performed to identify if a decrease in 1MTPronation was associated with recurrence of the HV deformity (postoperative HVA>=20° Results: The decreased 1MTPronation group (n=26) had a statistically significant greater improvement in the PROMIS physical function scale by 7.2 points (95% confidence interval (CI) 2.1-12.3, P=0.007) compared to the no change/increased 1MTPronation group (n=13). There were no statistically significant differences in PROMIS pain interference (P=0.380) or pain intensity (P=0.443) scores between the two groups. The secondary analysis found that patients in the moderate pronation change group (n=15) had significantly better improvements in the PROMIS physical function and pain intensity domains than the minimal pronation change group (n=14) (Table 1). The moderate pronation change group also had greater improvements in the PROMIS pain interference and pain intensity domains than the substantial pronation (n=10) change group (Table 1). Recurrence rates were significantly lower in the decreased 1MTPronation pronation group when compared to the no change/increased 1MTPronation group (11.5% and 46.2%, respectively; risk ratio 0.25, 95% CI 0.07-0.84, P=0.025). Conclusion: In patients undergoing a modified Lapidus procedure for correction of their HV deformity, a postoperative decrease in pronation of the first metatarsal, especially between 2° and 8°, was associated with improvement in PROMIS scores at two- years postoperatively and a lower recurrence rate. These results suggest that the rotational component of the hallux valgus deformity may play an important role in outcomes following surgery, and consequently, surgeons should consider addressing but not overcorrecting the first metatarsal pronation deformity when performing a surgical procedure for the treatment of hallux valgus.

The therapeutic benefits of metered dose inhalers (MDIs) in pulmonary disorders are mainly driven by aerosol performance, which depends on formulation variables (drug and excipients), device design, and patient interactions. The present study provides a comprehensive investigation to better understand the effect of formulation variables on mometasone furoate (MF) suspension-based MDI product performance. The effects of MF particle size (volume median diameter; X

Objective In patients with a history of lymphoma who demonstrate palatine tonsil uptake on posttreatment PET/CT (positron emission tomography/computed tomography), tonsillectomy is often performed to evaluate for lymphoma recurrence. However, predictive clinical and imaging factors for true tonsil recurrence in this setting are not well established; this will be explored herein. Study design Retrospective case series. Setting Patients treated at a tertiary medical center from January 2008 to May 2020. Methods Chart review was performed on all patients with a history of treated lymphoma in clinical remission who presented for evaluation of abnormal PET/CT imaging findings and subsequently underwent tonsillectomy. Results Among 15 patients who met inclusion criteria, 14 had benign findings on surgical pathology, yielding a false-positive rate of 93%. The patient with malignancy was identified on biopsy after inconclusive surgical pathology and is the only documented case of recurrence in this specific patient population throughout the literature. The patient presented with B symptoms, irregularly shaped tonsils, increased lymph node activity on PET/CT, and uptrending bilateral tonsil activity but with one of the lowest maximum standardized uptake values of the cohort. The singular distinguishing feature for the patient with recurrent disease was a prior tonsil biopsy suspicious for recurrence, which prompted the otolaryngology referral. Conclusion PET/CT lacks specificity in identifying lymphoma recurrence in the oropharynx. Clinical and radiographic features that were previously considered concerning for recurrence are most likely not indicative of malignancy in this patient population. Our findings call into question whether tonsillectomy should be routinely performed in this patient population.

Category: Trauma; Midfoot/Forefoot Introduction/ Purpose: Primary arthrodesis of Lisfranc and midfoot fracture-dislocations is a reliable treatment option, yet concerns remain about nonunion and dorsiflexion malunion. The use of a new generation of nitinol staples has proliferated in midfoot arthrodesis. The purpose of this study is to examine the use of nitinol staples in primary arthrodesis of acute Lisfranc fracture-dislocations, comparing outcomes to traditional plate and screw fixation. The primary hypothesis is that nonunion rates are lower with constructs that include nitinol staples than those with plates and screws alone. Secondary hypotheses are: 1. Total operative and tourniquet time are shorter using nitinol staples. 2. Reoperation rates are lower using nitinol staples. 3. Dorsiflexion malunion rates are lower using nitinol staples. 4. Functional outcome scores will indicate comparable post-arthrodesis disability. Methods: Midfoot fracture-dislocations treated with primary arthrodesis by seven foot and ankle orthopaedic surgeons at a tertiary referral center from 1/1/2012 to 8/1/2021 were reviewed. Patients with open fractures, fractures managed with external fixation, Charcot arthropathy, neuropathy, previous midfoot surgery, or concomitant hindfoot/ankle fractures were excluded. Of 160 eligible patients, 121 patients met the required 4-month minimum radiographic follow-up. Preoperative records were reviewed, evaluating for associated metatarsal and cuneiform fractures, operative and tourniquet time, joints included, and fixation construct. Outcomes were analyzed at both patient and individual joint levels. Patients (121 total) and individual joints (305 total) were categorized as either staples alone (45 patients, 154 joints), staples plus plates and screws (hybrid) (45 patients, 40 joints), or plates and screws alone (31 patients, 111 joints). Postoperative radiographs were analyzed for union and malunion at each joint fused. Medical records were reviewed for postoperative complications. FAAM, VR-12, and NPRS were collected. Results: When assessed at the individual joint level, the nonunion rate was higher (8.1%, 9/111) among joints fixed with plate and screw constructs than with hybrid (2.5%, 1/40) or staple only constructs (1.3%, 2/154) (P = 0.017). Of the 12 nonunions in the study, 6 had either a metatarsal or cuneiform fracture. Median OR and tourniquet time were both shorter for hybrid (92 & 83 minutes) and staple only (67 & 63 minutes) constructs compared to plate and screw only fixation (106 & 95 minutes) (P = 0.0003 & < 0.0001). There were 15 (12.4%) reoperations including 10 hardware removals, 3 nonunion revisions, and 1 malunion revision. There was no difference in reoperation, malunion (14 total, 11.6%), or patient reported outcome measure between fixation types. Conclusion: Nitinol staples are effective in achieving bony fusion when used alone or in combination with plates and screws. Their use should be considered for primary arthrodesis of Lisfranc and midfoot fracture-dislocations due to lower rates of nonunion and shorter tourniquet and operative time compared to traditional plate and screw fixation. Further studies are needed to determine if staples decrease the risk for dorsiflexion malunion and improve patient reported outcomes.

W51A is the most active star formation region of the giant H ii region W51. It harbors the two massive protoclusters W51e and W51 IRS2, which are very rare in the Galaxy. We aim to identify the newborn massive stars and ultracompact H ii regions to derive its distance and age. We performed Integral Field Unit observations with NIFS+ALTAIR of nine targets in the W51A subregion. The distance modulus was obtained using the spectral classification in the K band and a reddening law appropriate to the inner Galactic plane. We derived the distance and the spectral types for five of the targets, ranging from O8 to O9.5, similar to those derived from radio continuum data, except for two sources to which we assigned a somewhat later spectral type. We included another seven objects with precise spectral classification from other works, which allowed us to better constrain the distance estimate. Our spectrophotometric distance d = 4.80 ± 1.27 kpc is in good agreement with those derived from the Galactic rotation model and trigonometric parallaxes, placing the region near the tangent point of the Sagittarius arm. We conclude that the stars studied in this work have an age spread of 1.5–4 Myr, substantially older than thought to date.