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Large randomised trials provide the most reliable evidence of effectiveness of new treatments in clinical practice. However, the time and resources required to complete such trials can be daunting. An overarching clinical trial platform focused on a single condition or type of surgery, aiming to compare several treatments, with an option to stop any or add in new treatment options, can provide greater efficiency. This has the potential to accelerate knowledge acquisition and identify effective, ineffective, or harmful treatments faster. The master protocol of the platform defines the study population(s) and standardised procedures. Ineffective or harmful treatments can be discarded or study drug dose modified during the life cycle of the trial. Other adaptive elements that can be modified include eligibility criteria, required sample size for any comparison(s), randomisation assignment ratio, and the addition of other promising treatment options. There are excellent opportunities for anaesthetists to establish platform trials in perioperative medicine. Platform trials are highly efficient, with the potential to provide quicker answers to important clinical questions that lead to improved patient care.

Advances in radiology and imaging technologies and the emergent scope of practice have led to the capacity to provide services to a growing population of high-acuity patients with comorbid conditions. These procedures are often performed with the radiology nurse administering procedural sedation. Monitoring patients is challenging due to certain patient conditions and the unique environment, that is, the radiology procedure suite. The addition of capnography monitoring, along with standard monitoring, is a valuable modality that provides a continuous objective assessment of the patient's ventilatory status even when direct visualization of the patient is compromised. The purpose of this article is to provide clinical practice recommendations for the use of capnography by procedural sedation nurses outside the operating room setting.

Objective To assess the impact of multiple blastocyst biopsy and vitrification-warming procedures on clinical outcomes. Design Retrospective study. Setting Private fertility clinic. Patient(s) Preimplantation genetic diagnosis (PGD) patients undergoing comprehensive chromosome screening, including monogenic disorder and chromosome rearrangement cases. Intervention(s) Warming and transfer of euploid blastocysts biopsied and vitrified-warmed once (group 1 [G1, control]; n=2,130), biopsied once but vitrified-warmed twice (group 2 [G2]; n=34), or biopsied and vitrified-warmed twice (group 3 [G3]; n=29). Main Outcome Measure(s) Thaw (for transfer) survival rate and clinical pregnancy rate (CPR). Result(s) The thaw survival rates were 98.4% for G1, 97.3% for G2, and 93.3% for G3, with once biopsied and vitrified-warmed embryos being significantly higher than twice biopsied and vitrified-warmed embryos (G1 vs. G3; P =.032). There was a slight reduction in CPR with an additional vitrification-warming (G1 54.3% vs. G2 47.1%) and larger reduction with an additional embryo biopsy (G2 47.1% vs. G3 31.0%), but neither difference was statistically significant. However, the combined effect of both additional biopsy and vitrification-warming resulted in a significantly reduced CPR (G1 54.3% vs. G3 31.0%; P =.013). Conclusion(s) This study indicates that blastocysts biopsied and vitrified-warmed twice have reduced clinical outcomes compared with blastocysts biopsied and vitrified-warmed once. PGD patients should be advised that performing a second biopsy and vitrification-warming in cases of failure to obtain a result from initial biopsy will reduce the chance of pregnancy. Patients with inherited disorders may elect to proceed with the second biopsy and vitrification to avoid transfer of embryos with the genetic condition.

Summary Cancers from sun-exposed skin accumulate “driver” mutations, causally implicated in oncogenesis. Because errors incorporated during translesion synthesis (TLS) opposite UV lesions would generate these mutations, TLS mechanisms are presumed to underlie cancer development. To address the role of TLS in skin cancer formation, we determined which DNA polymerase is responsible for generating UV mutations, analyzed the relative contributions of error-free TLS by Polη and error-prone TLS by Polθ to the replication of UV-damaged DNA and to genome stability, and examined the incidence of UV-induced skin cancers in Polθ−/−, Polη−/−, and Polθ−/− Polη−/− mice. Our findings that the incidence of skin cancers rises in Polθ−/− mice and is further exacerbated in Polθ−/− Polη−/− mice compared with Polη−/− mice support the conclusion that error-prone TLS by Polθ provides a safeguard against tumorigenesis and suggest that cancer formation can ensue in the absence of somatic point mutations.

Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.

Emergency physicians come across a wide variety of painful conditions and perform a large number of uncomfortable procedures on a typical shift. This article describes the local anesthetic agents and their potential applications. The peripheral nerve blocks that are regularly done in the emergency department are described. Lastly, procedural sedation and analgesia are covered, to include general principles and specific agents for its use in the emergency department.

Developments at Sydney IVF in the successful culture of blastocysts, combined with day 5 or 6 blastocyst biopsy and blastocyst cryostorage after biopsy, permit up to five or six cells to be genetically tested, leaving the inner cell mass intact and enabling embryos to be electively transferred one at a time. These advantages can be obtained without diminishing the chance of pregnancy compared with cleavage-stage biopsy and testing.

We present palaeoenvironmental results from two cores, Winterton Holmes (GY2) and Somerton Holmes (GY3), south of Horsey, East Norfolk. The upper transgressive contact of the peat of cores GY2 and GY3 is dated to 2355–2742 cal. years bp and 2761–2949 cal. years bp, respectively. The litho- and biostratigraphical data show that both these peat contacts represent sea-level index points formed around mean high water spring tides during a positive tendency of sea-level movement, as saltmarsh indicators near the top of, and immediately above the peat show its deposition within intertidal environments. These sea-level index points when combined with other sea-level observations and predictions from East Norfolk, confirm an upward trend of Holocene relative sea-level change typical of an area at, or beyond, the margins of the last British ice sheet; rapid in the early Holocene then at a much reduced rate in the mid- and late Holocene. Late Holocene rates of relative uplift or subsidence are calculated for East Norfolk by subtracting a model of relative sea level from each index point and then calculating the best-fit linear trend. The late Holocene rate of relative sea-level rise (or land subsidence) is 0.67 ± 0.06 mm −1 which is c . 1 mm a −1 less than the twentieth-century mean sea-level trend estimated from Lowestoft tidal station, thus agreeing with the consensus of opinion that global sea levels have risen between 10 and 20 cm over the past century.

By the use of a mouse model, the enteropathic effects of the simian immunodeficiency virus (SIV) surface unit (SU) envelope glycoprotein were explored. Purified SU (0.01–0.45 nmol) was administered intraperitoneally to 6- to 8-day-old mouse pups and induced a dose-dependent diarrheal response. Surgical introduction of SU into adult mouse intestinal loops revealed fluid accumulation without histological alterations and SU-treated unstripped intestinal mucosa induced chloride (Cl − ) secretory currents in Ussing chambers. Similarly to rotavirus NSP4, the first described viral enterotoxin, SU induced a transient increase in intracellular calcium levels and increased inositol 1,4,5-triphosphate (IP 3 ) levels in HT-29 cells. These data indicate the calcium response is mediated by IP 3 . The presence of diarrhea and fluid accumulation within intestinal loops in the absence of histological alterations and induction of Cl − secretory currents demonstrate that SIV contains an enterotoxic domain localized within SU and is the second viral enterotoxin described.

The transdermal extraction of interstitial fluid by low‐frequency ultrasound offers a potential minimally invasive method of obtaining a fluid sample for at‐home blood glucose monitoring. Here we show that the application of low‐frequency ultrasound (20 kHz) enhances the transdermal transport of interstitial fluid across hairless rat skin. Using 3 H 2 O as a tracer injected intravenously, a measurable amount of water (>1 μL) was extracted without producing any histologic evidence of injury, even after repeated exposures. Piezoelectric transducers were imbedded in the extraction chamber and used to correlate ultrasound spectral properties to the amount of fluid extracted. Results indicate that the highest amount of water extracted occurs when the acoustic coupling media on the surface of the skin is cavitating, resulting in mild ablation of the stratum corneum and a reduction in its resistance to water mass transfer. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1170–1179, 2000

The rabbit model of rotavirus infection has proved to be useful for assessing active immunity and protection after infection or vaccination with virus or virus-like particles. One limitation of the rabbit model is that after experimental infection of rabbits, clinical diarrhea is not routinely induced. Lack of diarrhea in the rabbit model has been proposed to be due to the fluid absorptive capability of the cecum or attenuation of virus strains through tissue culture adaptation. To test whether a wild-type lapine rotavirus strain BAP (BAPwt) isolated from diarrheic rabbits would cause disease on passage in rabbits, 1-, 2-, 10-, and 16-week-old rabbits were orally inoculated with BAPwt, its tissue culture-adapted counterpart strain (BAP-2), tissue culture-adapted lapine strain ALA, or PBS. Lapine rotavirus infection in 1-week-old, but not ≥2-week-old, rabbits resulted in the development of disease characterized by soft, wet, yellow-to-brownish-green partially formed-to-liquid stools observed only at the time of virus antigen shedding. The level and duration of virus shedding after infection were prolonged in 1-week-old rabbits compared with rabbits ≥2 weeks of age. Although diarrhea was not observed beyond the first 2 weeks of life, histopathological changes, including villus shortening and fusion, increased vacuolation of epithelial cells, and mononuclear infiltration of the lamina propria, were observed throughout the small intestine between 12 and 120 h after ALA infection in 1-week-old, 1- to 2-month-old, and 11-month-old rabbits. In 11-month-old rabbits, onset of intestinal damage appeared to be slightly delayed, was less severe, and was not observed in the duodenum. There were no differences in the immune responses to rotavirus infection in rabbits of different age groups (1 week to 5 years of age). All lapine rotavirus-inoculated rabbits seroconverted and were protected from virus challenge at 28 days postinoculation. Like in mice, rotavirus disease is age restricted in rabbits.

The linearisation method and Robin's method of strain analysis of granular materials yield accurate strain estimates for a variety of materials deformed experimentally in pure shear. The breakdown of continuum behaviour at high pore fluid pressures causes the methods to overestimate the strain because they do not take added rigid-body rotation into account. Both methods tolerate some variation in initial shape ratio and some degree of initial preferred orientation at modest strains. Results of tests on polymict sandstone indicate that the lower than average ductility of competent clasts may be balanced against an unfavourable degree of preferred orientation to yield an improved strain estimate.

Rape is a violent act that inflicts injury on the very essence of the self. Reality therapy offers an applicable conceptual framework for the treatment of rape victims. Reality therapy groups minimize attention to the concept of mental illness. The warm, friendly atmosphere of the reality therapy group provides a supportive arena where the victim can tell her story, diminish her desire to withdraw from others, and recognize control over her behavior. Through her involvement she can begin to fulfill her needs to love and be loved, and feel worthwhile to herself and others.

Calcite grain aggregates, supported by a weaker, macroscopically ductile, matrix of set Portland cement, were deformed triaxially at room temperature with a confining pressure of 150 MPa and at rates corresponding to a pure shear, natural strain rate of 10−5 s−1. Extensive grain rotation accompanied the twinning of calcite. Stress orientations inside the specimens, determined from calcite twins, agree well with the stresses imposed upon the specimens. Thus calcite twins are sound kinematic indicators in this study. Various sample configurations were used to simulate pure shear, transpression and simple shear. In pure shear or coaxial strain, preferred dimensional orientations (PDO) of calcite are produced more efficiently in the presence of high pore fluid pressure. Those grain alignments are stronger than the bulk strain would predict assuming homogeneous strain. Strain is overestimated by methods assuming continuum behaviour because they fail to take into account the extensive interparticle motions that occur in the presence of high pore fluid pressure. Fluid pressure suppresses the twinning of calcite by reducing the intergranular stresses. During deformation, small rapid variations in pore fluid pressure are believed to represent ephemeral dilatations accompanying particulate flow as groups of grains slide past one another. In dry specimens, pure shear is more effective than simple shear in producing a PDO of the calcite grains. Calcite grains are rotated rigidly and somewhat strained to produce L At comparable strains in dry tests, e-twinning is best developed in transpression, next best developed in coaxial strain and least well shown by simple shear. High fluid pressure considerably reduces the incidence of twinning.

A task analysis survey was conducted in 1982 by the Certification Board of Infection Control (CBIC) to determine the tasks performed by ICPs and the knowledge and abilities needed to perform these tasks. Data were obtained from 473 (78.8%) respondents to a nationwide mail survey of 600 ICPs. The respondents represent a randomized, stratified sample of ICPs in various types of U.S. acute care hospitals ranging in size from fewer than 50 beds to more than 500 beds. The results of the survey were used, in part, to develop the Infection Control Certification Examination, offered for the first time on November 19, 1983. According to the survey results, the modal or typical ICP is a white woman between the ages of 31 and 50 years using the title of infection control nurse. She has been employed full time for 2 to 10 years in infection control practice in a Joint Commission on Accreditation of Hospitals (JCAH)-accredited community acute care hospital having 301 to 500 beds. She is working at the supervisory level, is on the nursing department payroll, votes as a member of the hospital's infection control committee, and received her last degree or diploma more than 15 years ago.

Respondents (N = 473) from a randomized stratified sample (N = 600) of U.S. hospital ICPs in a national survey sponsored by the Certification Board of Infection Control were asked to rate specific task, knowledge, and ability statements related to infection control for frequency and importance. The questions included 175 items, of which 99 were for specific tasks and 76 were for knowledge and abilities for practice. Areas covered included patient care practices, infectious diseases, epidemiology and statistics, microbiologic practices, sterilization and disinfection, education, employee health services, and management and communications. A “profile respondent” group (N = 317) was defined as persons most likely to be practicing the full scope of infection control practice and was used to identify key tasks, knowledge, and abilities for practice. Results showed that patient care practices (i.e., suctioning, dressing changes, and catheterization) were rarely performed. The development of infection control policies and procedures were key tasks. Knowledge of microbiology and infectious diseases in order to interpret laboratory reports and other patient data was rated as essential; however, few respondents actually performed laboratory procedures. Epidemiologic principles were frequently used for surveillance and problem investigation. Although presentation of epidemiologic data was rated as important, analytic statistics were rarely used. Assessment of educational needs and teaching were large components of ICPs' activities.

One aspect of the Certification Board of Infection Control's (CBIC) task analysis survey was to determine those tasks done most frequently and considered most important by ICPs. A randomized stratified sample of ICPs was taken from U.S. hospitals of various bed-size categories. There were 473 responses (78.8%) from a targeted sample of 600 ICPs. Statistical analyses were done to find if a relationship existed between hospital size and the tasks performed. The frequency of performance and importance of the majority of infection control tasks studied were found to vary in relation to hospital size. Some tasks were found to be both important and frequently performed by the majority of ICPs in all hospital bed-size categories. These included performing and reporting epidemiologic surveillance, educating personnel, developing infection control policies and procedures, and consulting with hospital personnel. Other tasks were found to be relatively less important and infrequently performed by the majority of ICPs in all hospital bed-size categories. These included performing bedside patient care procedures, recommending specific antimicrobial therapy, and using statistical methods. The greatest differences in the performance of tasks were found in the subsample of the ICPs from hospitals with ≤100 beds. (Am J INFECT CONTROL 12:221–227, 1984.)