Use of Advanced Flexible Modeling Approaches for Survival Extrapolation from Early Follow-up Data in two Nivolumab Trials in Advanced NSCLC with Extended Follow-up.

OBJECTIVES: Immuno-oncology (IO) therapies are often associated with delayed responses that are deep and durable, manifesting as long-term survival benefits in patients with metastatic cancer. Complex hazard functions arising from IO treatments may limit the accuracy of extrapolations from standard parametric models (SPMs). We evaluated the ability of flexible parametric models (FPMs) to improve survival extrapolations using data from 2 trials involving patients with non-small-cell lung cancer (NSCLC). METHODS: Our analyses used consecutive database locks (DBLs) at 2-, 3-, and 5-y minimum follow-up from trials evaluating nivolumab versus docetaxel in patients with pretreated metastatic squamous (CheckMate-017) and nonsquamous (CheckMate-057) NSCLC. For each DBL, SPMs, as well as 3 FPMs-landmark response models (LRMs), mixture cure models (MCMs), and Bayesian multiparameter evidence synthesis (B-MPES)-were estimated on nivolumab overall survival (OS). The performance of each parametric model was assessed by comparing milestone restricted mean survival times (RMSTs) and survival probabilities with results obtained from externally validated SPMs. RESULTS: For the 2- and 3-y DBLs of both trials, all models tended to underestimate 5-y OS. Predictions from nonvalidated SPMs fitted to the 2-y DBLs were highly unreliable, whereas extrapolations from FPMs were much more consistent between models fitted to successive DBLs. For CheckMate-017, in which an apparent survival plateau emerges in the 3-y DBL, MCMs fitted to this DBL estimated 5-y OS most accurately (11.6% v. 12.3% observed), and long-term predictions were similar to those from the 5-y validated SPM (20-y RMST: 30.2 v. 30.5 mo). For CheckMate-057, where there is no clear evidence of a survival plateau in the early DBLs, only B-MPES was able to accurately predict 5-y OS (14.1% v. 14.0% observed [3-y DBL]). CONCLUSIONS: We demonstrate that the use of FPMs for modeling OS in NSCLC patients from early follow-up data can yield accurate estimates for RMST observed with longer follow-up and provide similar long-term extrapolations to externally validated SPMs based on later data cuts. B-MPES generated reasonable predictions even when fitted to the 2-y DBLs of the studies, whereas MCMs were more reliant on longer-term data to estimate a plateau and therefore performed better from 3 y. Generally, LRM extrapolations were less reliable than those from alternative FPMs and validated SPMs but remained superior to nonvalidated SPMs. Our work demonstrates the potential benefits of using advanced parametric models that incorporate external data sources, such as B-MPES and MCMs, to allow for accurate evaluation of treatment clinical and cost-effectiveness from trial data with limited follow-up. HIGHLIGHTS: Flexible advanced parametric modeling methods can provide improved survival extrapolations for immuno-oncology cost-effectiveness in health technology assessments from early clinical trial data that better anticipate extended follow-up.Advantages include leveraging additional observable trial data, the systematic integration of external data, and more detailed modeling of underlying processes.Bayesian multiparameter evidence synthesis performed particularly well, with well-matched external data.Mixture cure models also performed well but may require relatively longer follow-up to identify an emergent plateau, depending on the specific setting.Landmark response models offered marginal benefits in this scenario and may require greater numbers in each response group and/or increased follow-up to support improved extrapolation within each subgroup.

Tropical fish community does not recover 45 years after predator introduction.

Predation is considered to be an important factor structuring natural communities. However, it is often difficult to determine how it may influence long-term, broad-scale, diversity patterns, particularly in diverse tropical systems. Biological introductions can provide powerful insight to test the sustained consequences of predation in natural communities, if pre-introduction data are available. Half a century ago, Zaret and Paine demonstrated strong and immediate community-level effects following the introduction of a novel apex predator (peacock bass, Cichla monoculus) into Lake Gatun, Panama. To test for long-term changes associated with this predator introduction, we followed up on their classic study by replicating historical sampling methods and examining changes in the littoral fish community at two sites in Lake Gatun 45 years post-introduction. To broaden our inference, we complemented this temporal comparison with a spatial analysis, wherein we compared the fish communities from two lakes with and one lake without peacock bass. Comparisons with historical data revealed that the peacock bass remains the most abundant predator in Lake Gatun. Furthermore, the collapse of the littoral prey community observed immediately following the invasion has been sustained over the past 45 years. The mean abundance of native littoral fish is now 96% lower than it was prior to the introduction. Diversity (rarefied species richness) declined by 64% post-introduction, and some native species appear to have been locally extirpated. We observed a similar pattern across invaded and uninvaded lakes: the mean abundance of native fishes was 5-40 times lower in lakes with (Gatun, Alajuela) relative to the lake without peacock bass (Bayano). In particular, small-bodied native fishes (Characidae, Peociliidae), which are common prey of the peacock bass, were more than two orders of magnitude (307 times) less abundant in Gatun and one order of magnitude (28 times) less abundant in Alajuela than in Bayano. However, total native fish diversity did not differ significantly across lakes, suggesting that while many native species have declined in abundance, few have been completely extirpated. Introduced predators can have strong effects on community structure and functional diversity, even in highly diverse tropical communities, and these effects can persist over multiple decades.

Radon testing in rapid access lung clinics: an opportunity for secondary prevention.

BACKGROUND: Radon is a naturally occurring radioactive gas and a level 1 carcinogen. It acts synergistically with cigarette smoke to cause lung cancer. In Ireland, radon is estimated to be associated with 13 % of all lung cancers. Rapid access lung cancer clinics (RALC's) were established in the UK and Ireland to improve lung cancer management outcomes. There has been no attempt to date to provide advice on household radon exposure assessments in this setting. AIMS: We performed a prospective feasibility study of radon assessment in our RALC to test the hypothesis that patients would avail of this service and that it would provide an opportunity for secondary prevention in at risk persons. METHODS: We investigated household radon levels in consecutive patients who were newly referred with symptoms of lung cancer to the RALC in Galway University Hospital, Ireland over a 6-month period. RESULTS: Of 50 patients enrolled, 42 returned valid results. Overall 21 % of patients had radon levels recorded above the national reference level. Only 5 % of patients were aware of the association between radon gas and lung cancer. Smokers were significantly less likely to engage fully in radon testing. CONCLUSIONS: The development of RALC's offers a novel opportunity to integrate the concepts of radon exposure, cigarette smoking and the development of lung cancer, and to reinforce this message in the minds of at risk patients.

Little evidence for morphological change in a resilient endemic species following the introduction of a novel predator.

Human activities, such as species introductions, are dramatically and rapidly altering natural ecological processes and often result in novel selection regimes. To date, we still have a limited understanding of the extent to which such anthropogenic selection may be driving contemporary phenotypic change in natural populations. Here, we test whether the introduction of the piscivorous Nile perch, Lates niloticus, into East Africa's Lake Victoria and nearby lakes coincided with morphological change in one resilient native prey species, the cyprinid fish Rastrineobola argentea. Drawing on prior ecomorphological research, we predicted that this novel predator would select for increased allocation to the caudal region in R. argentea to enhance burst-swimming performance and hence escape ability. To test this prediction, we compared body morphology of R. argentea across space (nine Ugandan lakes differing in Nile perch invasion history) and through time (before and after establishment of Nile perch in Lake Victoria). Spatial comparisons of contemporary populations only partially supported our predictions, with R. argentea from some invaded lakes having larger caudal regions and smaller heads compared to R. argentea from uninvaded lakes. There was no clear evidence of predator-associated change in body shape over time in Lake Victoria. We conclude that R. argentea have not responded to the presence of Nile perch with consistent morphological changes and that other factors are driving observed patterns of body shape variation in R. argentea.

Multiple Symmetrical Lipomatosis--a mitochondrial disorder of brown fat.

Multiple Symmetrical Lipomatosis (MSL) is an unusual disorder characterized by the development of axial lipomas in adulthood. The pathoetiology of lipoma tissue in MSL remains unresolved. Seven patients with MSL were followed for a mean period of 12 years (8-20 years). All patients had cervical lipomas ranging from subtle lesions to disfiguring masses; six patients had peripheral neuropathy and five had proximal myopathy. Myoclonus, cerebellar ataxia and additional lipomas were variably present. All patients showed clinical progression. Muscle histopathology was consistent with mitochondrial disease. Five patients were positive for mtDNA point mutation m.8344A>G, three of whom underwent lipoma resection--all samples were positive for uncoupling protein-1 mRNA (unique to brown fat). Lipoma from one case stained positive for adipocyte fatty-acid protein-2 (unique to brown fat and immature adipocytes). This long-term study hallmarks the phenotypic heterogeneity of MSL's associated clinical features. The clinical, genetic and molecular findings substantiate the hypothesis that lipomas in MSL are due to a mitochondrial disorder of brown fat.

Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes.

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.

The "two-week wait" referral pathway allows prompt treatment but does not improve outcome for patients with oesophago-gastric cancer.

INTRODUCTION: The Two Week Wait Referral Service (2WW) has been implemented as a means of fast-tracking patients with suspected upper gastrointestinal cancers for endoscopy. Whether or not it impacts on the outcome of these patients is unclear. The aim of this study was to compare the outcome of patients referred through 2WW with that of patients with oesophago-gastric cancer identified through alternate referral pathways (routine, emergency). METHODS: The study population was 340 patients with oesophago-gastric carcinoma (gastric 154) diagnosed during the time period 01/2006-12/2007 at University Hospitals of Leicester NHS Trust. Data were collected prospectively by the MDT co-ordinator and analysed retrospectively. RESULTS: 135 of the 340 patients with oesophago-gastric cancer were diagnosed through the 2WW, 115 patients through routine referral pathways, and 90 patients were admitted on an emergency basis. Patients referred through 2WW had a median referral to 1st treatment time of 47 days (routine 79, emergency 28, p < 0.001 all group comparisons). The number of patients treated with potentially curative intent was 37 of 135 for the 2WW, 42 of 115 for the routine referrals and 10 of 90 for patients admitted as emergencies. The corresponding median survivals for the groups were 239 days (2WW), 405 days (routine) and 121 days (emergency), p < 0.001 (log rank). CONCLUSIONS: Referral by 2WW resulted in more rapid treatment than routine referral but this did not translate into an improvement in survival. This suggests that the targeting of endoscopy to patients with alarm symptoms is flawed and a less selective approach should be promoted if curable cancers are to be detected.

Intermediate hair follicles: a new more clinically relevant model for hair growth investigations.

BACKGROUND: Alopecia causes widespread psychological distress, but is relatively poorly controlled. The development of new treatments is hampered by the lack of suitable human hair follicle models. Although intermediate and vellus hair follicles are the main clinical targets for pharmacological therapy, terminal hair follicles are more frequently studied as smaller hair follicles are more difficult to obtain. OBJECTIVES: This investigation was designed to quantify in vivo morphological and in vitro behavioural differences in organ culture between matched intermediate and terminal hair follicles, in order to develop a new clinically relevant model system. METHODS: Microdissected terminal and intermediate hair follicles, from the same individuals, were analysed morphometrically (250 follicles; five individuals), or observed and measured over 9 days of organ culture (210 follicles; six individuals). RESULTS: Intermediate hair follicles were less pigmented and smaller, penetrating less below the skin surface (mean +/- SEM) (2.59 +/- 0.07 vs. 3.52 +/- 0.10 mm; P = 0.02), with smaller fibre (0.03 +/- 0.002 vs. 0.07 +/- 0.002 mm), connective tissue sheath (0.24 +/- 0.01 mm vs. 0.33 +/- 0.01 mm), bulb (0.19 +/- 0.01 vs. 0.31 +/- 0.01 mm) and dermal papilla (0.06 +/- 0.002 vs. 0.12 +/- 0.01 mm) diameters (P < 0.001). Intermediate hair follicle bulbs appeared 'tubular', unlike their 'bulbous' terminal follicle counterparts. In organ culture they also grew more slowly (0.044 +/- 0.002 vs. 0.067 +/- 0.003 mm per day; P < 0.001), remained in anagen longer (84 +/- 0.03% vs. 74 +/- 0.03% at day 9; P = 0.012) and produced less hair fibre (0.36 +/- 0.02 vs. 0.50 +/- 0.03 mm; P < 0.001) than terminal follicles. CONCLUSIONS: Smaller intermediate hair follicles showed major morphological differences from terminal follicles in vivo and retained significant, biologically relevant differences in vitro in organ culture. Therefore, intermediate hair follicles offer a novel, exciting, more clinically relevant, albeit technically difficult, model for future investigations into hair growth. This should be particularly important for developing new therapies.

Re-visiting Luck's classification: a histological analysis of Dupuytren's disease.

Luck (1959) described a histological staging system for Dupuytren's disease, classifying the disease into three stages. Previous biochemical and immunochemical studies have detailed the decrease in type III/I collagen ratio with disease progression. Herovici (1963) described a histological stain that produced a differential red/purple and blue colour for type I and III collagen respectively. We stained 15 specimens of Dupuytren's disease and quantified the different collagen types in each using computer analysis. We found a corresponding decrease in the amount of type III collagen as a percentage of the total collagen with disease progression: stage I range 35-49% (mean 38%); stage 2 range 21-33% (mean 27%) and stage 3 range 11-19% (mean 14%). We propose a new staging system based on the relative amount of type III collagen, where stage 1: >35%, stage 2: >20% and <35%, and stage 3: <20%.

Lymph node retrieval in colorectal cancer resection specimens: national standards are achievable, and low numbers are associated with reduced survival.

OBJECTIVES: The current guidelines identify the retrieval of at least 12 lymph nodes as crucial for accurate staging of colorectal cancer. We set out to review our figures from a single centre to see whether this standard has been met, and to examine for factors which may influence the number of lymph nodes retrieved. The influence of a low lymph node harvest on survival in patients with Dukes' A and B cancers was specifically investigated. METHOD: Data were collected from all patients with colorectal cancer undergoing resectional surgery from our prospectively compiled database between June 1998 and May 2007. A multivariate analysis was performed to identify factors resulting in low lymph node yields in those patients undergoing formal resection. Survival analyses were performed in patients with Dukes' A and B cancers to assess whether a low lymph node yield negatively impacted on survival. RESULTS: A total of 2449 patients underwent formal resection and were included in the analysis. The median lymph node retrieval was 13 nodes (range 0-136). On multivariate analysis, preoperative chemo-radiotherapy, operation type, specimen length and patient age all independently influenced lymph node retrieval. Patient gender, ethnicity, operative mode, operative team and consultant presence had no influence. Survival in patients with Dukes' A and B cancers was significantly reduced if <12 nodes were sampled. CONCLUSIONS: As a unit, we are achieving the national standard for lymph node harvest. This standard was maintained whether the surgeon performing the surgery was a consultant or a trainee, and also when the surgery was performed in the emergency setting. These data support the concept of 12 nodes being required for accurate staging.

Prevention of suicidal behaviour among army personnel: a qualitative study.

OBJECTIVES: To examine the context of suicidal behaviour among soldiers in the United Kingdom and identify factors that could reduce the risk of such behaviour. METHOD: A series of in-depth interviews with service providers involved in treating soldiers following deliberate self harm. Their responses were compared with those of a small sub-sample of soldiers who presented to Army medical services following self harm. RESULTS: We interviewed 21 service providers with a range of experience and professional backgrounds and 10 soldiers. Service providers told us that the rarity of suicide among soldiers together with lower levels of mental illness amongst those who end their lives made suicide prevention in the Army a difficult task. However they highlighted concerns about recruitment and retention of young soldiers, and stated that stigmatisation of mental illness in the Army sometimes prevented those with suicidal ideation seeking help. They also highlighted the role of alcohol use in precipitating self-harm. Soldiers who had self-harmed told us that they struggled to balance the demands of work and family life and described harming themselves impulsively often while intoxicated with alcohol. Soldiers look to sources of support outside the Army, and see commanding officers, rather than healthcare professionals, as helping resolve their problems. Neither service providers nor soldiers mentioned helplines and other 'independent' sources of confidential advice and support which are available to soldiers serving with the British Army. CONCLUSION: Our findings highlight problems associated with efforts to reduce suicide among soldiers but suggest that these should focus continuing to try to reduce stigmatisation of mental distress and specifically on the role of commanding officers. Greater efforts should also be made to publicise existing sources of help and reduce levels of alcohol misuse.

17beta-estradiol regulates the secretion of TGF-beta by cultured human dermal fibroblasts.

Estrogen plays an important role in skin homeostasis, as demonstrated by the changes seen in the skin of post-menopausal women, changes reversed by HRT. Estrogen also has a role in wound healing, since estrogen deficiency as occurs post-menopausally and in ovariectomised animals, is associated with a reduced rate of wound healing. Estrogen appears to modulate all phases of wound healing with effects on inflammatory cells, epithelialization, angiogenesis, extracellular matrix deposition and tissue remodelling. This study was designed to investigate the effects of 17beta-estradiol on cultured human dermal fibroblasts using an in vitro wound-healing assay. The end points investigated were cell migration, proliferation, total collagen secretion and active TGF-beta1 secretion. 17beta-estradiol significantly increased the migration and proliferation of cultured dermal fibroblasts following mechanical wounding, although the secretion of total soluble collagen was not altered. An increase in TGF-beta1 was demonstrated by unwounded confluent dermal fibroblast monolayers in response to 17beta-estradiol, but paradoxically, a decrease in the secretion of TGF-beta1 was demonstrated in the mechanically wounded dermal fibroblasts. These results identify human dermal fibroblasts as estrogen target cells and provide further evidence for a role by which estrogen regulates this particular cell type as part of the wound-healing process. However, the paradoxical nature of the effect of estrogen on TGF-beta1 secretion following mechanical wounding suggests that the cellular mechanism of action is complex. A greater understanding of the cell-specific action of estrogen may help to develop therapies that will improve cutaneous wound healing in the future.

A framework for integrating interprofessional education curriculum in the health sciences.

CONTEXT: Traditionally, the structures of health professional education in Canada and elsewhere have been largely based on "silos" in which health professionals are educated in relative isolation to one another. The curriculum content and structure has followed strict disciplinary lines. Recent commissions, committees and policy documents in Canada have identified the importance of reshaping educational preparation and the professional training of health care professionals (Commission on the Future of Health Care in Canada, 2002; Health Council of Canada, 2005). OBJECTIVES: This brief communication describes an interprofessional curricular approach that combines characteristics of Barr et al.'s (2005) extracurricular and crossbar models of interprofessional education curriculum. METHODS: An interprofessional education curriculum that combines principles of an integrative, continuous, early-to-late and blended learning approach. DISCUSSION: The curricular approach supports exposing students to interprofessional education at an early stage in their training and then to continue with regular reinforcement. Another guiding principle is that interprofessional education is integrative rather than supplementary to the existing core curriculum. Early evaluation results suggest favourable satisfaction amongst students and faculty as well as significant effect on attitudes toward interprofessional teamwork and education. An ongoing evaluation is continuing based upon the various levels of Freeth et al.'s (2002) interprofessional education evaluation framework.

Gaseous ozone treatment inactivates Listeria innocua in vitro.

AIMS: To investigate the effects of ozone on inactivation of Listeria innocua on solid media. METHODS AND RESULTS: Suspensions of L. innocua ranging from 4.5 x 10(4 )- 6.4 x 10(4) CFU ml(-1) were inoculated onto potato dextrose agar (PDA, pH 5.6 and 6.8) and nutrient agar (NA, pH 6.0 and 6.8), then exposed to gaseous ozone. Variable factors included postinoculation standing time at 20 degrees C before exposure to ozone, ozone concentration, treatment duration and treatment temperature (5 or 20 degrees C). The interaction among ozone concentration, treatment duration, media and temperature in effecting changes in colony-forming units (CFU) was significant. The 100 nl l(-1) ozone treatment for 2 h reduced the microbial populations by 2-3 log CFU ml(-1). Cell viability decreased more rapidly on PDA than on NA. The average time to obtain a 2 log CFU ml(-1) reduction was 1.3 h at 20 degrees C and 2.5 h at 5 degrees C (P < 0.001). CONCLUSIONS: Gaseous ozone effectively inactivates L. innocua at concentrations of 50 and 100 nl l(-1) during short exposure times at both 5 and 20 degrees C. The Gompretz model can be utilized for determining the response of L. innocua to ozone over time. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides useful information on ozone inactivating Listeria spp., which may be imposed on ensuring quality and safety of horticultural produce and food products.

The Bradford Burn Study: the epidemiology of burns presenting to an inner city emergency department.

OBJECTIVE: The Bradford Burn Study prospectively reviewed all burn attendances at a single emergency department in the UK over a 1 year period. The study reviewed the epidemiology, demographics and outcomes of all patients entered into the study. DESIGN AND SETTING: A 12 month prospective study of burn injuries attending an inner city emergency department serving a population of 1 million people. RESULTS: 460 patients were enrolled into the study. Average patient age was 22.7 years, male: female ratio was 1:1.4, and children <10 years of age accounted for 36% of the case mix. Asian patients accounted for 41% of all attendances; 85% of the cases in the study were accidental in nature, with scalds accounting for 52% of the injuries. Final outcomes were as follows: 54% of patients were reviewed by the emergency department physicians and only one of these patients ultimately needed skin grafting; 19% had follow-up by their primary care physicians; 12% were reviewed by plastic surgeons, and 5% were admitted; of those patients admitted, 16% needed surgery; only 12 patients (3%) were admitted to specialised burn units. CONCLUSIONS: Emergency departments manage patients with burns well, and referrals to plastic surgery departments are appropriate. The majority of burns can be prevented by addressing educational issues and vulnerable sections of the population.

Skin nodules after semipermanent cosmetic dermal filler.

The authors present what they believe is only the third reported incidence of orofacial granulomas after injection of semipermanent cosmetic filler.

Burn patterns of Asian ethnic minorities living in West Yorkshire, UK.

Whereas burn morbidity and mortality have been well studied among natives of Southeast Asia, few have studied the epidemiology of burn injury among UK Asian ethnic minority immigrants. A 1 year prospective study of all patients presenting with burns to Bradford Royal Infirmary was carried out. Four hundred and sixty patients were studied, 188 (41%) were Asian ethnic minorities. The average patient age was 17 years for the Asian group and 27 years for the non-Asian patients. Contact burns were responsible for 29% of injuries in Asian patients and 19% in the other group. Thirty-seven percent of contact burns in the Asian ethnic minority group were caused by hot irons. Eleven percent of Asian patients had treated their burn with inappropriate remedies including saiti, butter, and toothpaste. There were no significant differences between Asian and non-Asian patients in terms of large or deep burns, nor in mortality. Morbidity and mortality from burn injury among UK Asian patients and other groups in the UK are similar; however, a disproportionate number of Asian patients sustain smaller burns. Much of this is behaviour related, and it is hoped that through preventative measures a marked reduction in the number of Asian ethnic minority burns can be achieved.

Pentoxifylline inhibits mature burn scar fibroblasts in culture.

Fibroblasts are thought to be (in part) responsible for the persisting contractile forces that result in burn contractures. Using monolayer and fibroblast populated collagen lattice (FPCL) models we subjected burn scar fibroblasts to the anti-fibrinolytic agent Pentoxifylline (PFX) in an attempt to reduce proliferation and contraction of these cells. Fibroblasts were isolated from mature burn scars at reconstructive surgery. Fibroblasts were grown in monolayer or incorporated into FPCL's and exposed to PFX. Fibroblast numbers and FPCL surface areas were calculated using digital photography and image analysis. PFX showed a dose-dependent inhibition of contraction and reduced proliferation of burn scar fibroblasts. In monolayer, cell number proliferation was markedly reduced. FPCL's containing 0, 0.25, 0.5, 1, and 2 mg/ml of PFX had relative surface areas of 31, 40, 43, 59, and 85%, respectively. One and 2 mg/ml FPCL's contracted significantly less than controls (p < 0.0001). This is the first study to show the dose-dependent effects of Pentoxifylline on the proliferation and contraction of burn scar fibroblasts. This study suggests that Pentoxifylline has a direct effect on inhibiting burn scar fibroblasts. Further study of PFX on burn scars will provide opportunities to reduce burn scar contractures in vivo.

Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial.

OBJECTIVES: Whether beta-blockers reduce atrial arrhythmias and, when added to an angiotensin-converting enzyme (ACE) inhibitor, ventricular arrhythmia is unknown. BACKGROUND: Ventricular and atrial arrhythmias are common after acute myocardial infarction (AMI) and are associated with a poor prognosis. Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia. METHODS: The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, which enrolled 1,959 patients with reduced left ventricular systolic function after AMI, 98% of whom were treated with an ACE inhibitor. RESULTS: The incidence of atrial fibrillation/flutter was 53 to 984 (5.4%) in the placebo group and 22 to 975 (2.3%) in the carvedilol group, giving a carvedilol/placebo hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.25 to 0.68; p = 0.0003). The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 (3.9%) and 9 to 975 (0.9%) (HR 0.24, 95% CI 0.11 to 0.49; p < 0.0001). CONCLUSIONS: Carvedilol has a powerful antiarrhythmic effect after AMI, even in patients already treated with an ACE inhibitor. Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients.