Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

N2O Temporal Variability from the Middle Troposphere to the Middle Stratosphere Based on Airborne and Balloon-Borne Observations during the Period 1987–2018

Nitrous oxide (N2O) is the fourth most important greenhouse gas in the atmosphere and is considered the most important current source gas emission for global stratospheric ozone depletion (O3 ). It has natural and anthropogenic sources, mainly as an unintended by-product of food production activities. This work examines the identification and quantification of trends in the N2O concentration from the middle troposphere to the middle stratosphere (MTMS) by in situ and remote sensing observations. The temporal variability of N2O is addressed using a comprehensive dataset of in situ and remote sensing N2O concentrations based on aircraft and balloon measurements in the MTMS from 1987 to 2018. We determine N2O trends in the MTMS, based on observations. This consistent dataset was also used to study the N2O seasonal cycle to investigate the relationship between abundances and its emission sources through zonal means. The results show a longterm increase in global N2O concentration in the MTMS with an average of 0.89 ± 0.07 ppb/yr in the troposphere and 0.96 ± 0.15 ppb/yr in the stratosphere, consistent with 0.80 ppb/yr derived from ground-based measurements and 0.799 ± 0.024 ppb/yr ACE-FTS (Atmospheric Chemistry Experiment Fourier Transform Spectrometer) satellite measurements

N2_2O Temporal Variability from the Middle Troposphere to the Middle Stratosphere Based on Airborne and Balloon-Borne Observations during the Period 1987–2018

Nitrous oxide (N$_2$O) is the fourth most important greenhouse gas in the atmosphere and is considered the most important current source gas emission for global stratospheric ozone depletion (O$_3$). It has natural and anthropogenic sources, mainly as an unintended by-product of food production activities. This work examines the identification and quantification of trends in the N$_2$O concentration from the middle troposphere to the middle stratosphere (MTMS) by in situ and remote sensing observations. The temporal variability of N$_2$O is addressed using a comprehensive dataset of in situ and remote sensing N$_2$O concentrations based on aircraft and balloon measurements in the MTMS from 1987 to 2018. We determine N$_2$O trends in the MTMS, based on observations. This consistent dataset was also used to study the N$_2$O seasonal cycle to investigate the relationship between abundances and its emission sources through zonal means. The results show a long-term increase in global N$_2$O concentration in the MTMS with an average of 0.89 ± 0.07 ppb/yr in the troposphere and 0.96 ± 0.15 ppb/yr in the stratosphere, consistent with 0.80 ppb/yr derived from ground-based measurements and 0.799 ± 0.024 ppb/yr ACE-FTS (Atmospheric Chemistry Experiment Fourier Transform Spectrometer) satellite measurements

PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma

Background Many urothelial carcinomas (UC) contain activating PIK3CA mutations. In telomerase-immortalized normal urothelial cells (TERT-NHUC), ectopic expression of mutant PIK3CA induces PI3K pathway activation, cell proliferation and cell migration. However, it is not clear whether advanced UC tumors are PIK3CA-dependent and whether PI3K pathway inhibition is a good therapeutic option in such cases. Methods We used retrovirus-mediated delivery of shRNA to knock down mutant PIK3CA in UC cell lines and assessed effects on pathway activation, cell proliferation, migration and tumorigenicity. The effect of the class I PI3K inhibitor GDC-0941 was assessed in a panel of UC cell lines with a range of known molecular alterations in the PI3K pathway. Results Specific knockdown of PIK3CA inhibited proliferation, migration, anchorage-independent growth and in vivo tumor growth of cells with PIK3CA mutations. Sensitivity to GDC-0941 was dependent on hotspot PIK3CA mutation status. Cells with rare PIK3CA mutations and co-occurring TSC1 or PTEN mutations were less sensitive. Furthermore, downstream PI3K pathway alterations in TSC1 or PTEN or co-occurring AKT1 and RAS gene mutations were associated with GDC-0941 resistance. Conclusions Mutant PIK3CA is a potent oncogenic driver in many UC cell lines and may represent a valuable therapeutic target in advanced bladder cancer

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Proceedings of the Sixth Caldwell Conference, St. Catherines Island, Georgia, May 20-22, 2011.

494 pages : illustrations (some color), maps (some color) ; 26 cm. Conference sponsored by the American Museum of Natural History and the St. Catherines Island Foundation.Although this volume covers a broad range of temporal and methodological topics, the chapters are unified by a geographic focus on the archaeology of the Georgia Bight. The various research projects span multiple time periods (including Archaic, Woodland, Mississippian, and contact periods) and many incorporate specialized analyses (such as petrographic point counting, shallow geophysics, and so forth). The 26 contributors conducting this cutting-edge work represent the full spectrum of the archaeological community, including museum, academic, student, and contract archaeologists. Despite the diversity in professional and theoretical backgrounds, temporal periods examined, and methodological approaches pursued, the volume is unified by four distinct, yet interrelated, themes. Contributions in Part I discuss a range of analytical approaches for understanding time, exchange, and site layout. Chapters in Part II model coastal landscapes from both environmental and social perspectives. The third section addresses site-specific studies of late prehistoric architecture and village layout throughout the Georgia Bight. Part IV presents new and ongoing research into the Spanish mission period of this area. These papers were initially presented and discussed at the Sixth Caldwell Conference, cosponsored by the American Museum of Natural History and the St. Catherines Island Foundation, held on St. Catherines Island, Georgia, May 20-22, 2011. TABLE OF CONTENTS: Revising the ¹⁴C reservoir correction for St. Catherines Island, Georgia / David Hurst Thomas, Matthew C. Sanger, and Royce H. Hayes -- An assessment of coastal faunal data from Georgia and northeast Florida / Alexandra L. Parsons and Rochelle A. Marrinan -- Archaeological geophysics on St. Catherines Island : beyond prospection / Ginessa J. Mahar -- Paste variability and clay resource utilization at the Fountain of Youth site, St. Augustine, 8SJ31 / Ann S. Cordell and Kathleen A. Deagan -- Petrographic analysis of pottery and clay samples from the Georgia Bight : evidence of regional social interactions / Neill J. Wallis and Ann S. Cordell -- Past shorelines of the Georgia coast / Chester B. DePratter and Victor D. Thompson -- Coastal landscapes and their relationship to human settlement on the Georgia coast / John A. Turck and Clark R. Alexander -- The role of small islands in foraging economies of St. Catherines Island / Matthew F. Napolitano -- Ever-shifting landscapes : tracking changing spatial usage along coastal Georgia / Matthew C. Sanger -- A paleoeconomic model of the Georgia coast (4500-300 B.P.) / Thomas G. Whitley -- A survey of Irene phase architecture on the Georgia coast / Deborah A. Keene and Ervan G. Garrison -- Life and death on the Ogeechee : a view from the Redbird Creek village / Ryan O. Sipe -- Mission San Joseph de Sapala : mission-period archaeological research on Sapelo Island / Richard W. Jefferies and Christopher R. Moore -- The Guale landscape of Mission Santa Catalina de Guale : 30 years of geophysics at a Spanish colonial mission / Elliot H. Blair -- Missions San Buenaventura and Santa Cruz de Guadalquini : retreat from the Georgia coast / Keith H. Ashley, Vicki L. Rolland, and Robert L. Thunen -- Entangling events : the Guale coastal landscape and the Spanish missions / Victor D. Thompson, John A. Turck, Amanda D. Roberts Thompson, and Chester B. DePratter -- Island and coastal archaeology on the Georgia Bight / Scott M. Fitzpatrick

The beads of St. Catherines Island. (Anthropological papers of the American Museum of Natural History, no. 89)

xi, 300 p. : ill. (some col.), col. map ; 26 cm. Issued April 1, 2009. Includes bibliographical references (p. 185-204).This volume examines the almost 70,000 individual beads recovered during extensive archaeological excavations on St. Catherines Island (Georgia)--primarily from Mission Santa Catalina de Guale. Founded in the 16th century, this site was the capital and administrative center of the province of Guale in Spanish Florida for the better part of a century. This volume describes and classifies this extraordinary bead assemblage, putting the entire collection into a worldwide perspective. Part I describes the global origins of beadmaking and provides an overview of previous studies of bead manufacture. Particular attention is paid to the beads of the Spanish colonial empire, the source of most trade beads recovered on the Island. Part II presents a history of archaeological research on St. Catherines Island, a long-term perspective of the aboriginal people who lived there, and the details of archaeological work at Mission Santa Catalina de Guale. It also presents a comprehensive catalog of the St. Catherines Island bead assemblage. Part III discusses the Santa Catalina bead assemblage from a global perspective, specifically examining presumed centers of origin and the diverse manufacturing techniques employed by various glassmaking guilds in Europe. Part IV concludes with a consideration of the bead assemblage within the cultural matrix of 16th- and 17th-century Mission Santa Catalina de Guale.Published by: American Museum of Natural history, New York, NY

Sexual Absorption of Vaginal Progesterone: A Randomized Control Trial

Objective. To determine if sexual intercourse reduces absorption of vaginal progesterone gel in women and to determine if progesterone is absorbed by the male during intercourse. Study Design. Prospective, randomized, cross over, controlled study of 20 reproductive-aged women and their male sexual partners randomized to receive vaginal progesterone gel (Crinone 8% gel, Actavis Inc., USA) or placebo cream. Serum progesterone for both male and female partners were measured 10 hours after intercourse. One week later, subjects were crossed over to receive the opposite formulation. In the third week, women used progesterone gel at night and abstained from intercourse. Results. Serum progesterone was significantly reduced with vaginal progesterone gel + intercourse compared with vaginal progesterone gel + abstinence (P=0.0075). Men absorbed significant progesterone during intercourse with a female partner using vaginal progesterone gel compared to placebo (P=0.0008). Conclusion(s). Vaginal progesterone gel is reduced in women after intercourse which may decrease drug efficacy during luteal phase support. Because men absorb low levels of progesterone during intercourse, exposure could cause adverse effects such as decreased libido. This study is registered under Clinical Trial number NCT01959464