Full Extrapolation Research Articles

ASC4KIDS: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Chronic Myeloid Leukemia in the Chronic Phase

Background Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients with chronic myeloid leukemia in the chronic phase (CML-CP). More treatment options with improved efficacy and safety profiles are needed for pediatric patients. Asciminib is a first-in-class allosteric inhibitor of ABL (non-receptor tyrosine) kinases, specifically targeting the ABL myristoyl pocket (STAMP), and does not inhibit other protein kinases. Asciminib was approved by the US Food and Drug Administration (FDA) with subsequent approvals worldwide for patients aged ≥18 years with Philadelphia chromosome-positive (Ph+) CML-CP treated with ≥2 prior TKIs in October 2021. Asciminib 40 mg twice daily (bid) has demonstrated improved major molecular response rates (25.5% vs 13.2% at week 24) and a favorable safety profile compared with bosutinib 500 mg once daily (qd) in adult patients with Ph+ CML-CP in the phase 3 ASCEMBL study (NCT03106779). This study aims to characterize the pharmacokinetics (PK), long-term safety profile, and antileukemic effects of asciminib in pediatric patients and identify a pediatric formulation dose that will lead to asciminib exposure comparable to 80 mg qd or 40 mg bid in adult patients. Methods This multicenter, open-label study (NCT04925479) includes patients aged 1 to <18 years with Ph+ CML-CP, without a BCR::ABL1 T315I mutation, treated with ≥1 prior TKI. For the pediatric formulation group, at least 15 patients will be included in each of the two age groups (1 to <12 years and 12 to <18 years), consisting of Part 1, 2 and 3. The study started with an exploratory adult formulation group of Adolescent patients (aged 14 to <18 years, body weight ≥40 kg) treated with the adult formulation dose (40 mg bid or 80 mg qd tablet) under fasting conditions. The primary endpoint includes PK parameters; secondary endpoints include: hematologic and molecular responses, safety, and acceptability/palatability of the pediatric formulations. Part 1 (dose-determining cohort): 4 to 6 patients will receive the asciminib pediatric formulation bid (a mini-tablet of 1.3 mg/kg with food) to assess safety, and to assess if the exposure in pediatric patients is comparable to exposure with the adult formulation over the first 28 days (patients either from pediatric or adult categories). After the interim analysis, if a dose adjustment is required, an additional 4 to 6 patients will be assessed at an adjusted dose. Part 2 (expansion cohort, 40 mg bid regimen): 14 to 16 patients will receive the dose determined in part 1. The second interim PK and safety analysis will be conducted after all patients from parts 1 and 2 complete 28 days of treatment. Part 3 (expansion cohort, 80 mg qd regimen): 10 patients (5 from each age group) will receive the same total daily dose of asciminib qd. The PK, safety profile, and pharmacodynamic endpoints will be assessed for the bid regimen after all patients in parts 1 and 2 complete 52 weeks of treatment. The primary analysis for the combined bid and qd regimen will be performed after all patients complete 52 weeks of treatment (total treatment period: 5 years [ Figure]). A final analysis will be performed after all patients complete treatment. Patients who discontinue treatment early will be followed up for survival until the end of the study. There are 32 study sites open out of planned 35 study sites in 14 countries worldwide. The exploratory and the pediatric formulation groups recruited 4 patients and 9 patients, respectively, as of June 07, 2023, with a total of 13 patients in the study. The study is still recruiting. This study will determine a pediatric dose for asciminib and support a strategy of full extrapolation from adult data to use in the pediatric patients with CML-CP.

Recent Use of Pediatric Extrapolation in Pediatric Drug Development in US

ABSTRACT The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials, for drugs developed in both adults and children. However, when scientifically justified, relying on extrapolation may be acceptable. Historically, the FDA’s extrapolation approach was based on draft guidance published in 2014, which introduced the categories of full, partial, and no extrapolation. The European Medicines Agency (EMA) took a different view on pediatric extrapolation. To better understand the use of extrapolation to support pediatric drug development and approval, we reviewed the pediatric labeling changes published by the FDA, focusing on the labeling updates between 1/1/2015 and 7/31/2021, the period where the extrapolation approach is in transition to harmonize with the EMA. Within this time window, among the 265 drugs and biological products with pediatric labeling changes, 169 (63.8%) were identified where extrapolation was used. This includes 64 (24.2%) labeling changes, where full extrapolation was used, and 105 (39.6%) labeling changes, where partial extrapolation was used. The major disease areas that extrapolation was used include neuroscience (40/53, 75.5%) and infectious disease (20/28, 71.4%). The extrapolation approach was identified in terms of source population beyond the use of adult as well as extrapolation from clinical trials conducted in the same drug class. The use of extrapolation increased the rates of new and expanded pediatric indication in the period. This review gives the most recent landscape of pediatric labeling changes using extrapolation. With the released ICH (International Council for Harmonization) E11A guidance in April 2022, the paper also provides insights for future pediatric drug development programs.

PB1903: TRIAL IN PROGRESS: A MULTICENTER, OPEN-LABEL, PHASE IB/II STUDY TO DETERMINE THE DOSE AND SAFETY OF ASCIMINIB IN PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP)

Background: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with CML-CP. Five TKIs are approved for adults: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. However, only imatinib, dasatinib, and nilotinib are approved for pediatric pts. Efficacy and safety profiles of TKIs are similar in adult and pediatric pts; however, growth retardation has been reported in the pediatric population, in whom long-term adverse effects are unknown. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is a recently approved drug that inhibits BCR::ABL1 by Specifically Targeting the ABL Myristoyl Pocket (STAMP). In the phase III ASCEMBL trial for adults with heavily pretreated CML-CP, asciminib (40 mg twice daily [BID]) had an improved major molecular response rate (25.5% vs 13.2%) at week 24 and a better safety profile compared with bosutinib (500 mg once daily). Here we present the phase Ib/II trial evaluating asciminib in pediatric pts. Aims: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose leading to an asciminib exposure comparable to the adult dose, 40 mg BID. Methods: This is a multicenter, open-label study (NCT04925479). Eligible pts have Philadelphia chromosome–positive CML-CP treated with ≥1 prior TKI, do not have a T315I mutation, and are aged ≥1 to <18 years, provided informed consent. Adolescent pts aged ≥14 to <18 years and weighing ≥40 kg will be enrolled in the exploratory adult formulation group, receiving the adult dose, until the pediatric formulation is available. In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to <18 years will receive the pediatric formulation (body weight–adjusted dose of asciminib taken with food) to obtain ≥4 participants evaluable for PK data. This evaluation will determine whether median exposure in pediatric pts is comparable to asciminib 40 mg BID taken without food in adult pts. PK and safety will be assessed during the first 28 days after treatment initiation. In part 2 (expansion cohort), the body weight–adjusted dose determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to <12 years and 15 pts aged 12 to <18 years). Pts receiving the adult formulation may switch to the pediatric formulation in part 2 but will not be counted toward the 30 pts enrolled in part 2. A 2nd interim PK and safety analysis will be conducted after all pts in part 2 have completed 28 days of treatment. The total duration of the study treatment period is 5 years (Figure). The primary PK endpoints, safety, and pharmacodynamics will be assessed after all pts have been on study for 52 weeks or discontinued earlier. After all pts have been on study for 5 years or discontinued earlier, a final analysis will be performed. Pts who discontinue the study early will be followed up for survival until the study is complete. Results: The primary endpoints include PK parameters. Secondary endpoints include hematologic and molecular responses, safety, acceptability, and palatability of asciminib. Image:Summary/Conclusion: Data from this study will be used to provide a pediatric dose and support a strategy of full extrapolation from adult data to use in the pediatric setting.

Model-Informed Drug Development Approaches to Assist New Drug Development in the COVID-19 Pandemic.

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID‐19) pandemic. Model‐informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID‐19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.

Trial in Progress: A Multicenter, Open-Label, Phase Ib/II Study to Determine the Dose and Safety of Asciminib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Treated with ≥1 Prior Tyrosine Kinase Inhibitor

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). In adults, 5 TKIs are approved: imatinib, dasatinib, nilotinib, bosutinib and ponatinib. In the pediatric population, however, only imatinib, dasatinib and nilotinib are approved. Pediatric pts have similar cytogenetic and molecular response rates to first-line (1L) imatinib and 1L second-generation TKIs nilotinib and dasatinib as adults. While the safety profiles for TKIs are similar in adult and pediatric pts, growth retardation has been reported specifically in the pediatric population. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is an investigational drug that inhibits BCR-ABL1 by specifically targeting the ABL myristoyl pocket (STAMP inhibitor). Asciminib has shown promising efficacy and safety in adults with CML-CP in phase I-III trials, given without food for 1 hour prior and 2 hours after taking asciminib (fasted). In the phase I asciminib monotherapy trial in heavily pretreated adult pts, 48% and 28% without and with T315I mutations, respectively, achieved or maintained major molecular response (MMR) by 12 months. In the phase III ASCEMBL trial for adults with CML-CP who are resistant to or intolerant of ≥2 TKIs, 25.5% of pts on asciminib vs 13.2% of pts on bosutinib achieved MMR at 24 weeks. Here we present the phase Ib/II trial evaluating asciminib monotherapy in pediatric pts.OBJECTIVE: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose (taken with food) leading to an asciminib exposure comparable to that of 40 mg twice daily (BID) in adult pts (fasted).DESIGN: This is a multicenter, open-label, phase Ib/II study (NCT04925479, Figure 1). Eligible pts have Philadelphia chromosome-positive CML-CP resistant to or intolerant of ≥1 prior TKI, do not bear T315I mutations and are aged ≥1 to <18 years. Adolescent pts aged ≥14 to <18 years and weighing ≥40 kg will be enrolled in the exploratory adult formulation group, receiving 40 mg asciminib BID in the fasted state until the pediatric formulation is available. There is no prespecified sample size for this group.In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to <18 years will receive the pediatric formulation (body weight-adjusted dose of asciminib minitablets taken with food) to obtain ≥4 participants evaluable for PK data. This evaluation will determine whether median exposure in pediatric pts is comparable to that of asciminib 40 mg BID in adult pts (fasted). Dose adjustments will be made if the minimum exposure is less than that of 20 mg BID in adults or higher than double the maximum exposure in adults at 40 mg BID. During the first 28 days after treatment initiation, safety will be assessed based on predefined dose-limiting toxicities.In part 2 (expansion cohort), the body weight-adjusted dosing determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to <12 years and 15 pts aged 12 to <18 years). Pts receiving the adult formulation will have the opportunity to switch to the pediatric formulation in part 2 but will not be counted toward the 30 pts enrolled in part 2. A second interim PK and safety analysis will be conducted after all pts in part 2 have completed 28 days of treatment (Figure 2).The total duration of the study treatment period is 5 years. The primary analysis (primary PK endpoints, safety, and pharmacodynamics) will be assessed after all pts have been on study for 52 weeks or discontinued earlier. A final analysis will be completed after all pts have been on study for 5 years or discontinued earlier. Pts who discontinue the study early will be followed up for survival until the study is complete.MAIN OUTCOMES MEASURES: The primary endpoints include PK parameters. Secondary endpoints include treatment-associated AEs, hematologic and molecular responses, and acceptability and palatability of asciminib (Table 1).CONCLUSIONS: Data from this study will be used to support a strategy of full extrapolation from adult data to use in the pediatric setting.This study is sponsored by Novartis. [Display omitted] DisclosuresHijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Descamps: Novartis: Current Employment. Bayar: Novartis: Current Employment. Ramscar: Novartis: Current Employment.

التّکرار صورٌ، مقاماتٌ وأسرار فی ضوء أقوال النبی ( ص ) فی صحیح البخاری

الملخص في هذا البحث استقراء تام لما وقع فيه التکرار من أقواله rالتي وردت في صحيح البخاري بغرض الوقوف على صوره التي جاء عليها، ومقاماته وأسراره. وقد اعتمدت المنهج الاستقرائي التحليلي في هذه الدراسة التي کان أهم ما توصلت إليه من نتائج: تعدد صور التکرار ومقاماته في أقواله r ، وکما کان لتکرار الجملة الإنشائية النصيب الأکبر من صوره، کان لمقامي التعليم والدعاء الحظ ذاته من مقاماته التي کان وراءها أسرار أبرزها: التأکيد والمبالغة والترغيب والترهيب والتأنيس والتسکين . Abstract In this research, a full extrapolation of the repetition of prophet`s words (peace be upon him) included in Sahih al-Bukhari for the purpose of identifying his images, his contexts and his secrets. I adopted the inductive analytical approach in this study, which was the most important of its findings: The repetition of images and contexts in prophet`s words, and as the repetition of the constructive sentence had the largest share of his images, the context of education and prayer had the same luck from his context, which had secrets behind them, the most prominent of which are: assertion, exaggeration, alienation, intimidation, desecration and alleviation.

Identifiability Analysis of Degradation Model Parameters from Transient CO2 Release in Low-Temperature PEM Fuel Cell under Various AST Protocols

The detrimental effects of the catalyst degradation on the overall envisaged lifetime of low-temperature proton-exchange membrane fuel cells (LT-PEMFCs) represent a significant challenge towards further lowering platinum loadings and simultaneously achieving a long cycle life. The elaborated physically based modeling of the degradation processes is thus an invaluable step in elucidating causal interaction between fuel cell design, its operating conditions, and degradation phenomena. However, many parameters need to be determined based on experimental data to ensure plausible simulation results of the catalyst degradation models, which proves to be challenging with the in situ measurements. To fill this knowledge gap, this paper demonstrates the application of a mechanistically based PEMFC modeling framework, comprising real-time capable fuel cell performance, and platinum and carbon support degradation models, to model transient CO2 release rates in the LT-PEMFCs with the consistent calibration of reaction rate parameters under multiple different accelerated stress tests at once. The results confirm the credibility of the physical and chemical modeling basis of the proposed modeling framework, as well as its prediction and extrapolation capabilities. This is confirmed by an increase of only 29% of root mean square deviations values when using a model calibrated on all three data sets at once in comparison to a model calibrated on only one data set. Furthermore, the unique identifiability and interconnection of individual model calibration parameters are determined via Fisher information matrix analysis. This analysis enables optimal reduction of the set of calibration parameters, which results in the speed up of both the calibration process and the general simulation time while retaining the full extrapolation capabilities of the framework.

Remdesivir: Preliminary Data and Clinical Use Versus Recommended Use.

* Abbreviations: COVID-19 — : coronavirus disease 2019 FDA — : Food and Drug Administration Remdesivir inhibits viral replication of severe acute respiratory coronavirus 2 in vitro and has been shown to reduce time to recovery in adults with coronavirus disease 2019 (COVID-19). It is currently the only antiviral approved by the Food and Drug Administration (FDA) for the treatment of COVID-19.1–4 Although remdesivir is being used in children with COVID-19, it is not approved for patients <12 years of age. Fortunately, if treatment with remdesivir of COVID-19 meets key assumptions, the drug may qualify for the extrapolation pathway, whereby efficacy data in adults can be used to support efficacy in children. However, safety data cannot be extrapolated; population-specific safety data are needed to support FDA labeling for pediatric use. Thus, we read with anticipation the safety data on compassionate use of remdesivir in 77 children with severe COVID-19 presented by Goldman et al5 in this issue of Pediatrics . Goldman et al5 describe low rates of adverse events, including elevated liver aminotransferase levels and anemia, similar to the safety profile seen in adults receiving remdesivir. In light of these data, we will consider whether the concept of extrapolation could be used to support efficacy of remdesivir in children … Address correspondence to Danny K. Benjamin, MD, PhD, Duke Clinical Research Institute, Durham Centre, Suite 800, 300 W Morgan St., Durham, NC 27701. E-mail: danny.benjamin{at}duke.edu

Particularities of IBD Trials in Children.

Pediatric inflammatory bowel diseases (IBD) are similar to the adult-onset type in many aspects, including the necessity of high-quality randomized controlled trials. However, recruiting children into clinical trials is conceptually more challenging than in adults. Furthermore, the long delay between adult and pediatric approval of new drugs leads not only to the unbearable extensive use of these drugs as off-label without appropriate dosing and safety data but also to more challenges when eventually the pediatric trial is performed. This review offers possible solutions to age-specific pitfalls in performing trials in pediatric IBD. Many of the challenges could be adequately addressed by accepting full extrapolation of efficacy from adult trials. This is advisable if small pharmacokinetics/ pharmacodynamics (PK/PD) studies show similarity to adult data. Then, pediatric trials can focus on dosing and safety while avoiding the controversial use of placebo. Judicious use of non-invasive activity scores and biomarkers, providing immediate and effective treatment in active disease and ensuring equipoise of treatments both within and outside the trial are the mainstay of a feasible trial in children. The recent trend of including adolescents in adult phase-3 trials addresses some obstacles but introduces others. Acknowledging and addressing these age-specific challenges would facilitate pediatric drug development in IBD.

Exposure-Response of Palonosetron for Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients.

Extrapolation of efficacy from adult populations to pediatrics may be appropriate if it is reasonable to assume that the 2 populations have similar disease progression and response to intervention. When full extrapolation of efficacy is deemed appropriate, the pediatric dose can be determined by "matching" exposure to a drug with that observed in adult patients. This approach has been used in certain therapeutic areas to alleviate the burden of pediatric clinical trials. We present here a case in which exposure matching is not appropriate. Data analyses including pharmacokinetics and exposure-response were performed using data obtained from 2 pediatric chemotherapy-induced nausea and vomiting trials for intravenously administered palonosetron (Aloxi; a 5-HT3 receptor antagonist) injection and the results were compared with adult findings. At the approved doses for adults (0.25 mg) and pediatric patients (20 μg/kg), mean systemic exposure (area under the curve) of palonosetron in pediatric patients was approximately 3-fold higher than that in adults, whereas the response rate was similar between the 2 populations. Across pediatric patients, those younger than 6 years of age appeared to have a higher response than those ages 6 years or older, even though estimated systemic exposure was comparable between these age groups. Overall, these analyses provide an example in which pediatric and adult exposure data alone are insufficient to adequately identify effective pediatric doses and raise questions about the appropriateness of exposure matching for other drugs in the same therapeutic class. In such cases, pediatric dose-ranging and efficacy studies are needed.

A Survey of Neonatal Pharmacokinetic and Pharmacodynamic Studies in Pediatric Drug Development.

Conducting clinical trials in neonates is challenging, and knowledge gaps in neonatal clinical pharmacology exist. We surveyed the US Food and Drug Administration databases and identified 43 drugs studied in neonates or referring to neonates between 1998 and 2014. Twenty drugs were approved in neonates. For 10 drugs, approval was based on efficacy data in neonates, supplemented by pharmacokinetic data for four drugs. Approval for neonates was based on full extrapolation from older patients for six drugs, and partial extrapolation was the basis of approval for four drugs. Dosing recommendations differed from older patients for most drugs, and used body-size based adjustment in neonates. Trial failures were associated with various factors including inappropriate dose selection. Successful drug development in neonates could be facilitated by an improved understanding of the natural history and pathophysiology of neonatal diseases and identification and validation of clinically relevant biomarkers.

Extrapolation to the complete basis set limit for binding energies of noncovalent interactions

A means of extrapolating from double and triple-valence basis sets to a complete basis set is examined in the context of the pnicogen bonds in the BH2P⋯NH3 complexes, with B=CH3, H, NH2, CF3, OH, Cl, F, and NO2. Binding energies converge smoothly, and the trends for the various substituents B are unaffected by the basis set size, extrapolation, or level of inclusion of electron correlation, including MP2 and CCSD(T). The approach appears to be successful also for H-bonded systems, in particular the water dimer. In the event that full extrapolation within the context of CCSD(T) is not feasible, several more economical but attractive options are suggested, including a quantitative measure of the accuracy to be expected with each.

Reducing Potentially Avoidable Complications in Patients with Chronic Diseases: The Prometheus Payment Approach

OBJECTIVE (OR STUDY QUESTION): To determine whether a new payment model can reduce current incidence of potentially avoidable complications (PACs) in patients with a chronic illness. A claims database of 3.5 million commercially insured members under age 65. We analyzed the database using the Prometheus Payment model's analytical software for six chronic conditions to quantify total costs, proportion spent on PACs, and their variability across the United States. We conducted a literature review to determine the feasibility of reducing PACs. We estimated the financial impact on a prototypical practice if that practice received payments based on the Prometheus Payment model. We find that (1) PACs consume an average of 28.6 percent of costs for the six chronic conditions studied and vary significantly; (2) reducing PACs to the second decile level would save U.S.$116.7 million in this population; (3) current literature suggests that practices in certain settings could decrease PACs; and (4) using the Prometheus model could create a large potential incentive for a prototypical practice to reduce PACs. By extrapolating these findings we conclude that costs might be reduced through payment reform efforts. A full extrapolation of these results, while speculative, suggests that total costs associated to the six chronic conditions studied could decrease by 3.8 percent.

You See UC: An Animal Model of Ulcerative Colitis

You See UC: An Animal Model of Ulcerative Colitis

Compressed wavefield extrapolation with curvelets

An explicit algorithm for the extrapolation of one-way wavefields is proposed which combines recent developments in information theory and theoretical signal processing with the physics of wave propagation. Because of excessive memory requirements, explicit formulations for wave propagation have proven to be a challenge in 3-D. By using ideas from “compressed sensing”, we are able to formulate the (inverse) wavefield extrapolation problem on small subsets of the data volume, thereby reducing the size of the operators. According to compressed sensing theory, signals can successfully be recovered from an imcomplete set of measurements when the measurement basis is incoherent with the representation in which the wavefield is sparse. In this new approach, the eigenfunctions of the Helmholtz operator are recognized as a basis that is incoherent with curvelets that are known to compress seismic wavefields. By casting the wavefield extrapolation problem in this framework, wavefields can successfully be extrapolated in the modal domain via a computationally cheaper operatoion. A proof of principle for the “compressed sensing” method is given for wavefield extrapolation in 2-D. The results show that our method is stable and produces identical results compared to the direct application of the full extrapolation operator.

Are genetically modified mice useful for the understanding of acute pancreatitis?

Treatment of patients with acute pancreatitis has greatly improved due to a better understanding of the pathophysiology of the disease. This pathophysiology includes the activation and release of pancreatic enzymes in the interstitium, the autodigestion of the pancreas, and a multiple organ dysfunction after their release into the systemic circulation. Moreover, significant evidence exists that synthesis and release of proinflammatory cytokines and chemokines are also responsible for the local injury and systemic dispersion of the inflammation. The use of knockout mice devoid of active pro- or anti-inflammatory mediators allows examination of the effects of a specific cytokine without any drawbacks induced by pharmacological manipulations. The results obtained from these genetically modified mice show that numerous mediators have a major role in the pathophysiology of acute pancreatitis. They also clearly demonstrate that a single genetic deletion cannot completely prevent the occurrence of pancreatic or distant organ injury. However, the fact that the immune system is characterized by redundancies of ligands and receptors complicates the full understanding of each report. The utility of such experimental models might have limitations, and a full extrapolation of experimental data from genetically modified mice to humans must be done with caution.

Temperature dependence of the absolute third-order rate constant for the reaction between K + O 2 + N 2 over the range 680–1010K studied by time-resolved atomic resonance absorption spectroscopy

We present a direct kinetic study of the third-order recombination reaction K+O 2+N 2→KO 2+N 2 across the temperature range 680–1010K. K(4 2S 1 2 ) was generated by pulsed irradiation and monitored by time-resolved atomic resonance absorption spectroscopy in the “single shot mode” in the presence of O 2 and N 2 using the Rydberg transition at λ = 404 nm ( K(5 2P J) ← K(4 2S 1 2 ) ). While the resulting data for k 4 can be empirically expressed within this temperature range by the form k 4(680–1010 K) = (6.63 ± 0.66 × 10 −23)( T K ) −2.6±0.28 cm 6 molecule −2 s −1, a full extrapolation based on the unimolecular rate theory of Tröe was carried out in order to extend the data to flame temperatures (2000K), given the importance of potassium additives in flame inhibition. The full extrapolation across the range 200–2000K can be expressed to within 10% by (k 4/cm 6 molecule −2S −1)=−0.2558 [ln( T K )] 2+1.361 ln( T K )−66.14 These results are compared with data derived from measurements on a fast flow reactor which show a much smaller temperature dependence and indicate an extrapolated value for k 4 at flame temperatures significantly higher than derived from the present investigations.

Modern Ideas on Spontaneous Generation.

Man has always been a probing, exploring creature, whether it be as a traveler or a visitor of strange new lands or in the realm of ideas. Perhaps that is what made him man. A puzzle second only to the one which deals with the significance and mechanism of life itself concerns the origin of life as we know it. Man looks backward into antiquity to find origins. When this antiquity is measured by millions of years, he immediately confronts the need of full extrapolation. What he can judge as he studies the properties of life today must be used to test the circumstances under which life may have arisen on earth. This symposium deals with the beginnings of life and not the now defunct heresy of spontaneous generation occurring continually. Since the days of Spallanzani and Pasteur, no sensible man has believed that repeated acts of spontaneous generation occur