Vardenafil Activity in Lung Fibrosis and In Vitro Synergy with Nintedanib.

Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-ß1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-ß1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required.

Utility of Transbronchial Biopsy in the Immunocompromised Host With New Pulmonary Radiographic Abnormalities.

OBJECTIVE: To assess how often transbronchial biopsy (TBBx) added unique positive findings apart from other synchronous bronchoscopic sampling techniques including the bronchoalveolar lavage-immunocompromised host (BAL-ICH) panel that justified changes in management in an array of immunocompromised patients with new pulmonary radiographic abnormalities. METHODS: We retrospectively reviewed all bronchoscopies performed at Mayo Clinic Rochester between January 2012 and December 2017; on the basis of the physician's selection of a BAL-ICH panel, we identified 192 immunocompromised patients who underwent bronchoscopy with both a BAL-ICH panel and TBBx. The results of the BAL-ICH panel and TBBx were compared and subsequent management decisions analyzed from clinical notes. We identified changes in immunosuppressive agents, antibiotics, chemotherapy, goals of care, and decisions on further evaluation and procedures. We assessed whether the TBBx findings added information not identified on the BAL-ICH panel and other bronchoscopic sampling methods performed during the same procedure that justified subsequent management changes. RESULTS: Of 192 bronchoscopic procedures performed on immunocompromised patients with acute and subacute pulmonary radiographic abnormalities, management changes justified by the unique positive results of the TBBx occurred 28% (51/192) of the time. Those immunocompromised by solid malignant neoplasms and receiving active immunosuppressive therapy had management changes justified 62.1% (18/29) of the time by the TBBx results. No additional fungal organisms were identified on TBBx that were accounted for on the BAL-ICH panel. CONCLUSION: Transbronchial biopsy may add information to other bronchoscopic findings in immunocompromised patients, especially those with solid malignant neoplasms receiving active immunosuppressive treatment. These potential benefits must be weighed against the risks inherent to the procedure.

Pleuritis and Pericarditis in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

BACKGROUND: Pleural and pericardial involvements are well recognized in eosinophilic granulomatosis with polyangiitis (EGPA) but considered rare manifestations of the other forms of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). RESEARCH QUESTION: What are the frequency and clinical characteristics of pleuritis and pericarditis in AAV? STUDY DESIGN: and Methods: Using an institutional database of 1,830 patients with AAV, we analyzed clinical notes and diagnosis codes for key words related to pleuritis and pericarditis. Chart review to confirm these findings was performed. RESULTS: Eighty-eight of 1,058 patients (8.3%) with granulomatosis with polyangiitis (GPA), 27 of 267 (10.1%) with microscopic polyangiitis (MPA), and 35 of 201 (17.4%) with EGPA had a manifestation of pleuritis and/or pericarditis attributable to vasculitis. There was a higher frequency of pericarditis in EGPA compared with that in the other AAVs (P < .01). There was no difference in the frequency of pleuritis in GPA, MPA, or EGPA. In the 156 patients with AAV with pleuritis and/or pericarditis, this was a presenting feature in 127 (81.4%). Overall, it was a presenting feature in 6.9% of all patients with AAV, including 6.5% with GPA, 8.6% with MPA, and 15.9% with EGPA. INTERPRETATION: Pleuritis and pericarditis occur across all the AAVs and, when present, are commonly presenting features of these diseases. Patients with EGPA have a higher proportion of pericardial involvement compared with pleural involvement, whereas this distribution is more equal in patients with GPA and MPA. Pleuritis and pericarditis are underrecognized features of AAV. All forms of AAV should be considered in the differential diagnosis when evaluating a patient with pleuritis or pericarditis.

Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine Regardless of Age or Body Mass Index: Exploratory Analysis from a Phase 3 Open-Label Trial in Postsurgical Pain.

INTRODUCTION: Advanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD. METHODS: Patients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate < 10 breaths per minute and/or oxygen saturation < 90%. RESULTS: A total of 724 surgical patients with a mean age of 54.5 ± 15.9 years and a mean NRS score of 6.2 ± 2.1 were included in this analysis; 33.3% (241/724) were ≥ 65 years of age and 46.3% (335/724) had BMI (body mass index) ≥ 30 kg/m2. The overall OIRD incidence was 13.7% with no patients requiring naloxone. The OIRD incidence was similar in the elderly and younger adults' cohorts [10.8 vs. 15.1%, OR 0.68 (0.42, 1.1), p = 0.11], and in obese and non-obese groups [14.0 vs. 13.4%, OR 1.06 (0.69, 1.62), p = 0.80]. In patients that were both elderly and obese (n = 120), the incidence was 10.8%. The multivariate analysis identified baseline NRS ≥ 6 [OR 1.6 (1.0, 2.4), p = 0.0499], PCA administration [OR 1.9 (1.2, 3.1), p = 0.005], and concomitant use of benzodiazepines and/or gabapentinoids [OR 1.6 (1.0, 2.6), p = 0.045], as being associated with OIRD. CONCLUSIONS: Postoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD.

The informational properties of the throwing arm for anticipation of goal-directed action.

We examined the informational value of biological motion from the arm in predicting the location of a thrown ball. In three experiments, participants were classified as being skilled and less skilled based on their actual performance on the task (i.e., using a within-task criterion). We then presented participants with a range of stick figure representations and required them to predict throw direction. In Experiment 1, we presented stick figure movies of a full body throwing action, right throwing arm plus left shoulder and throwing arm only. Participants were able to anticipate throw direction above chance under all conditions irrespective of perceptual skill level, with the perceptually skilled participants excelling under full body conditions. In Experiment 2, we neutralized dynamical differences in motion to opposing throw directions from the shoulder, elbow and wrist of the throwing arm. Neutralizing the wrist location negatively affected anticipation performance in all participants reducing accuracy to below chance. In Experiment 3, we presented movies of the motion wrist location alone and the upper section of the throwing arm (shoulder-elbow). Participants were able to successfully anticipate above chance in these latter two conditions. Our findings suggest that motion of the throwing arm contains multiple sources of information that can help facilitate the anticipation of goal-directed action. Perceptually skilled participants were superior in extracting informational value from motion at both the local and global levels when compared to less skilled counterparts.

Cumulative Incidence of Revision for a Balanced Knee System at a Mean 8-Year Follow-Up: A Retrospective Review of 500 Consecutive Total Knee Arthroplasties.

PURPOSE: The primary purpose of this study was to evaluate mid-term survival of a Balanced Knee System in the first 500 total knee arthroplasty (TKA) cases using a fully cemented, posterior stabilized TKA at a high-volume private practice. PATIENTS AND METHODS: In this IRB approved retrospective cohort study, data were extracted from a surgical registry at a high-volume orthopaedic practice for the first 500 total knee arthroplasty (TKA) cases performed using the Balanced Knee® System (BKS, Ortho Development®, Draper, Utah, USA). Procedures were performed between June 2000 and September 2003 by one of two orthopaedic surgeons. Follow-up was performed at 6 weeks, 6 months, 1 year, 5 years, and 10 years. 48 patients (9.6%) were considered lost to follow-up. A competing risk analysis was performed to evaluate the cumulative incidence of revision while accounting for the competing risk of death. In the model, failure was defined as revision of any BKS component. Those who failed prior to two years remained in the analysis. RESULTS: The mean age of the population was 69 years (range: 40-94) and 73% were female. The cumulative incidence of revision of any component was approximately 1% at a mean 8-year follow-up (range: 0.11-14.1 years) when accounting for the competing risk of death. When considering all those lost to follow-up as failures, the cumulative incidence of failure at 8 years was approximately 10%. CONCLUSION: Based on the results of the current study, a posterior stabilized primary TKA, implanted using a flexion and extension gap balancing technique, had excellent survivorship and outcomes at a mean 8-year follow-up.

Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC).

PURPOSE: Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells. EXPERIMENTAL DESIGN: Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays. RESULTS: In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo. CONCLUSIONS: Our data suggest that PDGFRA may be a promising target for therapy in IBC.

The sawtooth sign is predictive of obstructive sleep apnea.

BACKGROUND: The sawtooth sign in spirometry is associated with redundant upper airway tissue and snoring, but its predictive value for identifying obstructive sleep apnea (OSA) is disputed. We retrospectively assessed the predictive value of the spirometric sawtooth sign in terms of the odds ratio (OR) of association with a diagnosis of OSA compared to those without the sign. METHODS: Consecutive spirometry reports showing a sawtooth sign were identified from our laboratory. We identified 50 subjects with sawtooth sign and 100 control subjects without sawtooth sign, matched for age, BMI, and gender. The electronic medical record of each patient was queried for a diagnosis of OSA based on physician-reported diagnoses. RESULTS: Of the 50 subjects with sawtooth sign, 22 were found to have a current diagnosis of OSA (44%). Twenty-seven of the 100 controls (27%) also had OSA. From logistic regression analysis, sawtooth sign was associated with an increased likelihood of OSA (OR = 2.12, 95% C.I. 1.04 to 4.35). Similar results were obtained after adjustment for age, gender, pack years, and BMI (OR = 2.61, 95% C.I. 1.13 to 6.21). CONCLUSIONS: Patients with the sawtooth sign have greater odds of having a diagnosis of OSA compared with those without the sign. If prospectively evaluated, as a result of improved identification, we hypothesize that the sawtooth sign may show an even stronger association with OSA. This relatively common finding, which adds no cost to routine spirometry, may serve as an indicator for OSA workup for some individuals not already identified as having OSA.

Immunosuppression and a serious opportunistic infection: an unfortunate price to pay.

A 57-year-old woman with diabetes mellitus type 1, status postcadaveric pancreas transplant alone 11 years ago, on chronic immunosuppression, and dialysis-dependent end-stage renal disease, presented with 2 months of progressive generalised weakness, lumbar back pain with right lower extremity radiculopathy and episodic symptomatic hypotension. Preliminary infectious disease work up was unremarkable. She was discharged following symptomatic improvement. She represented 3 days later with continued functional decline and leucocytosis. Chest X-ray demonstrated diffuse pulmonary nodules, confirmed on chest CT scan. CT-guided biopsy of a right upper lobe nodule was performed; studies confirmed Nocardia farcinica. Further imaging revealed bilateral white matter intracranial lesions, and extensive Nocardia-positive fluid collections in the right gluteal and vastus musculature, requiring periodic surgical debridement. She was treated with multiple antimicrobials, including trimethoprim-sulfamethoxazole, amoxicillin/clavulanate and moxifloxacin. She was discharged after a 6-month hospitalisation.

Information underpinning anticipation of goal-directed throwing.

We identified the information used to anticipate throw direction in handball. In two experiments, we examined how anticipation performance is affected when the information from one of five body areas (right arm, shoulders, hips, trunk, or total throw side) was either neutralized or decoupled from the motion of other body segments. In the first experiment, performance was significantly reduced when information from the throwing arm was neutralized, irrespective of skill levels. Skilled participants were negatively affected when the shoulders, hips, and trunk were neutralized, whereas less-skilled participants showed trends toward improvement under identical conditions. In the second experiment, partially disrupting relative motion via decoupling was not enough to reduce the anticipation performance among skilled participants to chance levels, whereas less-skilled participants lost their ability to anticipate in three conditions. Our findings suggest that skilled and less-skilled participants employ different information extraction strategies, yet information from the throwing arm is critical to anticipation for both groups. The two experiments suggest that relative motion mediated by both the absolute displacement trajectories of individual marker locations and their relative timings are important in informing anticipation, irrespective of skill level.

The dynamical structure of handball penalty shots as a function of target location.

We used principal components analysis (PCA) to investigate variations in the dynamical structure of handball penalty shots as a factor of target location and phase of shot. Participants completed a total of 10 successful shots to each of four target locations in the handball goal. Three dimensional movement time series data were analyzed. Also, data were analyzed across three temporally distinct time windows in line with the evolving kinematic chain. Statistical analyses were undertaken to determine differences across target locations. There were no significant differences between dynamical structures as a factor of target or phase. Covariance between time evolutions as a factor of target reduced in line with the ranking of the component. When shots were analyzed as three distinct time windows, only the low time evolution covariances suggested differences between targets in any time window. Our findings show that the dynamical structure underpinning the handball penalty shot does not differ greatly across locations. However, the time evolution of principal components suggests there are some variations in dynamics which may differentiate shot direction.

Physical therapists' perceptions of ease of care in patients receiving 2 forms of analgesia after total hip arthroplasty.

BACKGROUND: Pain management modalities that facilitate patient mobility may contribute to recovery after total hip replacement (THR) surgery. OBJECTIVE: The aim of this study was to evaluate the impact of morphine intravenous (IV) patient-controlled analgesia (PCA) and the fentanyl iontophoretic transdermal system (fentanyl ITS) on physical therapists' ability to complete care tasks for patients after THR. DESIGN: The data were from an open-label, randomized, multicenter, active-control phase IIIb clinical trial. METHODS: The settings were 52 US-based teaching and community hospitals. The patients were >or=18 years of age (mean [SEM]: 62.8 [0.6] years in the fentanyl ITS group and 62.9 [0.6] years in the morphine IV PCA group); had an American Society of Anesthesiologists physical status of I, II, or III; and were scheduled to undergo primary unilateral THR surgery. The patients were randomized to receive analgesia for up to 72 hours via the fentanyl ITS (40 microg of fentanyl over 10 minutes for up to 6 doses per hour for 24 hours or 80 doses per system, whichever occurred first) or morphine IV PCA (1-mg bolus doses [with a 5-minute lockout interval between doses] for up to 10 doses per hour for 24 hours). All patients received the usual treatment administered by physical therapists. After each therapy session, physical therapists completed a validated Physical Therapist Ease-of-Care Questionnaire, which included time efficiency and convenience subscales (lower scores indicated more positive responses) and a satisfaction subscale (a higher score indicated a more positive response). Therapists whose average scores were or=4 on both items of the satisfaction subscale were considered responders. RESULTS: Higher percentages of physical therapists were responders for the fentanyl ITS than for morphine IV PCA on the subscales that assessed time efficiency (84.9% and 59.1%, respectively), convenience (86.6% and 71.2%, respectively), and satisfaction (54.3% and 30.5%, respectively). Higher percentages of physical therapists favored the fentanyl ITS than favored morphine IV PCA. Limitations The trial was limited by its open-label design, and physical therapists were more familiar with IV PCA than with the fentanyl ITS. CONCLUSIONS: The findings demonstrate benefits to physical therapists of using the fentanyl ITS over morphine IV PCA in terms of time efficiency, convenience, and satisfaction.

Bilateral total knee arthroplasty in patients 70 years and older.

Recently an increase has been shown in perioperative morbidity and mortality in patients older than 70 years undergoing sequential or simultaneous total knee arthroplasty (TKA) using 1 anesthetic. This study prospectively compared perioperative morbidity, mortality, and functional outcomes in patients 70 years and older undergoing sequential bilateral TKA under 1 anesthetic vs a control undergoing only unilateral TKA. Seventy patients (140 knees), 70 years and older, who underwent sequential bilateral TKA under 1 anesthetic were matched with a control series of 312 patients undergoing unilateral TKA during the same time period. All patients were evaluated pre- and postoperatively at regular time intervals. No mortalities were noted in either group. Perioperative complication rates were not statistically different between groups. Knee Society scores and SF-36v2 scores were better at 6-month and 1-year follow-up in the sequential bilateral knee group. Results from this study were not as expected based on previous reports in the literature. Although functional outcomes in this study were consistent with previous reports, patients did not demonstrate the expected difference in complications. This study is the first prospective study looking specifically at patients 70 years and older undergoing unilateral vs bilateral TKA under 1 anesthetic. According to our data, age alone is not a reason to exclude patients from sequential bilateral TKA under 1 anesthetic.

Single-injection femoral and sciatic nerve blocks for pain control after total knee arthroplasty.

This study was designed to evaluate the addition of a single-injection sciatic nerve block to a femoral nerve block for analgesia after total knee arthroplasty. Fifty-seven patients undergoing primary total knee arthroplasty were randomized to receive femoral nerve blockade or a sham block. A subsequent 31 patients received both femoral and sciatic nerve blocks (FSNBs) before general anesthesia. Intravenous morphine use and visual analog pain scale scores were recorded at regular intervals. Femoral and sciatic nerve blocks were placed in less than five minutes, on average. Lower visual analog pain scale scores were noted in both femoral nerve blockade and FSNB groups compared to shams through 48 hours. Morphine use was significantly lower in the FSNB group. Femoral and sciatic nerve block can be placed quickly and consistently in the operating room with improved postoperative pain relief and reduced narcotic consumption.

Accounting for the role of habit in behavioural strategies for injury prevention.

The limited success of behavioural strategies in injury prevention has been attributed to failure to properly apply behaviour change models to intervention design and the explanation of safety behaviours. However, this paper contends that many health behaviour change interventions do not succeed because they fail to take into account the habitual quality of most health and safety-related behaviour; a more complete model of behaviour change needs to be based on a better understanding of the role of habit. The overall aim is to contribute to better understanding of behavioural strategies for injury prevention. When habits are weak, attitudes and intentions predict behaviours, but as behaviours turn into habits, they become better predictors of future behaviour than attitudes or intentions. Furthermore, where habits are strong, individuals are less likely to act on new information, evaluating counter-habitual information negatively. Integrating the concepts of strong and weak habits with upstream and downstream strategies, a framework is presented for tailoring strategies to the habit strength of the target behaviour.