Background: Growth factors are generally accepted to be essential mediators of tissue repair via well‐established mechanisms of action that include stimulatory effects on angiogenesis and cellullar ...proliferation, ingrowth, differentiation, and matrix biosynthesis. The aim of this study was to evaluate in a large‐scale, prospective, blinded, and randomized controlled clinical trial the safety and effectiveness of purified recombinant human platelet‐derived growth factor (rhPDGF‐BB) mixed with a synthetic beta‐tricalcium phosphate (β‐TCP) matrix for the treatment of advanced periodontal osseous defects at 6 months of healing.
Methods: Eleven clinical centers enrolled 180 subjects, each requiring surgical treatment of a 4 mm or greater intrabony periodontal defect and meeting all inclusion and exclusion criteria. Subjects were randomized into one of three treatment groups: 1) β‐TCP + 0.3 mg/ml rhPDGF‐BB in buffer; 2) β‐TCP + 1.0 mg/ml rhPDGF‐BB in buffer; and 3) β‐TCP + buffer (active control). Safety data were assessed by the frequency and severity of adverse events. Effectiveness measurements included clinical attachment levels (CAL) and gingival recession (GR) measured clinically and linear bone growth (LBG) and percent bone fill (% BF) as assessed radiographically by an independent centralized radiology review center. The area under the curve (AUC), an assessment of the rate of healing, was also calculated for CAL measurements. The surgeons, clinical and radiographic evaluators, patients, and study sponsor were all masked with respect to treatment groups.
Results: CAL gain was significantly greater at 3 months for group 1 (rhPDGF 0.3 mg/ml) compared to group 3 (β‐TCP + buffer) (3.8 versus 3.3 mm; P = 0.032), although by 6 months, this finding was not statistically significant (P = 0.11). This early acceleration of CAL gain led to group 1 exhibiting a significantly greater rate of CAL gain between baseline and 6 months than group 3 as assessed by the AUC (68.4‐ versus 60.1‐mm weeks; P = 0.033). rhPDGF (0.3 mg/ml)‐treated sites also had significantly greater linear bone gain (2.6 versus 0.9 mm, respectively; P <0.001) and percent defect fill (57% versus 18%, respectively; P <0.001) than the sites receiving the bone substitute with buffer at 6 months. There was less GR at 3 months in group 1 compared to group 3 (P = 0.04); at 6 months, GR for group 1 remained unchanged, whereas there was a slight gain in gingival height for group 3 resulting in comparable GR. There were no serious adverse events attributable to any of the treatments.
Conclusions: To our knowledge, this study is the largest prospective, randomized, triple‐blinded, and controlled pivotal clinical trial reported to date assessing a putative periodontal regenerative and wound healing therapy. The study demonstrated that the use of rhPDGF‐BB was safe and effective in the treatment of periodontal osseous defects. Treatment with rhPDGF‐BB stimulated a significant increase in the rate of CAL gain, reduced gingival recession at 3 months post‐surgery, and improved bone fill as compared to a β‐TCP bone substitute at 6 months.
Multiple myeloma promotes systemic skeletal bone disease that greatly contributes to patient morbidity. Resorption of type I collagen-rich bone matrix by activated osteoclasts results in the release ...of sequestered growth factors that can drive progression of the disease. Matrix metalloproteinase-13 (MMP13) is a collagenase expressed predominantly in the skeleton by mesenchymal stromal cells (MSC) and MSC-derived osteoblasts. Histochemical analysis of human multiple myeloma specimens also demonstrated that MMP13 largely localizes to the stromal compartment compared with CD138
myeloma cells. In this study, we further identified that multiple myeloma induces MMP13 expression in bone stromal cells. Because of its ability to degrade type I collagen, we examined whether bone stromal-derived MMP13 contributed to myeloma progression. Multiple myeloma cells were inoculated into wild-type or MMP13-null mice. In independent
studies, MMP13-null mice demonstrated significantly higher overall survival rates and lower levels of bone destruction compared with wild-type controls. Unexpectedly, no differences in type I collagen processing between the groups were observed.
stromal coculture assays showed reduced formation and activity in MMP13-null osteoclasts. Analysis of soluble factors from wild-type and MMP13-null MSCs revealed decreased bioavailability of various osteoclastogenic factors including CXCL7. CXCL7 was identified as a novel MMP13 substrate and regulator of osteoclastogenesis. Underscoring the importance of host MMP13 catalytic activity in multiple myeloma progression, we demonstrate the
efficacy of a novel and highly selective MMP13 inhibitor that provides a translational opportunity for the treatment of this incurable disease. SIGNIFICANCE: Genetic and pharmacologic approaches show that bone stromal-derived MMP13 catalytic activity is critical for osteoclastogenesis, bone destruction, and disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2415/F1.large.jpg.
Preclinical data suggest histone deacetylase inhibitors improve the therapeutic index of sorafenib. A phase I study was initiated to establish the recommended phase 2 dose of sorafenib combined with ...vorinostat in patients with unresectable hepatocellular carcinoma.
Patients received vorinostat (200 to 400 mg by mouth once daily, 5 of 7 d) and sorafenib at standard or reduced doses (400 mg cohort A or 200 mg cohort B by mouth twice daily). Patients who received 14 days of vorinostat in cycle 1 were evaluable for dose-limiting toxicity (DLT).
Sixteen patients were treated. Thirteen patients were evaluable for response. Three patients experienced DLTs, 2 in cohort A (grade gr 3 hypokalemia; gr 3 maculopapular rash) and 1 in cohort B (gr 3 hepatic failure; gr 3 hypophosphatemia; gr 4 thrombocytopenia). Eleven patients required dose reductions or omissions for non-DLTtoxicity. Ten patients (77%) had stable disease (SD). The median treatment duration was 4.7 months for response-evaluable patients. One patient with SD was on treatment for 29.9 months, and another patient, also with SD, was on treatment for 18.7 months. Another patient electively stopped therapy after 15 months and remains without evidence of progression 3 years later.
Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients, requiring dose modifications that prevented determination of the recommended phase 2 dose. The combination is not recommended for further exploration with this vorinostat schedule in this patient population.
Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance ...imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses
. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset
. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.
To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within ...participating centers.
In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol.
Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of > or =25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145-155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation.
The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.
Background and Aims
Patients with acute liver injury or failure (ALI/ALF) experience bleeding complications uncommonly despite an abnormal hemostatic profile. Rotational thromboelastometry (ROTEM), ...which assesses clot formation in whole blood, was used to determine the nature of abnormal hemostasis and whether it contributes to bleeding events, illness severity, or survival.
Approach and Results
A total of 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta devices. Consistent with standard laboratory evidence of hypocoagulability (median international normalized ratio = 2.9 and platelet count = 144 × 109/L), patients frequently exhibited ROTEM parameters outside the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non‐acetaminophen ALI/ALF than those with acetaminophen ALI/ALF (clot initiation P < 0.001, assembly P = 0.02, firmness at 10 minutes P = 0.05, and maximal firmness P = 0.06). Patients with more severe systemic complications (high‐grade hepatic encephalopathy and need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypocoagulable ROTEM parameters (clot initiation (P = 0.005), stiffness at 10 minutes (P = 0.05), and maximal stiffness by fibrin assembly (P = 0.004)) were observed in patients who died or underwent liver transplantation than those who survived with their native liver.
Conclusions
In patients with ALI/ALF, abnormal ROTEM parameters are frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.
Increases in wildfire activity and rainfall intensification are driving more postfire debris flows (PFDF) in many regions around the world. PFDFs are most common in the first postfire year and may ...even occur before a fire is fully controlled. This underscores the importance of assessing postfire hazards before a fire starts. Evaluation of PFDF hazards prior to fire can help strategize interventions lessening the negative effects of future fires. However, debris‐flow runout and inundation analyses are not routine in PFDF hazard assessments, partially due to time constraints and substantial uncertainties in boundary conditions. Here, we propose a prefire PFDF inundation assessment framework using a debris‐flow runout model based on the Herschel‐Bulkley (HB) rheology (HEC‐RAS v6.1). We constrain model inputs and parameters using Bayesian posterior analysis, rainfall‐runoff simulations, and a debris‐flow volume model. We use observations from recent PFDF incidents in northern Arizona, USA, to calibrate model components and then apply our prefire inundation assessment framework in a nearby unburned area. Specifically, we (a) identify yield stress as the most influential factor on inundation extent and arrival time in a HB model, (b) establish posterior distributions for model parameters suitable for forward modeling by leveraging uncertainties in field observations, and (c) implement a predictive forward analysis in an area that has not burned recently to evaluate PFDF inundation under several future fire scenarios. This study improves our ability to assess postfire debris‐flow hazards before a fire begins and provides guidance for future applications of single‐phase rheological models when assessing PFDF hazards.
Plain Language Summary
Wildfires and increased rainfall are causing more dangerous postfire debris flows around the world. These are most likely within the first year after a fire, sometimes even while the fire is ongoing. Recognizing this, it's important to assess these hazards before a fire starts to minimize damage. Current methods for predicting where and how debris flow will happen after a fire are not used often enough, mainly because they take a lot of time and there are many uncertainties involved. Our study proposes a new approach using a model to predict debris flow behavior before a fire occurs. This model, tested with data from northern Arizona, helps us understand factors like the mud's “stickiness” which influences how far and fast it travels. We also improve the way we estimate model parameters by incorporating uncertainties from real‐world observations. Finally, we use this model to foresee the impact of debris flow in different fire scenarios that could happen in the future. This work not only gets us better prepared for postfire debris flow but also offers guidance on how to use these models in future hazard assessments.
Key Points
Yield stress has the greatest influence on postfire debris flows (PFDF) inundation extent and arrival time in the Herschel‐Bulkley model
Posterior distributions for model parameters are established for forward modeling by leveraging observation uncertainties
A predictive forward analysis can be implemented to evaluate PFDF inundation for future fire scenarios
Is parenteral nutrition via peripherally inserted central catheters (PICCs) associated with better delivery of nutrition and growth and fewer adverse events compared with short peripheral cannulas in ...neonates?
Compared with short peripheral cannulas, parenteral nutrition via PICCs is associated with better nutrient delivery and lower rates of subsequent catheters or cannulas placed and is not associated with increased rates of invasive infection.
Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and ...liver transplantation provide support and rescue, respectively.
To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers.
Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440).
31 liver disease and transplant centers in the United States.
Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070).
Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013).
Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival TFS, 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% P < 0.010 for each). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% P < 0.001 in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period.
The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers.
Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study.
National Institutes of Health.
The Hubbard Brook Experimental Forest (HBEF) was established in 1955 by the U.S. Department of Agriculture, Forest Service out of concerns about the effects of logging increasing flooding and ...erosion. To address this issue, within the HBEF hydrological and micrometeorological monitoring was initiated in small watersheds designated for harvesting experiments. The Hubbard Brook Ecosystem Study (HBES) originated in 1963, with the idea of using the small watershed approach to study element fluxes and cycling and the response of forest ecosystems to disturbances, such as forest management practices and air pollution. Early evidence of acid rain was documented at the HBEF and research by scientists at the site helped shape acid rain mitigation policies. New lines of investigation at the HBEF have built on the long legacy of watershed research resulting in a shift from comparing inputs and outputs and quantifying pools and fluxes to a more mechanistic understanding of ecosystem processes within watersheds. For example, hydropedological studies have shed light on linkages between hydrologic flow paths and soil development that provide valuable perspective for managing forests and understanding stream water quality. New high frequency in situ stream chemistry sensors are providing insights about extreme events and diurnal patterns that were indiscernible with traditional weekly sampling. Additionally, tools are being developed for visual and auditory data exploration and discovery by a broad audience. Given the unprecedented environmental change that is occurring, data from the small watersheds at the HBEF are more relevant now than ever and will continue to serve as a basis for sound environmental decision‐making.
The Hubbard Brook Experimental Forest was established in 1955 as a major center for hydrologic research in the northeastern US. Since that time, the scope of study has expanded to a collaborative, multidisciplinary research program that includes long‐term investigations of air, water, soils, plants, and animals. New lines of research continue to improve understanding of watershed response to disturbance to better inform land management decisions and policies.
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