The influence on survival of delay in the presentation and treatment of symptomatic breast cancer

The aim of this study was to examine the possible influence on survival of delays prior to presentation and/or treatment among women with breast cancer. Duration of symptoms prior to hospital referral was recorded for 2964 women who presented with any stage of breast cancer to Guy's Hospital between 1975 and 1990. Median follow-up is 12.5 years. The impact of delay (defined as having symptoms for 12 or more weeks) on survival was measured from the date of diagnosis and from the date when the patient first noticed symptoms to control for lead-time bias. Thirty-two per cent (942/2964) of patients had symptoms for 12 or more weeks before their first hospital visit and 32% (302/942) of patients with delays of 12 or more weeks had locally advanced or metastatic disease, compared with only 10% (210/2022) of those with delays of less than 12 weeks (P< 0.0001). Survival measured both from the date of diagnosis (P< 0.001) and from the onset of the patient's symptoms (P= 0.003) was worse among women with longer delays. Ten years after the onset of symptoms, survival was 52% for women with delays less than 12 weeks and 47% for those with longer delays. At 20 years the survival rates were 34% and 24% respectively. Furthermore, patients with delays of 12–26 weeks had significantly worse survival rates than those with delays of less than 12 weeks. Multivariate analyses indicated that the adverse impact of delay in presentation on survival was attributable to an association between longer delays and more advanced stage. However, within individual stages, longer delay had no adverse impact on survival. Analyses based on ‘total delay’ (i.e. the interval between a patient first noticing symptoms and starting treatment) yielded very similar results in terms of survival to those based on delay to first hospital visit (delay in presentation). © 1999 Cancer Research Campaig

Virologic Failures on Initial Boosted-PI Regimen Infrequently Possess Low-Level Variants with Major PI Resistance Mutations by Ultra-Deep Sequencing

It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects.To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen.Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights >12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r.Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, low-level variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping

Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype

BACKGROUND: MMTV-Wnt1 transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate FGF proto-oncogenes or remove the tumor suppressor genes Pten or P53, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to Wnt1-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in MMTV-Neu transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase. METHODS: cDNA or DNA from the mammary glands and mammary tumors from MMTV-Wnt1, MMTV-Wnt1/p53(-/-), MMTV-Neu transgenic mice, and newly generated MMTV-Wnt1/MMTV-Neu bitransgenic mice, was sequenced to seek activating mutations in H-Ras, K-Ras, and N-Ras genes, or in the MMTV-Neu transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype. RESULTS: We found activating mutations at codons 12, 13, and 61 of H-Ras in just over half of the mammary tumors in MMTV-Wnt1 transgenic mice, and we confirmed the high frequency of activating mutations of Neu in tumors in MMTV-Neu transgenic mice. Tumors appeared earlier in bitransgenic MMTV-Wnt1/MMTV-Neu mice, but no Ras or MMTV-Neu mutations were found in these tumors, which were phenotypically similar to those arising in MMTV-Wnt1 mice. In addition, no Ras mutations were found in the mammary tumors that arise in MMTV-Wnt1 transgenic mice lacking an intact P53 gene. CONCLUSIONS: Tumorigenic properties of cells undergoing functionally significant secondary mutations in H-Ras or the MMTV-Neu transgene allow selection of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype

Small-scale coexistence of two mouse lemur species (Microcebus berthae and M. murinus) within a homogeneous competitive environment

Understanding the co-occurrence of ecologically similar species remains a puzzling issue in community ecology. The species-rich mouse lemurs (Microcebus spec.) are distributed over nearly all remaining forest areas of Madagascar with a high variability in species distribution patterns. Locally, many congeneric species pairs seem to co-occur, but only little detailed information on spatial patterns is available. Here, we present the results of an intensive capture–mark–recapture study of sympatric Microcebus berthae and M. murinus populations that revealed small-scale mutual spatial exclusion. Nearest neighbour analysis indicated a spatial aggregation in Microcebus murinus but not in M. berthae. Although the diet of both species differed in proportions of food categories, they used the same food sources and had high feeding niche overlap. Also, forest structure related to the spatial distribution of main food sources did not explain spatial segregation because parts used by each species exclusively did not differ in density of trees, dead wood and lianas. We propose that life history trade-offs that result in species aggregation and a relative increase in the strength of intra-specific over inter-specific competition best explain the observed pattern of co-occurrence of ecologically similar congeneric Microcebus species

Impact of Empiric Antimicrobial Therapy on Outcomes in Patients with Escherichia coli and Klebsiella pneumoniae Bacteremia: A Cohort Study

<p>Abstract</p> <p>Background</p> <p>It is unclear whether appropriate empiric antimicrobial therapy improves outcomes in patients with bacteremia due to <it>Escherichia coli </it>or <it>Klebsiella</it>. The objective of this study is to assess the impact of appropriate empiric antimicrobial therapy on in-hospital mortality and post-infection length of stay in patients with <it>Escherichia coli </it>or <it>Klebsiella </it>bacteremia while adjusting for important confounding variables.</p> <p>Methods</p> <p>We performed a retrospective cohort study of adult patients with a positive blood culture for <it>E. coli </it>or <it>Klebsiella </it>between January 1, 2001 and June 8, 2005 and compared in-hospital mortality and post-infection length of stay between subjects who received appropriate and inappropriate empiric antimicrobial therapy. Empiric therapy was defined as the receipt of an antimicrobial agent between 8 hours before and 24 hours after the index blood culture was drawn and was considered appropriate if it included antimicrobials to which the specific isolate displayed <it>in vitro </it>susceptibility. Data were collected electronically and through chart review. Survival analysis was used to statistically assess the association between empiric antimicrobial therapy and outcome (mortality or length of stay). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).</p> <p>Results</p> <p>Among 416 episodes of bacteremia, 305 (73.3%) patients received appropriate empiric antimicrobial therapy. Seventy-one (17%) patients died before discharge from the hospital. The receipt of appropriate antimicrobial agents was more common in hospital survivors than in those who died (p = 0.04). After controlling for confounding variables, there was no association between the receipt of appropriate empiric antimicrobial therapy and in-hospital mortality (HR, 1.03; 95% CI, 0.60 to 1.78). The median post-infection length of stay was 7 days. The receipt of appropriate antimicrobial agents was not associated with shortened post-infection length of stay, even after controlling for confounding (HR, 1.11; 95% CI 0.86 to 1.44).</p> <p>Conclusion</p> <p>Appropriate empiric antimicrobial therapy for <it>E. coli </it>and <it>Klebsiella </it>bacteremia is not associated with lower in-hospital mortality or shortened post-infection length of stay. This suggests that the choice of empiric antimicrobial agents may not improve outcomes and also provides data to support a randomized trial to test the hypothesis that use (and overuse) of broad-spectrum antibiotics prior to the availability of culture results is not warranted.</p

Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009). From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27).Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications

A Topical Microbicide Gel Formulation of CCR5 Antagonist Maraviroc Prevents HIV-1 Vaginal Transmission in Humanized RAG-hu Mice

For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field

Stages of development and injury patterns in the early years: a population-based analysis

BACKGROUND: In Canada, there are many formal public health programs under development that aim to prevent injuries in the early years (e.g. 0–6). There are paradoxically no population-based studies that have examined patterns of injury by developmental stage among these young children. This represents a gap in the Canadian biomedical literature. The current population-based analysis explores external causes and consequences of injuries experienced by young children who present to the emergency department for assessment and treatment. This provides objective evidence about prevention priorities to be considered in anticipatory counseling and public health planning. METHODS: Four complete years of data (1999–2002; n = 5876 cases) were reviewed from the Kingston sites of the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP), an ongoing injury surveillance initiative. Epidemiological analyses were used to characterize injury patterns within and across age groups (0–6 years) that corresponded to normative developmental stages. RESULTS: The average annual rate of emergency department-attended childhood injury was 107 per 1000 (95% CI 91–123), with boys experiencing higher annual rates of injury than girls (122 vs. 91 per 1000; p < 0.05). External causes of injury changed substantially by developmental stage. This lead to the identification of four prevention priorities surrounding 1) the optimization of supervision; 2) limiting access to hazards; 3) protection from heights; and 4) anticipation of risks. CONCLUSION: This population-based injury surveillance analysis provides a strong evidence-base to inform and enhance anticipatory counseling and other public health efforts aimed at the prevention of childhood injury during the early years