Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report.

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Impact of Professional Society Guideline Publications in Medicine Subspecialties From 2012 to 2022: Implications for Clinical Care and Health Policy.

Clinical guidelines have become an integral part of clinical care. We assessed professional society-based clinical guidelines from 2012 to 2022 to elucidate the trends in numbers of documents, recommendations, and classes of recommendations. Our results found that 40% of the guidelines do not follow all recommendations made by the Institute of Medicine for trustworthy documents. There has been a significant increase in documents in cardiology, gastroenterology, and hematology/oncology. In addition, of more than 20,000 recommendations, there was significant variability in recommendations made by different professional societies within a specialty. In documents from 11 of the 14 professional societies, more than 50% of the recommendations are supported with the lowest levels of evidence. In cardiology, in addition to the guideline documents, 140 nonguideline documents provide 1812 recommendations using the guideline verbiage, and 74% of the recommendations are supported by the lowest level of evidence. These data have important implications for health care because guidelines and guideline-like documents can be used for health policy issues such as assessment of quality of care, medical liability, education, and payment.

Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence.

BACKGROUND: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here. METHODS: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients. RESULTS: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)). CONCLUSIONS: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas. TRIAL REGISTRATION NUMBER: NCT01546571.

Force-Induced Changes of PilY1 Drive Surface Sensing by Pseudomonas aeruginosa.

During biofilm formation, the opportunistic pathogen Pseudomonas aeruginosa uses its type IV pili (TFP) to sense a surface, eliciting increased second-messenger production and regulating target pathways required to adapt to a surface lifestyle. The mechanisms whereby TFP detect surface contact are still poorly understood, although mechanosensing is often invoked, with few data supporting this claim. Using a combination of molecular genetics and single-cell analysis, with biophysical, biochemical, and genomics techniques, we show that force-induced changes mediated by the von Willebrand A (vWA) domain-containing, TFP tip-associated protein PilY1 are required for surface sensing. Atomic force microscopy shows that TFP/PilY1 can undergo force-induced, sustained conformational changes akin to those observed for mechanosensitive proteins like titin. We show that mutation of a single cysteine residue in the vWA domain of PilY1 results in modestly lower surface adhesion forces, reduced sustained conformational changes, and increased nanospring-like properties, as well as reduced c-di-GMP signaling and biofilm formation. Mutating this cysteine has allowed us to genetically separate a role for TFP in twitching motility from surface-sensing signaling. The conservation of this Cys residue in all P. aeruginosa PA14 strains and its absence in the ∼720 sequenced strains of P. aeruginosa PAO1 may contribute to explaining the observed differences in surface colonization strategies observed for PA14 versus PAO1. IMPORTANCE Most bacteria live on abiotic and biotic surfaces in surface-attached communities known as biofilms. Surface sensing and increased levels of the second-messenger molecule c-di-GMP are crucial to the transition from planktonic to biofilm growth. The mechanism(s) underlying TFP-mediated surface detection that triggers this c-di-GMP signaling cascade is unclear. Here, we provide key insight into this question; we show that the eukaryote-like vWA domain of the TFP tip-associated protein PilY1 responds to mechanical force, which in turn drives the production of a key second messenger needed to regulate surface behaviors. Our studies highlight a potential mechanism that may account for differing surface colonization strategies.

Site-specific acetyl-mimetic modification of cardiac troponin I modulates myofilament relaxation and calcium sensitivity.

OBJECTIVE: Cardiac troponin I (cTnI) is an essential physiological and pathological regulator of cardiac relaxation. Significant to this regulation, the post-translational modification of cTnI through phosphorylation functions as a key mechanism to accelerate myofibril relaxation. Similar to phosphorylation, post-translational modification by acetylation alters amino acid charge and protein function. Recent studies have demonstrated that the acetylation of cardiac myofibril proteins accelerates relaxation and that cTnI is acetylated in the heart. These findings highlight the potential significance of myofilament acetylation; however, it is not known if site-specific acetylation of cTnI can lead to changes in myofilament, myofibril, and/or cellular mechanics. The objective of this study was to determine the effects of mimicking acetylation at a single site of cTnI (lysine-132; K132) on myofilament, myofibril, and cellular mechanics and elucidate its influence on molecular function. METHODS: To determine if pseudo-acetylation of cTnI at 132 modulates thin filament regulation of the acto-myosin interaction, we reconstituted thin filaments containing WT or K132Q (to mimic acetylation) cTnI and assessed in vitro motility. To test if mimicking acetylation at K132 alters cellular relaxation, adult rat ventricular cardiomyocytes were infected with adenoviral constructs expressing either cTnI K132Q or K132 replaced with arginine (K132R; to prevent acetylation) and cell shortening and isolated myofibril mechanics were measured. Finally, to confirm that changes in cell shortening and myofibril mechanics were directly due to pseudo-acetylation of cTnI at K132, we exchanged troponin containing WT or K132Q cTnI into isolated myofibrils and measured myofibril mechanical properties. RESULTS: Reconstituted thin filaments containing K132Q cTnI exhibited decreased calcium sensitivity compared to thin filaments reconstituted with WT cTnI. Cardiomyocytes expressing K132Q cTnI had faster relengthening and myofibrils isolated from these cells had faster relaxation along with decreased calcium sensitivity compared to cardiomyocytes expressing WT or K132R cTnI. Myofibrils exchanged with K132Q cTnI ex vivo demonstrated faster relaxation and decreased calcium sensitivity. CONCLUSIONS: Our results indicate for the first time that mimicking acetylation of a specific cTnI lysine accelerates myofilament, myofibril, and myocyte relaxation. This work underscores the importance of understanding how acetylation of specific sarcomeric proteins affects cardiac homeostasis and disease and suggests that modulation of myofilament lysine acetylation may represent a novel therapeutic target to alter cardiac relaxation.

The actin 'A-triad's' role in contractile regulation in health and disease.

Striated muscle contraction is regulated by Ca2+ -dependent modulation of myosin cross-bridge binding to F-actin by the thin filament troponin (Tn)-tropomyosin (Tm) complex. In the absence of Ca2+ , Tn binds to actin and constrains Tm to an azimuthal location where it sterically occludes myosin binding sites along the thin filament surface. This limits force production and promotes muscle relaxation. In addition to Tn-actin interactions, inhibitory Tm positioning requires associations between other thin filament constituents. For example, the actin 'A-triad', composed of residues K326, K328 and R147, forms numerous, highly favourable electrostatic contacts with Tm that are critical for establishing its inhibitory azimuthal binding position. Here, we review recent findings, including the identification and interrogation of modifications within and proximal to the A-triad that are associated with disease and/or altered muscle behaviour, which highlight the surface feature's role in F-actin-Tm interactions and contractile regulation.

Fropofol decreases force development in cardiac muscle.

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca2+ concentration ([Ca2+]i) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca2+]i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca2+-activated force ( Fmax) and increased the [Ca2+]i required for 50% of Fmax (Ca50) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.-Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle.

Arthroscopic Superior Capsular Reconstruction With Acellular Dermal Allograft for the Treatment of Massive Irreparable Rotator Cuff Tears: Short-Term Clinical Outcomes and the Radiographic Parameter of Superior Capsular Distance.

PURPOSE: This outcome analysis presents 88 consecutive shoulders presenting with irreparable rotator cuff tears that we treated with arthroscopic superior capsular reconstruction (SCR) using an acellular dermal allograft. We also present the concept of superior capsular distance to quantitatively measure the decreased distance present upon restoration of superior capsular integrity. METHODS: A retrospective review was conducted of patients treated with arthroscopic SCR with a minimum 12-month follow-up. Outcome analysis was performed via an internet-based outcome-tracking system to evaluate visual analog scale (VAS) and American Shoulder and Elbow Surgeons (ASES) scores. Radiographic analysis of anteroposterior radiographs analyzed acromiohumeral interval and superior capsular distance. Digital dynamometric strength and functional range of motion assessments were also obtained. The main inclusion criteria for patients in this analysis was all patients who underwent superior capsular reconstruction during the time period of this report. RESULTS: Eighty-six patients with an average age of 59.4 years presented with massive rotator cuff tears (Cofield >5 cm). Outcome data revealed improvement in VAS (4.0-1.5), and ASES (52-82) scores at 1 year (P = .005). Radiographic analysis showed increase in acromiohumeral interval (mean 7.1 mm preoperatively to mean 9.7 mm at 1 year) (P = .049) and superior capsular distance (mean 52.9 mm preoperatively to mean 46.2 mm at 1 year) (P = .011). Strength improved significantly (forward flexion/abduction/external rotation of 4.8/4.1/7.7 lb preoperatively to 9.8/9.2/12.3 lb at 1 year) as well as range of motion (forward flexion/abduction of 120°/103° preoperatively to 160°/159° at 1 year) (P = .044/P = .007/P = .02). At follow-up, 90% of patients were satisfied. CONCLUSIONS: This analysis reveals that arthroscopic SCR with acellular dermal allograft has been successful in decreasing pain and improving function in this patient subset. Radiographic analysis has also shown a consistent and lasting decrease in superior capsular distance and increase in acromiohumeral interval, indicating maintenance of superior capsular stability. LEVEL OF EVIDENCE: Level IV, retrospective case series.

A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton's neuroma.

Intermetatarsal neuroma or Morton's neuroma is a painful condition of the foot resulting from an entrapment of the common digital nerve typically in the third intermetatarsal space. The pain can be severe and especially problematic with walking. Treatment options are limited and surgery may lead to permanent numbness in the toes. Capsaicin, the pungent ingredient of hot peppers, produces analgesia by inducing retraction of nociceptive afferents from the area of innervation and is effective in treating certain neuropathic pain disorders. A randomized double-blind placebo-controlled study was conducted to test the efficacy, tolerability, and safety of a single 0.1 mg dose of capsaicin vs placebo injected into the region of the neuroma. A total of 58 subjects diagnosed with Morton's neuroma with foot pain ≥4 (0-10 numerical pain rating scale) were injected with 2 mL of lidocaine into the intermetatarsal space proximal to the neuroma to provide local anesthesia. After 5 minutes, 0.1 mg capsaicin or placebo was injected into the intermetatarsal space containing the painful neuroma. Average foot pain was rated for 2 weeks before through 4 weeks after injection. At weeks 1 and 4, the decrease in pain was significantly greater in the subjects treated with capsaicin (P = 0.021 and P = 0.019, respectively). A trend toward significance was noted at weeks 2 and 3. Improvements in functional interference scores and reductions in oral analgesic use were also seen in the capsaicin-treated group. These findings suggest that injection of capsaicin is an efficacious treatment option for patients with painful intermetatarsal neuroma.

Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy.

AIMS: Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling. METHODS AND RESULTS: Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. CONCLUSION: Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response.

An open-label pilot study of pulsed electromagnetic field therapy in the treatment of failed back surgery syndrome pain.

Persistent pain following back surgery remains a major treatment challenge. The primary objective of this open-label exploratory study was to investigate the analgesic effectiveness of pulsed electromagnetic field therapy administered twice daily over a 45-day period in 34 subjects (68% female) with persistent or recurrent pain following back surgery. A secondary goal was to guide the design of future randomized controlled trials that could target responsive subpopulations. All predefined primary and secondary outcomes, including change in pain intensity (PI), physical function (Oswestry Disability Index), analgesic consumption, and overall well-being (Patient Global Impression of Change), are reported. A responder analysis (≥30% reduction in PI versus baseline) was added as a post hoc evaluation. Safety outcomes, as well as results of a cost-avoidance survey, are also summarized. Of the 30 per-protocol subjects who completed the study, 33% reported a clinically meaningful (≥30%) reduction in PI. A higher response rate (60%) was reported for subjects who had undergone discectomy prior to the trial compared to subjects who had undergone other types of surgical interventions (decompression or fusion) without discectomy. Improvements in PI were paralleled by improvements in secondary outcomes. Relative to baseline, responders reported an average 44% and 55% reduction in back PI and leg PI (respectively), and an average 13% improvement in Oswestry Disability Index scores. In the per-protocol population, 50% of responders and 12% of nonresponders reported less analgesia consumption at the end of treatment versus baseline. Sixty-seven percent of per-protocol responders and 0% of nonresponders reported clinically meaningful improvement in overall well-being on the Patient Global Impression of Change scale.

Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury.

The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.

In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain.

Pseudo-phosphorylation of cardiac myosin regulatory light chain (RLC) has never been examined as a rescue method to alleviate a cardiomyopathy phenotype brought about by a disease causing mutation in the myosin RLC. This study focuses on the aspartic acid to valine substitution (D166V) in the myosin RLC shown to be associated with a malignant phenotype of familial hypertrophic cardiomyopathy (FHC). The mutation has also been demonstrated to cause severe functional abnormalities in transgenic mice expressing D166V in the heart. To explore this novel rescue strategy, pseudo-phosphorylation of D166V was used to determine whether the D166V-induced detrimental phenotype could be brought back to the level of wild-type (WT) RLC. The S15D substitution at the phosphorylation site of RLC was inserted into the recombinant WT and D166V mutant to mimic constitutively phosphorylated RLC proteins. Non-phosphorylatable (S15A) constructs were used as controls. A multi-faceted approach was taken to determine the effect of pseudo-phosphorylation on the ability of myosin to generate force and motion. Using mutant reconstituted porcine cardiac muscle preparations, we showed an S15D-induced rescue of both the enzymatic and binding properties of D166V-myosin to actin. A significant increase in force production capacity was noted in the in vitro motility assays for S15D-D166V vs. D166V reconstituted myosin. A similar pseudo-phosphorylation induced effect was observed on the D166V-elicited abnormal Ca(2+) sensitivity of force in porcine papillary muscle strips reconstituted with phosphomimic recombinant RLCs. Results from this study demonstrate a novel in vitro rescue strategy that could be utilized in vivo to ameliorate a malignant cardiomyopathic phenotype. We show for the first time that pseudo-RLC phosphorylation can reverse the majority of the mutation-induced phenotypes highlighting the importance of RLC phosphorylation in combating cardiac disease.

Evaluating therapeutic benefit in postsurgical analgesia requires global assessment: an example from liposome bupivacaine in hemorrhoidectomy.

BACKGROUND AND OBJECTIVE: Interpreting analgesic efficacy based solely on measures of pain intensity can be misleading. Here, we use data from an adult hemorrhoidectomy study to demonstrate the importance of evaluating pain intensity scores with other outcome measures in interpreting analgesic study results. METHODOLOGY: We looked for coordinated outcome measures including pain intensity at rest using a numeric rating scale (NRS), postsurgical consumption of rescue medication, subject-reported results from the Brief Pain Inventory, subject satisfaction with postsurgical analgesia, and adverse events. RESULTS: The analgesic efficacy of liposome bupivacaine was reflected in a significant reduction in pain intensity scores at each timed assessment during the first 12 to 24 hours after surgery (mean NRS at 12 hours: liposome bupivacaine, 2.2; placebo, 2.9; P = 0.04), and less consumption of opioid rescue medications thereafter through 72 hours postsurgery (mean total amount of opioids consumed: liposome bupivacaine, 10 mg; placebo, 18 mg; P = 0.0006). These observations are supported by results of other outcome measures, including time to first use of opioid rescue medication, pain-related interference of subject functionality, and subject satisfaction with postsurgical analgesia. CONCLUSION: Liposome bupivacaine produced superior analgesia when compared with placebo at early postoperative time points, but appropriate use of rescue medication diminished this effect after 12 hours. However, based on our assessment of multiple outcome measures used in the study, it appears that the therapeutic benefit associated with the tested analgesic lasted throughout the 72-hour study period.

Onset of action of diclofenac potassium liquid-filled capsules in dental surgery patients.

OBJECTIVE: Diclofenac potassium soft gelatin capsules (DPSGC) are a low-dose, liquid-filled formulation that uses patented dispersion technology to facilitate rapid and consistent gastrointestinal absorption. Onset of pain relief experienced by patients receiving DPSGC was evaluated in two dental pain studies. Confirmed perceptible pain relief was evaluated in a post hoc analysis from these randomized controlled trials. RESEARCH DESIGN AND METHODS: Adult patients (n = 514) were enrolled in two multicenter, parallel group, double-blind, placebo-controlled studies. Patients undergoing third molar extraction and experiencing a requisite level of pain (≥50 mm on a 100-mm visual analog scale within 4 hours post-surgery) were randomized to receive single doses of DPSGC 25 mg, 50 mg, 100 mg, or placebo. Pain was assessed at baseline and during 6 hours after dosing. Times to onset of perceptible and meaningful pain relief were recorded using the two-stopwatch method. Confirmed perceptible pain relief was determined in the DPSGC and placebo groups by calculating the median time to onset of perceptible pain relief (first stopwatch) in only those individuals who reported meaningful pain relief (second stopwatch). RESULTS: More than 80% of patients achieved confirmed perceptible pain relief in the DPSGC groups compared with less than 30% of patients in the placebo group (Study 1 and Study 2, p < 0.0001). The median time to onset of confirmed perceptible pain relief in the two studies was less than 30 minutes for patients receiving any dose of DPSGC and more than 360 minutes in the placebo group (Study 1 and Study 2, p < 0.0001). DPSGC was well tolerated and no serious adverse events were reported. Study design limitations include the short duration of the trial and evaluation of a relatively limited patient population. CONCLUSIONS: These results indicate that DPSGC was efficacious in providing a rapid onset of confirmed perceptible pain relief within 30 minutes of administration in these single dose postoperative dental pain studies.

College students' expectancies for light cigarettes and potential reduced exposure products.

OBJECTIVES: To determine positive and negative beliefs about light cigarettes and potential reduced exposure products (PREPs) among college student smokers and non-smokers. METHODS: A web-based survey conducted in October-November 2004 among 424 students rating 5 advertisements for cigarette brands (Marlboro Red, Light, and Ultralight; Quest; Eclipse) on 28 items tapping positive and negative product expectancies. RESULTS: Marlboro Light and Ultralight were rated more positively and less negatively than their Red counterpart. PREPs showed low positive and negative ratings relative to Marlboro Light. Positive expectancies were significantly related to willingness to try each brand. CONCLUSIONS: Advertising plays a role in influencing how college students view light and PREP cigarette brands.

Smoking expectancies for flavored and non-flavored cigarettes among college students.

Several tobacco companies have introduced specially flavored cigarettes, yet little is known about their appeal among college student nonsmokers, regular smokers, and those susceptible to smoking. Undergraduates (N=424) rated 12 brands of cigarettes on multiple attributes based on manufacturer advertisements. This paper focused on two brands with flavored and non-flavored versions (Camel and Salem). Despite brand, regular smokers and those susceptible to smoking initiation had higher positive expectancies and lower negative expectancies about smoking than nonsmokers. Flavored cigarettes elicited higher positive expectancies than non-flavored counterparts across all groups, including nonsmokers. Indeed, the degree to which flavored Camels had higher positive expectancies than Camel Lights was at least as large in a group of susceptible nonsmokers and experimenters (susceptible/experimenters). Despite being present in nonsmokers and susceptible/experimenters, negative expectancies were significantly lower for flavored versus non-flavored brands. Logistic regressions revealed that positive expectancies predicted "intention to try" each brand for regular smokers and susceptible/experimenters. These findings suggest that targeting the marketing of positive attributes may be useful in preventing smoking behavior.

Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.

PURPOSE: Postoperative ileus presents significant clinical challenges that potentially prolong hospital stay, contribute to readmission, and increase morbidity. There is no approved treatment for postoperative ileus. Alvimopan is a novel, peripherally acting, mu opioid receptor antagonist currently in development for the management of postoperative ileus. METHODS: Patients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan 6 mg (n = 152), alvimopan 12 mg (n = 146), or placebo (n = 153) orally 2 hours before surgery and twice daily thereafter until discharge or for up to seven days. The primary efficacy end point, time to return of gastrointestinal function, was a composite measure of passage of flatus or stool and tolerating solid food. Secondary end points included time to the hospital discharge order written. Adverse events were monitored throughout the study. RESULTS: Mean time to gastrointestinal recovery was significantly reduced in patients treated with alvimopan 6 mg vs. placebo (hazard ratio = 1.45; P = 0.003), with a smaller reduction seen with alvimopan 12 mg (hazard ratio = 1.28; P = 0.059). Mean time to the hospital discharge order written was significantly accelerated in patients treated with alvimopan 6 mg (hazard ratio = 1.50; P < 0.001). The most common treatment-emergent adverse events across all treatment groups were nausea, vomiting, and hypotension; the incidence of nausea and vomiting was reduced by 53 percent in the alvimopan 12-mg group. CONCLUSIONS: In patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial.

PURPOSE: To determine the response rate, time to disease progression, survival duration and rate, and toxicity with the combination of cetuximab and gemcitabine in patients with epidermal growth factor receptor (EGFR)-expressing advanced pancreatic cancer. PATIENTS AND METHODS: Patients with measurable locally advanced or metastatic pancreatic cancer who had never received chemotherapy for their advanced disease and had immunohistochemical evidence of EGFR expression were eligible for the multicenter phase II trial. Patients were treated with cetuximab at an initial dose of 400 mg/m(2), followed by 250 mg/m(2) weekly for 7 weeks. Gemcitabine was administered at 1,000 mg/m(2) for 7 weeks, followed by 1 week of rest. In subsequent cycles, cetuximab was administered weekly, and gemcitabine was administered weekly for 3 weeks every 4 weeks. RESULTS: Sixty-one patients were screened for EGFR expression, 58 patients (95%) had at least 1+ staining, and 41 were enrolled onto the trial. Five patients (12.2%) achieved a partial response, and 26 (63.4%) had stable disease. The median time to disease progression was 3.8 months, and the median overall survival duration was 7.1 months. One-year progression-free survival and overall survival rates were 12% and 31.7%, respectively. The most frequently reported grade 3 or 4 adverse events were neutropenia (39.0%), asthenia (22.0%), abdominal pain (22.0%), and thrombocytopenia (17.1%). CONCLUSION: Cetuximab in combination with gemcitabine showed promising activity against advanced pancreatic cancer. Further clinical investigation is warranted.