Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.

Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.

Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.

Friston et al. (1995, NeuroImage 2:45-53) presented a method for detecting activations in fMRI time-series based on the general linear model and a heuristic analysis of the effective degrees of freedom. In this communication we present corrected results that replace those of the previous paper and solve the same problem without recourse to heuristic arguments. Specifically we introduce a proper and unbiased estimator for the error terms and provide a more generally correct expression for the effective degrees of freedom. The previous estimates of error variance were biased and, in some instances, could have led to a 10-20% overestimate of Z values. Although the previous results are almost correct for the random regressors chosen for validation, the present theoretical results are exact for any covariate or waveform. We comment on some aspects of experimental design and data analysis, in the light of the theoretical framework discussed here.

Molecular typing based on 12 loci containing variable numbers of tandem repeats of mycobacterial interspersed repetitive units (MIRU-VNTRs) has been adopted in combination with spoligotyping as the basis for large-scale, high-throughput genotyping of Mycobacterium tuberculosis. However, even the combination of these two methods is still less discriminatory than IS6110 fingerprinting. Here, we define an optimized set of MIRU-VNTR loci with a significantly higher discriminatory power. The resolution and the stability/robustness of 29 loci were analyzed, using a total of 824 tubercle bacillus isolates, including representatives of the main lineages identified worldwide so far. Five loci were excluded for lack of robustness and/or stability in serial isolates or isolates from epidemiologically linked patients. The use of the 24 remaining loci increased the number of types by 40%--and by 23% in combination with spoligotyping--among isolates from cosmopolitan origins, compared to those obtained with the original set of 12 loci. Consequently, the clustering rate was decreased by fourfold--by threefold in combination with spoligotyping--under the same conditions. A discriminatory subset of 15 loci with the highest evolutionary rates was then defined that concentrated 96% of the total resolution obtained with the full 24-locus set. Its predictive value for evaluating M. tuberculosis transmission was found to be equal to that of IS6110 restriction fragment length polymorphism typing, as shown in a companion population-based study. This 15-locus system is therefore proposed as the new standard for routine epidemiological discrimination of M. tuberculosis isolates and the 24-locus system as a high-resolution tool for phylogenetic studies.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Scientists working with large volumes of high-dimensional data, such as global climate patterns, stellar spectra, or human gene distributions, regularly confront the problem of dimensionality reduction: finding meaningful low-dimensional structures hidden in their high-dimensional observations. The human brain confronts the same problem in everyday perception, extracting from its high-dimensional sensory inputs-30,000 auditory nerve fibers or 10(6) optic nerve fibers-a manageably small number of perceptually relevant features. Here we describe an approach to solving dimensionality reduction problems that uses easily measured local metric information to learn the underlying global geometry of a data set. Unlike classical techniques such as principal component analysis (PCA) and multidimensional scaling (MDS), our approach is capable of discovering the nonlinear degrees of freedom that underlie complex natural observations, such as human handwriting or images of a face under different viewing conditions. In contrast to previous algorithms for nonlinear dimensionality reduction, ours efficiently computes a globally optimal solution, and, for an important class of data manifolds, is guaranteed to converge asymptotically to the true structure.

Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.

The SWISS-PROT protein sequence data bank contains at present nearly 75,000 entries, almost two thirds of which include the potential N-glycosylation consensus sequence, or sequon, NXS/T (where X can be any amino acid but proline) and thus may be glycoproteins. The number of proteins filed as glycoproteins is however considerably smaller, 7942, of which 749 have been characterized with respect to the total number of their carbohydrate units and sites of attachment of the latter to the protein, as well as the nature of the carbohydrate-peptide linking group. Of these well characterized glycoproteins, about 90% carry either N-linked carbohydrate units alone or both N- and O-linked ones, attached at 1297 N-glycosylation sites (1.9 per glycoprotein molecule) and the rest are O-glycosylated only. Since the total number of sequons in the well characterized glycoproteins is 1968, their rate of occupancy is 2/3. Assuming that the same number of N-linked units and rate of sequon occupancy occur in all sequon containing proteins and that the proportion of solely O-glycosylated proteins (ca. 10%) will also be the same as among the well characterized ones, we conclude that the majority of sequon containing proteins will be found to be glycosylated and that more than half of all proteins are glycoproteins.

The most recent national data on obesity prevalence among U.S. adults, adolescents, and children show that more than one-third of adults and almost 17% of children and adolescents were obese in 2009–2010. Differences in prevalence between men and women diminished between 1999–2000 and 2009–2010, with the prevalence of obesity among men reaching the same level as that among women. Age differences in obesity prevalence varied between men and women. The prevalence of obesity was higher among older women compared with younger women, but there was no difference by age in obesity prevalence among men. Among children and adolescents, the prevalence of obesity was higher among adolescents than among preschool-aged children. There has been no change in obesity prevalence in recent years; however, over the last decade there has been a significant increase in obesity prevalence among men and boys but not among women and girls overall. The Healthy People 2010 goals of 15% obesity among adults and 5% obesity among children were not met (6).

Wolbachia are maternally inherited intracellular bacterial symbionts that are estimated to infect more than 60% of all insect species. While Wolbachia is commonly found in many mosquitoes it is absent from the species that are considered to be of major importance for the transmission of human pathogens. The successful introduction of a life-shortening strain of Wolbachia into the dengue vector Aedes aegypti that halves adult lifespan has recently been reported. Here we show that this same Wolbachia infection also directly inhibits the ability of a range of pathogens to infect this mosquito species. The effect is Wolbachia strain specific and relates to Wolbachia priming of the mosquito innate immune system and potentially competition for limiting cellular resources required for pathogen replication. We suggest that this Wolbachia-mediated pathogen interference may work synergistically with the life-shortening strategy proposed previously to provide a powerful approach for the control of insect transmitted diseases.

[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.

Recent advances in magnetic resonance imaging (MRI) technology now allow the tracing of developmental changes in the brains of children. We applied computer-matching algorithms and new techniques for measuring cortical thickness (in millimeters) to the structural MRI images of 45 children scanned twice (2 yr apart) between the ages 5 and 11. Changes in brain size were also assessed, showing local brain growth progressing at a rate of approximately 0.4-1.5 mm per year, most prominently in frontal and occipital regions. Estimated cortical thickness ranged from 1.5 mm in occipital regions to 5.5 mm in dorsomedial frontal cortex. Gray matter thinning coupled with cortical expansion was highly significant in right frontal and bilateral parieto-occipital regions. Significant thickening was restricted to left inferior frontal (Broca's area) and bilateral posterior perisylvian (Wernicke's area on the left) regions. In the left hemisphere, gray matter thickness was correlated with changing cognitive abilities. For the first time, developmental changes in gray matter thickness, brain size, and structure-function relationships have been traced within the same individuals studied longitudinally during a time of rapid cognitive development.

Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.

Multiwfn is a multifunctional program for wavefunction analysis. Its main functions are: (1) Calculating and visualizing real space function, such as electrostatic potential and electron localization function at point, in a line, in a plane or in a spatial scope. (2) Population analysis. (3) Bond order analysis. (4) Orbital composition analysis. (5) Plot density-of-states and spectrum. (6) Topology analysis for electron density. Some other useful utilities involved in quantum chemistry studies are also provided. The built-in graph module enables the results of wavefunction analysis to be plotted directly or exported to high-quality graphic file. The program interface is very user-friendly and suitable for both research and teaching purpose. The code of Multiwfn is substantially optimized and parallelized. Its efficiency is demonstrated to be significantly higher than related programs with the same functions. Five practical examples involving a wide variety of systems and analysis methods are given to illustrate the usefulness of Multiwfn. The program is free of charge and open-source. Its precompiled file and source codes are available from http://multiwfn.codeplex.com.

In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.

BACKGROUND

Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.

METHODS

In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.

RESULTS

1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).

CONCLUSIONS

Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.

BACKGROUND

Amgen.

EXECUTIVE SUMMARY The "Guideline for Prevention of Surgical Site Infection, 1999" presents the Centers for Disease Control and Prevention (CDC)'s recommendations for the prevention of surgical site infections (SSIs), formerly called surgical wound infections. This two-part guideline updates and replaces previous guidelines.1,2 Part I, "Surgical Site Infection: An Overview," describes the epidemiology, definitions, microbiology, pathogenesis, and surveillance of SSIs. Included is a detailed discussion of the pre-, intra-, and postoperative issues relevant to SSI genesis. Part II, "Recommendations for Prevention of Surgical Site Infection," represents the consensus of the Hospital Infection Control Practices Advisory Committee (HICPAC) regarding strategies for the prevention of SSIs.3 Whenever possible, the recommendations in Part II are based on data from well-designed scientific studies. However, there are a limited number of studies that clearly validate risk factors and prevention measures for SSI. By necessity, available studies have often been conducted in narrowly defined patient populations or for specific kinds of operations, making generalization of their findings to all specialties and types of operations potentially problematic. This is especially true regarding the implementation of SSI prevention measures. Finally, some of the infection control practices routinely used by surgical teams cannot be rigorously studied for ethical or logistical reasons (e.g., wearing vs not wearing gloves). Thus, some of the recommendations in Part II are based on a strong theoretical rationale and suggestive evidence in the absence of confirmatory scientific knowledge.It has been estimated that approximately 75% of all operations in the United States will be performed in "ambulatory," "same-day," or "outpatient" operating rooms by the turn of the century.4 In recommending various SSI prevention methods, this document makes no distinction between surgical care delivered in such settings and that provided in conventional inpatient operating rooms. This document is primarily intended for use by surgeons, operating room nurses, postoperative inpatient and clinic nurses, infection control professionals, anesthesiologists, healthcare epidemiologists, and other personnel directly responsible for the prevention of nosocomial infections. This document does not: Specifically address issues unique to burns, trauma, transplant procedures, or transmission of bloodborne pathogens from healthcare worker to patient, nor does it specifically address details of SSI prevention in pediatric surgical practice. It has been recently shown in a multicenter study of pediatric surgical patients that characteristics related to the operations are more important than those related to the physiologic status of the patients.5 In general, all SSI prevention measures effective in adult surgical care are indicated in pediatric surgical care. Specifically address procedures performed outside of the operating room (e.g., endoscopic procedures), nor does it provide guidance for infection prevention for invasive procedures such as cardiac catheterization or interventional radiology. Nonetheless, it is likely that many SSI prevention strategies also could be applied or adapted to reduce infectious complications associated with these procedures. Specifically recommend SSI prevention methods unique to minimally invasive operations (i.e., laparoscopic surgery). Available SSI surveillance data indicate that laparoscopic operations generally have a lower or comparable SSI risk when contrasted to open operations.6-11 SSI prevention measures applicable in open operations (e.g., open cholecystectomy) are indicated for their laparoscopic counterparts (e.g., laparoscopic cholecystectomy). Recommend specific antiseptic agents for patient preoperative skin preparations or for healthcare worker hand/forearm antisepsis. Hospitals should choose from products recommended for these activitie

OBJECTIVE

To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment.

METHODS

Multicenter, randomized clinical trial.

METHODS

Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial.

METHODS

At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment.

METHODS

Mean change in visual acuity.

RESULTS

Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P>> 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF).

CONCLUSIONS

Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

To establish a more appropriate animal recipient for xenotransplantation, NOD/SCID/gamma(c)(null) mice double homozygous for the severe combined immunodeficiency (SCID) mutation and interleukin-2Rgamma (IL-2Rgamma) allelic mutation (gamma(c)(null)) were generated by 8 backcross matings of C57BL/6J-gamma(c)(null) mice and NOD/Shi-scid mice. When human CD34+ cells from umbilical cord blood were transplanted into this strain, the engraftment rate in the peripheral circulation, spleen, and bone marrow were significantly higher than that in NOD/Shi-scid mice treated with anti-asialo GM1 antibody or in the beta2-microglobulin-deficient NOD/LtSz-scid (NOD/SCID/beta2m(null)) mice, which were as completely defective in NK cell activity as NOD/SCID/gamma(c)(null) mice. The same high engraftment rate of human mature cells was observed in ascites when peripheral blood mononuclear cells were intraperitoneally transferred. In addition to the high engraftment rate, multilineage cell differentiation was also observed. Further, even 1 x 10(2) CD34+ cells could grow and differentiate in this strain. These results suggest that NOD/SCID/gamma(c)(null) mice were superior animal recipients for xenotransplantation and were especially valuable for human stem cell assay. To elucidate the mechanisms involved in the superior engraftment rate in NOD/SCID/gamma(c)(null) mice, cytokine production of spleen cells stimulated with Listeria monocytogenes antigens was compared among these 3 strains of mice. The interferon-gamma production from dendritic cells from the NOD/SCID/gamma(c)(null) mouse spleen was significantly suppressed in comparison with findings in 2 other strains of mice. It is suggested that multiple immunological dysfunctions, including cytokine production capability, in addition to functional incompetence of T, B, and NK cells, may lead to the high engraftment levels of xenograft in NOD/SCID/gamma(c)(null) mice.

In late summer 1999, an outbreak of human encephalitis occurred in the northeastern United States that was concurrent with extensive mortality in crows (Corvus species) as well as the deaths of several exotic birds at a zoological park in the same area. Complete genome sequencing of a flavivirus isolated from the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes amplified from several other species including mosquitoes and two fatal human cases, revealed that West Nile (WN) virus circulated in natural transmission cycles and was responsible for the human disease. Antigenic mapping with E-glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic analysis confirmed these viruses as WN. This North American WN virus was most closely related to a WN virus isolated from a dead goose in Israel in 1998.

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often, initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

BACKGROUND

Adverse drug events (ADEs) are a significant and costly cause of injury during hospitalization.

OBJECTIVE

To evaluate the efficacy of 2 interventions for preventing nonintercepted serious medication errors, defined as those that either resulted in or had potential to result in an ADE and were not intercepted before reaching the patient.

METHODS

Before-after comparison between phase 1 (baseline) and phase 2 (after intervention was implemented) and, within phase 2, a randomized comparison between physician computer order entry (POE) and the combination of POE plus a team intervention.

METHODS

Large tertiary care hospital.

METHODS

For the comparison of phase 1 and 2, all patients admitted to a stratified random sample of 6 medical and surgical units in a tertiary care hospital over a 6-month period, and for the randomized comparison during phase 2, all patients admitted to the same units and 2 randomly selected additional units over a subsequent 9-month period.

METHODS

A physician computer order entry system (POE) for all units and a team-based intervention that included changing the role of pharmacists, implemented for half the units.

METHODS

Nonintercepted serious medication errors.

RESULTS

Comparing identical units between phases 1 and 2, nonintercepted serious medication errors decreased 55%, from 10.7 events per 1000 patient-days to 4.86 events per 1000 (P=.01). The decline occurred for all stages of the medication-use process. Preventable ADEs declined 17% from 4.69 to 3.88 (P=.37), while nonintercepted potential ADEs declined 84% from 5.99 to 0.98 per 1000 patient-days (P=.002). When POE-only was compared with the POE plus team intervention combined, the team intervention conferred no additional benefit over POE.

CONCLUSIONS

Physician computer order entry decreased the rate of nonintercepted serious medication errors by more than half, although this decrease was larger for potential ADEs than for errors that actually resulted in an ADE.

Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-alpha messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-alpha production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-alpha therapies.