scholarly journals Using antibody synergy to engineer a high potency biologic cocktail against C. difficile

2021 ◽  
Author(s):  
Hui Zhao ◽  
Michael Tasch ◽  
Michael Dodds ◽  
Mesfin Gewe ◽  
Anissa Martinez ◽  
...  
Keyword(s):  
Single Agent ◽  
The United States ◽  
Mathematical Framework ◽  
High Potency ◽  
Current Therapies ◽  
At Risk Populations ◽  
Almost All ◽  
Antibody Interactions ◽  
Complementary Mechanism ◽  
Antibody Cocktail

We applied a mathematical framework originally used to model the effects of multiple inhibitors on enzyme activity to guide the development a therapeutic antibody cocktail, LMN-201, to prevent and treat C. difficile infection (CDI). CDI causes hundreds of thousands of cases of severe, often recurrent diarrhea and colitis in the United States annually and is associated with significant morbidity and mortality worldwide. Current therapies for preventing recurrent CDI are only partially successful, and there are no options available to prevent initial bouts of CDI in at-risk populations. Almost all antibody therapies have been developed and administered as monotherapies. Antibody cocktails are relatively rare even though they have the potential to greatly increase efficacy. One reason for this is our limited understanding of how antibody interactions can enhance potency, which makes it difficult to identify and develop antibodies that can be assembled into optimally effective cocktails. In contrast to the view that antibody synergies depend on unusual instances of cooperativity or allostery, we show that synergistic efficacy requires nothing more than that the antibodies bind independently to distinct epitopes on a common target. Therefore, synergy may be achieved much more readily than is generally appreciated. Due to synergy the LMN-201 antibody cocktail, which targets the C. difficile exotoxin B (TcdB), is 300- to 3000-fold more potent at neutralizing the most clinically prevalent TcdB toxin types than bezlotoxumab, the only monoclonal antibody currently approved for treatment or prevention of CDI. The efficacy of LMN-201 is further enhanced by inclusion of a phage-derived endolysin that destroys the C. difficile bacterium, and which therefore has a complementary mechanism of action to the antibody cocktail. These observations may serve as a paradigm for the development of high potency biologic cocktails against targets that have proven challenging for single-agent therapies.

scholarly journals Effects of B.1.1.7 and B.1.351 on COVID-19 Dynamics: A Campus Reopening Study

2021 ◽  
Author(s):  
Kevin Linka ◽  
Mathias Peirlinck ◽  
Amelie Schäfer ◽  
Oguz Ziya Tikenogullari ◽  
Alain Goriely ◽  
...  
Keyword(s):  
Online Education ◽  
The United States ◽  
Wild Type ◽  
Seir Model ◽  
Population Mixing ◽  
Santa Clara County ◽  
Increased Risk ◽  
Controversial Topic ◽  
Almost All ◽  
Local Reproduction

AbstractThe timing and sequence of safe campus reopening has remained the most controversial topic in higher education since the outbreak of the COVID-19 pandemic. By the end of March 2020, almost all colleges and universities in the United States had transitioned to an all online education and many institutions have not yet fully reopened to date. For a residential campus like Stanford University, the major challenge of reopening is to estimate the number of incoming infectious students at the first day of class. Here we learn the number of incoming infectious students using Bayesian inference and perform a series of retrospective and projective simulations to quantify the risk of campus reopening. We create a physics-based probabilistic model to infer the local reproduction dynamics for each state and adopt a network SEIR model to simulate the return of all undergraduates, broken down by their year of enrollment and state of origin. From these returning student populations, we predict the outbreak dynamics throughout the spring, summer, fall, and winter quarters using the inferred reproduction dynamics of Santa Clara County. We compare three different scenarios: the true outbreak dynamics under the wild-type SARS-CoV-2, and the hypothetical outbreak dynamics under the new COVID-19 variants B.1.1.7 and B.1.351 with 56% and 50% increased transmissibility. Our study reveals that even small changes in transmissibility can have an enormous impact on the overall case numbers. With no additional countermeasures, during the most affected quarter, the fall of 2020, there would have been 203 cases under baseline reproduction, compared to 4727 and 4256 cases for the B.1.1.7 and B.1.351 variants. Our results suggest that population mixing presents an increased risk for local outbreaks, especially with new and more infectious variants emerging across the globe. Tight outbreak control through mandatory quarantine and test-trace-isolate strategies will be critical in successfully managing these local outbreak dynamics.

scholarly journals The Effect of Vaccination Rates on the Infection of COVID-19 under the Vaccination Rate below the Herd Immunity Threshold

2021 ◽  
Vol 18 (14) ◽  
pp. 7491
Author(s):  
Yi-Tui Chen
Keyword(s):  
Infection Rate ◽  
Herd Immunity ◽  
The United States ◽  
Vaccination Rate ◽  
Infection Rates ◽  
Vaccination Rates ◽  
The United Kingdom ◽  
The World ◽  
Almost All ◽  
The Impact

Although vaccination is carried out worldwide, the vaccination rate varies greatly. As of 24 May 2021, in some countries, the proportion of the population fully vaccinated against COVID-19 has exceeded 50%, but in many countries, this proportion is still very low, less than 1%. This article aims to explore the impact of vaccination on the spread of the COVID-19 pandemic. As the herd immunity of almost all countries in the world has not been reached, several countries were selected as sample cases by employing the following criteria: more than 60 vaccine doses per 100 people and a population of more than one million people. In the end, a total of eight countries/regions were selected, including Israel, the UAE, Chile, the United Kingdom, the United States, Hungary, and Qatar. The results find that vaccination has a major impact on reducing infection rates in all countries. However, the infection rate after vaccination showed two trends. One is an inverted U-shaped trend, and the other is an L-shaped trend. For those countries with an inverted U-shaped trend, the infection rate begins to decline when the vaccination rate reaches 1.46–50.91 doses per 100 people.

scholarly journals Examining Variations in Surfactant Administration (ENVISION): A Neonatology Insights Pilot Project

Children ◽  
2021 ◽  
Vol 8 (4) ◽  
pp. 261
Author(s):  
Priya Patel ◽  
Andrew Houck ◽  
Daniel Fuentes
Keyword(s):  
Clinical Practice ◽  
Nurse Practitioners ◽  
Pilot Project ◽  
The United States ◽  
Institution Type ◽  
Respiratory Therapists ◽  
Respiratory Management ◽  
Surfactant Administration ◽  
Practice Variations ◽  
Almost All

Variability in neonatal clinical practice is well recognized. Respiratory management involves interdisciplinary care and often is protocol driven. The most recent published guidelines for management of respiratory distress syndrome and surfactant administration were published in 2014 and may not reflect current clinical practice in the United States. The goal of this project was to better understand variability in surfactant administration through conduct of health care provider (HCP) interviews. Questions focused on known practice variations included: use of premedication, decisions to treat, technique of surfactant administration and use of guidelines. Data were analyzed for trends and results were communicated with participants. A total of 54 HCPs participated from June to September 2020. In almost all settings, neonatologists or nurse practitioners intubated the infant and respiratory therapists administered surfactant. The INSURE (INtubation-SURrfactant-Extubation) technique was practiced by 83% of participants. Premedication prior to intubation was used by 76% of HCPs. An FiO2 ≥ 30% was the most common threshold for surfactant administration (48%). In conclusion, clinical practice variations exist in respiratory management and surfactant administration and do not seem to be specific to NICU level or institution type. It is unknown what effects the variability in clinical practice might have on clinical outcomes.

Philosophical implications of Tarski's work

1988 ◽  
Vol 53 (1) ◽  
pp. 80-91 ◽  
Author(s):  
Patrick Suppes
Keyword(s):  
United States ◽  
English Translation ◽  
The United States ◽  
International Congress ◽  
Unity Of Science ◽  
Scientific Philosophy ◽  
Philosophical Texts ◽  
Concept Of Truth ◽  
Almost All ◽  
Philosophical Questions

In his published work and even more in conversations, Tarski emphasized what he thought were important philosophical aspects of his work. The English translation of his more philosophical papers [56m] was dedicated to his teacher Tadeusz Kotarbiński, and in informal discussions of philosophy he often referred to the influence of Kotarbiński. Also, the influence of Leśniewski, his dissertation adviser, is evident in his early papers. Moreover, some of his important papers of the 1930s were initially given to philosophical audiences. For example, the famous monograph on the concept of truth ([33m], [35b]) was first given as two lectures to the Logic Section of the Philosophical Society in Warsaw in 1930. Second, his paper [33], which introduced the concepts of ω-consistency and ω-completeness as well as the rule of infinite induction, was first given at the Second Conference of the Polish Philosophical Society in Warsaw in 1927. Also [35c] was based upon an address given in 1934 to the conference for the Unity of Science in Prague; [36] and [36a] summarize an address given at the International Congress of Scientific Philosophy in Paris in 1935. The article [44a] was published in a philosophical journal and widely reprinted in philosophical texts. This list is of course not exhaustive but only representative of Tarski's philosophical interactions as reflected in lectures given to philosophical audiences, which were later embodied in substantial papers. After 1945 almost all of Tarski's publications and presentations are mathematical in character with one or two minor exceptions. This division, occurring about 1945, does not, however, indicate a loss of interest in philosophical questions but is a result of Tarski's moving to the Department of Mathematics at Berkeley. There he assumed an important role in the development of logic within mathematics in the United States.

International Conference on Safety of Life at Sea

1914 ◽  
Vol 8 (4) ◽  
pp. 758-768
Author(s):  
Everett P. Wheeler
Keyword(s):  
United States ◽  
The United States ◽  
International Conference ◽  
Human Skill ◽  
Almost All

In these days of wars which have engulfed almost all Europe it is a satisfaction to recall that thirteen nations sent their delegates to an international conference relating to safety of life at sea, no longer ago than December, 1913, and that they signed on the 20th of January, 1914, a convention which has been adopted by many of the nations and which was transmitted to the Senate of the United States by the President on the 17th of March. All the resources of human skill and science are now being used to destroy life. It is a pleasure to reflect that man has at one time been engaged in a more humane and, shall we not add, a more Christian undertaking.

CYSTIC FIBROSIS OF THE PANCREAS

PEDIATRICS ◽  
1957 ◽  
Vol 19 (6) ◽  
pp. 1136-1138
Author(s):  
Paul A. di Sant'Agnese ◽  
Charles Upton Lowe
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Evidence ◽  
Clinical Effect ◽  
Single Gene ◽  
Pancreatic Insufficiency ◽  
Recessive Gene ◽  
The United States ◽  
Live Births ◽  
Almost All ◽  
Very High

IN THE COURSE of a review of all features of the disease, the following points were particularly noteworthy: Incidence This disease accounts for almost all cases of pancreatic insufficiency in children. The incidence in the population of the United States is between 1 in 600 and 1 in 10,000 live births, with a probable average incidence of 1 in 2,500. There is no sex predominance. There is, however, a difference in racial predilection, being rarely seen in the Negro and never in Mongolians. It is a familial disease, displaying the characteristics of a mendelian recessive gene. This means that in an affected family the disease may occur in approximately 25% of the offspring, that both parents must be carriers of the trait and that two-thirds of the non-affected children are also carriers. Birth order has no effect on the inheritance of this disease. The fact that it is usually a lethal disease indicates that the mutation rate for this gene must be very high; the frequency of the single gene in the population has been calculated to be approximately 1 in 50. Pancreatic Insufficiency Clinical evidence of poor digestion and absorption of protein and fat is seen in the increased quantities of these substances in the feces, which causes the feces to be bulky, foul smelling, foamy and greasy. Another clinical effect of malabsorption is seen in the failure of the newborn infant with cystic fibrosis of the pancreas to regain birth weight in the first 10 days of life. In the absence of other evidence of disease, this is a sign suggestive of pancreatic failure.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3051-3051
Author(s):  
Nebojsa Skorupan ◽  
Mehwish Iqra Ahmad ◽  
Guillaume Joe Pegna ◽  
Cody J. Peer ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Pseudomonas Exotoxin A ◽  
Recombinant Immunotoxin ◽  
Level 1 ◽  
Expansion Cohort ◽  
Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

scholarly journals Signet-Ring Cell Carcinoma of the Colon: A Case Report and Review of the Literature

2015 ◽  
Vol 8 (3) ◽  
pp. 466-471 ◽  
Author(s):  
Peter Y. Park ◽  
Teresa Goldin ◽  
John Chang ◽  
Maurie Markman ◽  
Madappa N. Kundranda
Keyword(s):  
Cell Carcinoma ◽  
Early Stage ◽  
Single Agent ◽  
The United States ◽  
Signet Ring Cell Carcinoma ◽  
Signet Ring Cell ◽  
Early Stage Disease ◽  
Lower Quadrant ◽  
Signet Ring ◽  
Ring Cell

Background: Colorectal adenocarcinoma (CRC) is the third leading cause of death in the United States. One of the histologic subtypes of CRC is signet-ring cell carcinoma (SRCC), which has a distinct molecular and tumor biology from that of adenocarcinoma. Primary SRCC diagnosed at an early stage is very rare as most cases are detected at an advanced stage. Therefore, overall prognosis of SRCC is poor. Case Presentation: A 36-year-old female presented to her primary care physician with new-onset progressive right lower quadrant pain without any significant past medical or family history. Computed tomography scan of the abdomen and pelvis with contrast showed a 4.9 × 3.5 × 3.1 cm, lobulated, septated cystic mass arising from the cecum. The mass demonstrated wall enhancement and contained focal areas of coarse calcification. There was nodal involvement either locally or distally. The patient underwent right hemicolectomy, and pathology revealed a high-grade mucinous carcinoma with signet-ring cell variant invading through the muscularis propria and into the subserosal adipose tissue. The margins were negative for tumor, and no lymphovascular or perineural invasion was noted. None of the 14 resected pericolonic lymph nodes was positive for malignancy. Hence, she was staged as pT3, pN0, pMx-stage IIA. The appendix was not involved. Microsatellite instability testing showed the preservation of MLH1, PMS2, MSH2 and MSH6 proteins by IHC and PCR. Carcinoembryonic antigen level was within normal limits. Due to the patient's young age, aggressive histology and microsatellite-stable status, adjuvant fluropyrimidine (5-FU)-based therapy with the single agent capecitabine was initiated. The patient completed 6 months of adjuvant therapy and has been disease free for approximately 18 months. Conclusion: Primary SRCC of the cecum is a rare disease. Given the poor prognosis of these patients, early-stage disease with microsatellite-stable patients should be considered for adjuvant 5-FU-based therapy in an attempt to prevent recurrence.

Introduction to Dietary Reference Intakes

2006 ◽  
Vol 31 (1) ◽  
pp. 61-65 ◽  
Author(s):  
Susan I Barr
Keyword(s):  
Life Stage ◽  
Daily Intake ◽  
The United States ◽  
Reference Standards ◽  
Healthy Individuals ◽  
Gender Group ◽  
Dietary Reference Intakes ◽  
Intake Level ◽  
And Gender ◽  
Almost All

Dietary Reference Intakes (DRIs) are nutrient reference standards used for planning and assessing the diets of apparently healthy Canadians and Americans. The development of DRIs reflects a joint initiative by the United States and Canada to update, expand on, and replace the former Recommended Nutrient Intakes for Canadians and Recommended Dietary Allowances for Americans. DRIs include the Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), Adequate Intake (AI), and Tolerable Upper Intake Level (UL). The EAR is the average daily intake level that meets the requirement of 50% of healthy individuals in a life stage and gender group, whereas the RDA is set at a level that will meet the requirements of almost all (97%-98%) individuals in that life stage and gender group. An AI is a recommended intake level that is thought to meet the needs of almost all healthy individuals, and is set when there are insufficient data to establish an EAR (and therefore an RDA). The UL represents a threshold above which adverse effects of excessive intake may increase. In addition to these DRIs, macro nutrients have an Acceptable Macro nutrient Distribution Range (AMDR) and, for energy, an Estimated Energy Requirement (EER) is described.Key words: nutrient reference standards, nutrient requirements, nutrient toxicity.

scholarly journals IMPORTANT LESSONS FROM STUDYING THE CHINESE ECONOMY

2010 ◽  
Vol 55 (03) ◽  
pp. 419-434 ◽  
Author(s):  
GREGORY C. CHOW
Keyword(s):  
The United States ◽  
Chinese Economy ◽  
Economic Science ◽  
Republic Of China ◽  
Economic Advice ◽  
Chinese Official ◽  
The Government ◽  
The 1960S ◽  
Almost All ◽  
Official Data

In 1979 the United States and China established normal diplomatic relations, allowing me to visit China and study the Chinese economy. After doing so for 30 years since and advising the government of Taiwan in the 1960s and the 1970s and the government of the People's Republic of China in the 1980s and the 1990s, this is an opportune moment for me to summarize the important lessons I have learned. The lessons will be summarized in four parts: on economic science, on formulating economic policy and providing economic advice, on the special characteristics of the Chinese economy and on the experience of China's economic reform. At the beginning, I should comment on the quality of Chinese official data on which almost all quantitative studies referred to in this article were based. Chow (2006) has presented the view that by and large the official data are useful and fairly accurate. The main justification is that every time I tested an economic hypothesis or estimated an economic relation using the official data the result confirmed the well-established economic theory. It would be a miracle if I had the power to make the Chinese official statisticians fabricate data to support my hypotheses. Even if I had had the power, most of the data had already been published for years before I conceived the ideas of the studies reported in this article.

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