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[ { "docid": "31715818", "title": "New opportunities: the use of nanotechnologies to manipulate and track stem cells.", "text": "Nanotechnologies are emerging platforms that could be useful in measuring, understanding, and manipulating stem cells. Examples include magnetic nanoparticles and quantum dots for stem cell labeling and in vivo tracking; nanoparticles, carbon nanotubes, and polyplexes for the intracellular delivery of genes/oligonucleotides and protein/peptides; and engineered nanometer-scale scaffolds for stem cell differentiation and transplantation. This review examines the use of nanotechnologies for stem cell tracking, differentiation, and transplantation. We further discuss their utility and the potential concerns regarding their cytotoxicity." } ]

[ { "docid": "10608397", "title": "High-performance neuroprosthetic control by an individual with tetraplegia.", "text": "BACKGROUND Paralysis or amputation of an arm results in the loss of the ability to orient the hand and grasp, manipulate, and carry objects, functions that are essential for activities of daily living. Brain-machine interfaces could provide a solution to restoring many of these lost functions. We therefore tested whether an individual with tetraplegia could rapidly achieve neurological control of a high-performance prosthetic limb using this type of an interface. \n METHODS We implanted two 96-channel intracortical microelectrodes in the motor cortex of a 52-year-old individual with tetraplegia. Brain-machine-interface training was done for 13 weeks with the goal of controlling an anthropomorphic prosthetic limb with seven degrees of freedom (three-dimensional translation, three-dimensional orientation, one-dimensional grasping). The participant's ability to control the prosthetic limb was assessed with clinical measures of upper limb function. This study is registered with ClinicalTrials.gov, NCT01364480. \n FINDINGS The participant was able to move the prosthetic limb freely in the three-dimensional workspace on the second day of training. After 13 weeks, robust seven-dimensional movements were performed routinely. Mean success rate on target-based reaching tasks was 91·6% (SD 4·4) versus median chance level 6·2% (95% CI 2·0-15·3). Improvements were seen in completion time (decreased from a mean of 148 s [SD 60] to 112 s [6]) and path efficiency (increased from 0·30 [0·04] to 0·38 [0·02]). The participant was also able to use the prosthetic limb to do skilful and coordinated reach and grasp movements that resulted in clinically significant gains in tests of upper limb function. No adverse events were reported. \n INTERPRETATION With continued development of neuroprosthetic limbs, individuals with long-term paralysis could recover the natural and intuitive command signals for hand placement, orientation, and reaching, allowing them to perform activities of daily living. \n FUNDING Defense Advanced Research Projects Agency, National Institutes of Health, Department of Veterans Affairs, and UPMC Rehabilitation Institute." }, { "docid": "14827874", "title": "0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(3):760–771 Printed in U.S.A. Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-1923 REVIEW: Aromatase Inhibitors for Ovulation Induction", "text": "CONTEXT For the last 40 yr, the first line of treatment for anovulation in infertile women has been clomiphene citrate (CC). CC is a safe, effective oral agent but is known to have relatively common antiestrogenic endometrial and cervical mucous side effects that could prevent pregnancy in the face of successful ovulation. In addition, there is a significant risk of multiple pregnancy with CC, compared with natural cycles. Because of these problems, we proposed the concept of aromatase inhibition as a new method of ovulation induction that could avoid many of the adverse effects of CC. The objective of this review was to describe the different physiological mechanisms of action for CC and aromatase inhibitors (AIs) and compare studies of efficacy for both agents for ovulation induction. EVIDENCE ACQUISITION We conducted a systematic review of all the published studies, both controlled and noncontrolled, comparing CC and AI treatment, either alone or in combination with gonadotropins, for ovulation induction or augmentation, identified through the Entrez-PubMed search engine. EVIDENCE SYNTHESIS Because of the recent acceptance of the concept of using AIs for ovulation induction, few controlled studies were identified, and the rest of the studies were pilot or preliminary comparisons. Based on these studies, it appears that AIs are as effective as CC in inducing ovulation, are devoid of any antiestrogenic side effects, result in lower serum estrogen concentrations, and are associated with good pregnancy rates with a lower incidence of multiple pregnancy than CC. When combined with gonadotropins for assisted reproductive technologies, AIs reduce the dose of FSH required for optimal follicle recruitment and improve the response to FSH in poor responders. \n CONCLUSIONS Preliminary evidence suggests that AIs may replace CC in the future because of similar efficacy with a reduced side effect profile. Although worldwide experience with AIs for ovulation induction is increasing, at present, definitive studies in the form of randomized controlled trials comparing CC with AIs are lacking." }, { "docid": "26071782", "title": "Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control of apoptosis", "text": "Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein–Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation." }, { "docid": "195680777", "title": "Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.", "text": "BACKGROUND Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. \n METHODS We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. \n FINDINGS In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. \n INTERPRETATION 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. \n FUNDING Cancer Research UK; British Heart Foundation; UK Medical Research Council." }, { "docid": "95764370", "title": "Modification in the chemical bath deposition apparatus, growth and characterization of CdS semiconducting thin films for photovoltaic applications", "text": "Abstract In this paper, growth and characterization of CdS thin films by Chemical Bath Deposition (CBD) technique using the reaction between CdCl 2 , (NH 2 ) 2 CS and NH 3 in an aqueous solution has been reported. The parameters actively involved in the process of deposition have been identified. A commonly available CBD system has been sucessfully modified to obtain the precious control over the pH of the solution at 90°C during the deposition and studies have been made to understand the fundamental parameters like concentrations of the solution, pH and temperature of the solution involved in the chemical bath deposition of CdS. It is confirmed that the pH of the solution plays a vital role in the quality of the CBD–CdS films. Structural, optical and electrical properties have been analysed for the as-deposited and annealed films. XRD studies on the CBD–CdS films reveal that the change in Cadmium ion concentration in the bath results in the change in crystallization from cubic phase with (1 1 1) predominant orientation to a hexagonal phase with (0 0 2) predominant orientation. The structural changes due to varying cadmium ion concentration in the bath affects the optical and electrical properties. Optimum electrical resistivity, band gap and refractive index value are observed for the annealed films deposited from 0.8 M cadmium ion concentration. The films are suitable for solar cell fabrication. Further on, annealing the samples at 350°C in H 2 for 30 min resulted in an increased diffraction intensity as well as shifts in the peak towards lower scattering angles due to enlarged CdS unit cell. This in turn brought about an increase in the lattice parameters and narrowing in the band-gap values. The results are compared with the analysis of previous work." }, { "docid": "34386619", "title": "The first gene of the Bacillus subtilis clpC operon, ctsR, encodes a negative regulator of its own operon and other class III heat shock genes.", "text": "The Bacillus subtilis clpC operon is regulated by two stress induction pathways relying on either sigmaB or a class III stress induction mechanism acting at a sigmaA-like promoter. When the clpC operon was placed under the control of the isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible Pspac promoter, dramatic repression of the natural clpC promoters fused to a lacZ reporter gene was noticed after IPTG induction. This result strongly indicated negative regulation of the clpC operon by one of its gene products. Indeed, the negative regulator could be identified which is encoded by the first gene of the clpC operon, ctsR, containing a predicted helix-turn-helix DNA-binding motif. Deletion of ctsR abolished the negative regulation and resulted in high expression of both the clpC operon and the clpP gene under nonstressed conditions. Nevertheless, a further increase in clpC and clpP mRNA levels was observed after heat shock, even in the absence of sigmaB, suggesting a second induction mechanism at the vegetative promoter. Two-dimensional gel analysis and mRNA studies showed that the expression of other class III stress genes was at least partially influenced by the ctsR deletion. Studies with different clpC promoter fragments either fused to the reporter gene bgaB or used in gel mobility shift experiments with the purified CtsR protein revealed a possible target region where the repressor seemed to bind in vivo and in vitro. Our data demonstrate that the CtsR protein acts as a global repressor of the clpC operon, as well as other class III heat shock genes, by preventing unstressed transcription from either the sigmaB- or sigmaA-dependent promoter and might be inactivated or dissociate under inducing stress conditions." }, { "docid": "43385013", "title": "Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties.", "text": "It has been proposed that epithelial-mesenchymal transition (EMT) in mammary epithelial cells and breast cancer cells generates stem cell features, and that the presence of EMT characteristics in claudin-low breast tumors reveals their origin in basal stem cells. It remains to be determined, however, whether EMT is an inherent property of normal basal stem cells, and if the presence of a mesenchymal-like phenotype is required for the maintenance of all their stem cell properties. We used nontumorigenic basal cell lines as models of normal stem cells/progenitors and demonstrate that these cell lines contain an epithelial subpopulation (\"EpCAM+,\" epithelial cell adhesion molecule positive [EpCAM(pos)]/CD49f(high)) that spontaneously generates mesenchymal-like cells (\"Fibros,\" EpCAM(neg)/CD49f(med/low)) through EMT. Importantly, stem cell/progenitor properties such as regenerative potential, high aldehyde dehydrogenase 1 activity, and formation of three-dimensional acini-like structures predominantly reside within EpCAM+ cells, while Fibros exhibit invasive behavior and mammosphere-forming ability. A gene expression profiling meta-analysis established that EpCAM+ cells show a luminal progenitor-like expression pattern, while Fibros most closely resemble stromal fibroblasts but not stem cells. Moreover, Fibros exhibit partial myoepithelial traits and strong similarities with claudin-low breast cancer cells. Finally, we demonstrate that Slug and Zeb1 EMT-inducers control the progenitor and mesenchymal-like phenotype in EpCAM+ cells and Fibros, respectively, by inhibiting luminal differentiation. In conclusion, nontumorigenic basal cell lines have intrinsic capacity for EMT, but a mesenchymal-like phenotype does not correlate with the acquisition of global stem cell/progenitor features. Based on our findings, we propose that EMT in normal basal cells and claudin-low breast cancers reflects aberrant/incomplete myoepithelial differentiation." }, { "docid": "21257564", "title": "How long will long-term potentiation last?", "text": "The paramount feature of long-term potentiation (LTP) as a memory mechanism is its characteristic persistence over time. Although the basic phenomenology of LTP persistence was established 30 years ago, new insights have emerged recently about the extent of LTP persistence and its regulation by activity and experience. Thus, it is now evident that LTP, at least in the dentate gyrus, can either be decremental, lasting from hours to weeks, or stable, lasting months or longer. Although mechanisms engaged during the induction of LTP regulate its subsequent persistence, the maintenance of LTP is also governed by activity patterns post-induction, whether induced experimentally or generated by experience. These new findings establish dentate gyrus LTP as a useful model system for studying the mechanisms governing the induction, maintenance and interference with long-term memory, including very long-term memory lasting months or longer. The challenge is to study LTP persistence in other brain areas, and to relate, if possible, the properties and regulation of LTP maintenance to these same properties of the information that is actually stored in those regions." }, { "docid": "1191830", "title": "2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.", "text": "OBJECTIVE The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. \n METHODS A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'. \n RESULTS In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1). \n CONCLUSION This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'." }, { "docid": "6550579", "title": "A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.", "text": "Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling." }, { "docid": "40212412", "title": "Periosteal bone formation--a neglected determinant of bone strength.", "text": "Life forms that have low body mass can hunt for food on the undersurface of branches or along shear cliff faces quite unperturbed by gravity. For larger animals, the hunt for dinner and the struggle to avoid becoming someone else's meal require rapid movement against gravity. This need is met by the lever function of long bones, three-dimensional masterpieces of biomechanical engineering that, by their material composition and structural design, achieve the contradictory properties of stiffness and flexibility, strength and lightness.1 Material stiffness results from the encrusting of the triple-helical structure of collagen type I with hydroxyapatite crystals, which confers . . ." }, { "docid": "13231899", "title": "In situ regulation of DC subsets and T cells mediates tumor regression in mice.", "text": "Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recent studies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal, and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12, all correlated strongly with the magnitude of protective antitumor immunity and the generation of potent CD8(+) CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasive tumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic antitumor responses and provide a template for future vaccine design." }, { "docid": "27049238", "title": "Large deformation of red blood cell ghosts in a simple shear flow.", "text": "Red blood cells are known to change shape in response to local flow conditions. Deformability affects red blood cell physiological function and the hydrodynamic properties of blood. The immersed boundary method is used to simulate three-dimensional membrane-fluid flow interactions for cells with the same internal and external fluid viscosities. The method has been validated for small deformations of an initially spherical capsule in simple shear flow for both neo-Hookean and the Evans-Skalak membrane models. Initially oblate spheroidal capsules are simulated and it is shown that the red blood cell membrane exhibits asymptotic behavior as the ratio of the dilation modulus to the extensional modulus is increased and a good approximation of local area conservation is obtained. Tank treading behavior is observed and its period calculated." }, { "docid": "121581019", "title": "Electrical, optical, and structural properties of indium-tin-oxide thin films for organic light-emitting devices", "text": "High-quality indium–tin–oxide (ITO) thin films (200–850 nm) have been grown by pulsed laser deposition (PLD) on glass substrates without a postdeposition annealing treatment. The structural, electrical, and optical properties of these films have been investigated as a function of target composition, substrate deposition temperature, background gas pressure, and film thickness. Films were deposited from various target compositions ranging from 0 to 15 wt % of SnO2 content. The optimum target composition for high conductivity was 5 wt % SnO2+95 wt % In2O3. Films were deposited at substrate temperatures ranging from room temperature to 300 °C in O2 partial pressures ranging from 1 to 100 mTorr. Films were deposited using a KrF excimer laser (248 nm, 30 ns full width at half maximum) at a fluence of 2 J/cm2. For a 150-nm-thick ITO film grown at room temperature in an oxygen pressure of 10 mTorr, the resistivity was 4×10−4 Ω cm and the average transmission in the visible range (400–700 nm) was 85%. For a 170-n..." }, { "docid": "18953920", "title": "The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells", "text": "The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We here report that the induction of an EMT in immortalized human mammary epithelial cells (HMLEs) results in the acquisition of mesenchymal traits and in the expression of stem-cell markers. Furthermore, we show that those cells have an increased ability to form mammospheres, a property associated with mammary epithelial stem cells. Independent of this, stem cell-like cells isolated from HMLE cultures form mammospheres and express markers similar to those of HMLEs that have undergone an EMT. Moreover, stem-like cells isolated either from mouse or human mammary glands or mammary carcinomas express EMT markers. Finally, transformed human mammary epithelial cells that have undergone an EMT form mammospheres, soft agar colonies, and tumors more efficiently. These findings illustrate a direct link between the EMT and the gain of epithelial stem cell properties." }, { "docid": "7581911", "title": "Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs.", "text": "Human and mouse embryonic stem cells (ESCs) are derived from blastocyst-stage embryos but have very different biological properties, and molecular analyses suggest that the pluripotent state of human ESCs isolated so far corresponds to that of mouse-derived epiblast stem cells (EpiSCs). Here we rewire the identity of conventional human ESCs into a more immature state that extensively shares defining features with pluripotent mouse ESCs. This was achieved by ectopic induction of Oct4, Klf4, and Klf2 factors combined with LIF and inhibitors of glycogen synthase kinase 3beta (GSK3beta) and mitogen-activated protein kinase (ERK1/2) pathway. Forskolin, a protein kinase A pathway agonist which can induce Klf4 and Klf2 expression, transiently substitutes for the requirement for ectopic transgene expression. In contrast to conventional human ESCs, these epigenetically converted cells have growth properties, an X-chromosome activation state (XaXa), a gene expression profile, and a signaling pathway dependence that are highly similar to those of mouse ESCs. Finally, the same growth conditions allow the derivation of human induced pluripotent stem (iPS) cells with similar properties as mouse iPS cells. The generation of validated \"naïve\" human ESCs will allow the molecular dissection of a previously undefined pluripotent state in humans and may open up new opportunities for patient-specific, disease-relevant research." }, { "docid": "1156322", "title": "Collagen/Polypropylene composite mesh biocompatibility in abdominal wall reconstruction.", "text": "BACKGROUND Intraperitoneal placement of polypropylene mesh leads to extensive visceral adhesions and is contraindicated. Different coatings are used to improve polypropylene mesh properties. Collagen is a protein with unique biocompatibility and cell ingrowth enhancement potential. A novel acetic acid extracted collagen coating was developed to allow placement of polypropylene mesh in direct contact with viscera. The authors' aim was to evaluate the long-term influence of acetic acid extracted collagen coating on surgical aspects and biomechanical properties of polypropylene mesh implanted in direct contact with viscera, including complications, adhesions with viscera, strength of incorporation, and microscopic inflammatory reaction. \n METHODS Forty adult Wistar rats were divided into two groups: experimental (polypropylene mesh/acetic acid extracted collagen coating) and control (polypropylene mesh only). Astandardized procedure of mesh implantation was performed. Animals were killed 3 months after surgery and analyzed for complications, mesh area covered by adhesions, type of adhesions, strength of incorporation, and intensity of inflammatory response. \n RESULTS The mean adhesion area was lower for polypropylene mesh/acetic acid extracted collagen coating (14.5 percent versus 69.9 percent, p < 0.001). Adhesion severity was decreased in the experimental group: grades 0 and 1 were more frequent (p < 0.04 and p < 0.002, respectively) and grade 3 was less frequent (p < 0.0001). An association between adhesion area and severity was found (p < 0.0001). Complications, strength of incorporation, and intensity of inflammatory response to the mesh were similar. \n CONCLUSIONS Visceral adhesions to polypropylene mesh are significantly reduced because of acetic acid extracted collagen coating. The collagen coating does not increase complications or induce alterations of polypropylene mesh incorporation." }, { "docid": "26731863", "title": "Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction.", "text": "Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity. Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection. In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered. Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested. In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7. These results demonstrate the essential and distinct roles of thetwo factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response." }, { "docid": "19961177", "title": "Mortality from causes amenable and non-amenable to medical care: the experience of eastern Europe.", "text": "OBJECTIVE To investigate comparative national trends in mortality from conditions amenable to timely, appropriate medical care and from those considered not to be amenable to such care. \n DESIGN Analysis of trends in direct age standardised mortality from the 1950s to 1987. \n SETTING Four eastern European nations (Hungary, Czechoslovakia, Poland, the German Democratic Republic) and two western European (the Federal Republic of Germany and England and Wales) and two North American nations (United States and Canada). SUBJECTS The total populations of the relevant countries during the period examined. \n MAIN OUTCOME MEASURES Proportional changes over time in age standardised mortality. Mortality from amenable and non-amenable causes was restricted to the age group 0-64. \n RESULTS A divergence in the trends for all cause mortality between eastern Europe and the western nations occurred in about 1970, when the rates in western countries steadily declined but those in eastern Europe remained fairly static. In the age group 0-64 mortality from causes considered amenable to medical care fell less quickly in eastern Europe than in the West, particularly after 1970. In the same age group, mortality from non-amenable causes rose in eastern European countries from the late 1960s compared with substantial declines in such mortality in the West. \n CONCLUSIONS Non-amenable causes of death seem to be the principal, but not exclusive, reason for lack of improvement in trends in all cause mortality in eastern Europe from 1970. The agenda for action in eastern Europe should give priority to a healthier lifestyle and improvement of the environment though not neglect enhancements in the quality and efficiency of direct health services." }, { "docid": "3770726", "title": "Microfluidic platform to evaluate migration of cells from patients with DYT1 dystonia.", "text": "BACKGROUND Microfluidic platforms for quantitative evaluation of cell biologic processes allow low cost and time efficient research studies of biological and pathological events, such as monitoring cell migration by real-time imaging. In healthy and disease states, cell migration is crucial in development and wound healing, as well as to maintain the body's homeostasis. NEW METHOD The microfluidic chambers allow precise measurements to investigate whether fibroblasts carrying a mutation in the TOR1A gene, underlying the hereditary neurologic disease--DYT1 dystonia, have decreased migration properties when compared to control cells. \n RESULTS We observed that fibroblasts from DYT1 patients showed abnormalities in basic features of cell migration, such as reduced velocity and persistence of movement. COMPARISON WITH EXISTING METHOD The microfluidic method enabled us to demonstrate reduced polarization of the nucleus and abnormal orientation of nuclei and Golgi inside the moving DYT1 patient cells compared to control cells, as well as vectorial movement of single cells. \n CONCLUSION We report here different assays useful in determining various parameters of cell migration in DYT1 patient cells as a consequence of the TOR1A gene mutation, including a microfluidic platform, which provides a means to evaluate real-time vectorial movement with single cell resolution in a three-dimensional environment." } ]

[ { "docid": "13734012", "title": "Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey", "text": "OBJECTIVES To carry out a further survey of archived appendix samples to understand better the differences between existing estimates of the prevalence of subclinical infection with prions after the bovine spongiform encephalopathy epizootic and to see whether a broader birth cohort was affected, and to understand better the implications for the management of blood and blood products and for the handling of surgical instruments. \n DESIGN Irreversibly unlinked and anonymised large scale survey of archived appendix samples. \n SETTING Archived appendix samples from the pathology departments of 41 UK hospitals participating in the earlier survey, and additional hospitals in regions with lower levels of participation in that survey. SAMPLE 32,441 archived appendix samples fixed in formalin and embedded in paraffin and tested for the presence of abnormal prion protein (PrP). \n RESULTS Of the 32,441 appendix samples 16 were positive for abnormal PrP, indicating an overall prevalence of 493 per million population (95% confidence interval 282 to 801 per million). The prevalence in those born in 1941-60 (733 per million, 269 to 1596 per million) did not differ significantly from those born between 1961 and 1985 (412 per million, 198 to 758 per million) and was similar in both sexes and across the three broad geographical areas sampled. Genetic testing of the positive specimens for the genotype at PRNP codon 129 revealed a high proportion that were valine homozygous compared with the frequency in the normal population, and in stark contrast with confirmed clinical cases of vCJD, all of which were methionine homozygous at PRNP codon 129. \n CONCLUSIONS This study corroborates previous studies and suggests a high prevalence of infection with abnormal PrP, indicating vCJD carrier status in the population compared with the 177 vCJD cases to date. These findings have important implications for the management of blood and blood products and for the handling of surgical instruments." } ]

[ { "docid": "18617259", "title": "Research Letters", "text": "We report a case of preclinical variant Creutzfeldt-Jakob disease (vCJD) in a patient who died from a non-neurological disorder 5 years after receiving a blood transfusion from a donor who subsequently developed vCJD. Protease-resistant prion protein (PrP(res)) was detected by western blot, paraffin-embedded tissue blot, and immunohistochemistry in the spleen, but not in the brain. Immunohistochemistry for prion protein was also positive in a cervical lymph node. The patient was a heterozygote at codon 129 of PRNP, suggesting that susceptibility to vCJD infection is not confined to the methionine homozygous PRNP genotype. These findings have major implications for future estimates and surveillance of vCJD in the UK." }, { "docid": "4828631", "title": "Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults", "text": "BACKGROUND High body-mass index (BMI) predisposes to several site-specific cancers, but a large-scale systematic and detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not previously been undertaken. We aimed to investigate the links between BMI and the most common site-specific cancers. \n METHODS With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we fitted Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential confounders. We fitted linear then non-linear (spline) models; investigated effect modification by sex, menopausal status, smoking, and age; and calculated population effects. \n FINDINGS 5·24 million individuals were included; 166,955 developed cancers of interest. BMI was associated with 17 of 22 cancers, but effects varied substantially by site. Each 5 kg/m(2) increase in BMI was roughly linearly associated with cancers of the uterus (hazard ratio [HR] 1·62, 99% CI 1·56-1·69; p<0·0001), gallbladder (1·31, 1·12-1·52; p<0·0001), kidney (1·25, 1·17-1·33; p<0·0001), cervix (1·10, 1·03-1·17; p=0·00035), thyroid (1·09, 1·00-1·19; p=0·0088), and leukaemia (1·09, 1·05-1·13; p≤0·0001). BMI was positively associated with liver (1·19, 1·12-1·27), colon (1·10, 1·07-1·13), ovarian (1·09, 1.04-1.14), and postmenopausal breast cancers (1·05, 1·03-1·07) overall (all p<0·0001), but these effects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with prostate and premenopausal breast cancer risk, both overall (prostate 0·98, 0·95-1·00; premenopausal breast cancer 0·89, 0·86-0·92) and in never-smokers (prostate 0·96, 0·93-0·99; premenopausal breast cancer 0·89, 0·85-0·94). By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 0·99, 0·93-1·05; oral cavity 1·07, 0·91-1·26): inverse associations overall were driven by current smokers and ex-smokers, probably because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m(2) population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers positively associated with BMI. \n INTERPRETATION BMI is associated with cancer risk, with substantial population-level effects. The heterogeneity in the effects suggests that different mechanisms are associated with different cancer sites and different patient subgroups. \n FUNDING National Institute for Health Research, Wellcome Trust, and Medical Research Council." }, { "docid": "12438901", "title": "Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial", "text": "BACKGROUND For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. \n METHODS In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. \n FINDINGS Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). \n INTERPRETATION For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. \n FUNDING Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed." }, { "docid": "18340282", "title": "Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study", "text": "BACKGROUND Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene-environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study. \n METHODS We tested gene-environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption). \n FINDINGS After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene-environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162.4 cm [95% CI 162.1-162.7] vs 163.1 cm [162.9-163.2]; p=0.01 after allowance for multiple testing). \n INTERPRETATION Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors. \n FUNDING Cancer Research UK and the UK Medical Research Council." }, { "docid": "13770184", "title": "Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015", "text": "BACKGROUND The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. \n METHODS We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). \n FINDINGS Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. \n INTERPRETATION Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. \n FUNDING Bill & Melinda Gates Foundation." }, { "docid": "4506414", "title": "Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people", "text": "BACKGROUND The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease. \n METHODS We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years. This study is registered at ClinicalTrials.gov, number NCT01164371. \n FINDINGS During 5·2 years median follow-up, we recorded 83,098 initial cardiovascular disease presentations. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90-114 mm Hg and diastolic blood pressure of 60-74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32-1·58]), subarachnoid haemorrhage (1·43 [1·25-1·63]), and stable angina (1·41 [1·36-1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00-1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86-0·98]) and strongest for peripheral arterial disease (1·23 [1·20-1·27]). People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9-63·8) compared with 46·1% (45·5-46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8-5·2). Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years. \n INTERPRETATION The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them. \n FUNDING Medical Research Council, National Institute for Health Research, and Wellcome Trust." }, { "docid": "374902", "title": "Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model.", "text": "BACKGROUND Roughly 3 million people worldwide were receiving antiretroviral therapy (ART) at the end of 2007, but an estimated 6.7 million were still in need of treatment and a further 2.7 million became infected with HIV in 2007. Prevention efforts might reduce HIV incidence but are unlikely to eliminate this disease. We investigated a theoretical strategy of universal voluntary HIV testing and immediate treatment with ART, and examined the conditions under which the HIV epidemic could be driven towards elimination. \n METHODS We used mathematical models to explore the effect on the case reproduction number (stochastic model) and long-term dynamics of the HIV epidemic (deterministic transmission model) of testing all people in our test-case community (aged 15 years and older) for HIV every year and starting people on ART immediately after they are diagnosed HIV positive. We used data from South Africa as the test case for a generalised epidemic, and assumed that all HIV transmission was heterosexual. \n FINDINGS The studied strategy could greatly accelerate the transition from the present endemic phase, in which most adults living with HIV are not receiving ART, to an elimination phase, in which most are on ART, within 5 years. It could reduce HIV incidence and mortality to less than one case per 1000 people per year by 2016, or within 10 years of full implementation of the strategy, and reduce the prevalence of HIV to less than 1% within 50 years. We estimate that in 2032, the yearly cost of the present strategy and the theoretical strategy would both be US$1.7 billion; however, after this time, the cost of the present strategy would continue to increase whereas that of the theoretical strategy would decrease. \n INTERPRETATION Universal voluntary HIV testing and immediate ART, combined with present prevention approaches, could have a major effect on severe generalised HIV/AIDS epidemics. This approach merits further mathematical modelling, research, and broad consultation." }, { "docid": "841371", "title": "Reliability of patient responses in pay for performance schemes: analysis of national General Practitioner Patient Survey data in England", "text": "OBJECTIVE To assess the robustness of patient responses to a new national survey of patient experience as a basis for providing financial incentives to doctors. \n DESIGN Analysis of the representativeness of the respondents to the GP Patient Survey compared with those who were sampled (5.5 million patients registered with 8273 general practices in England in January 2009) and with the general population. Analysis of non-response bias looked at the relation between practice response rates and scores on the survey. Analysis of the reliability of the survey estimated the proportion of the variance of practice scores attributable to true differences between practices. \n RESULTS The overall response rate was 38.2% (2.2 million responses), which is comparable to that in surveys using similar methodology in the UK. Men, young adults, and people living in deprived areas were under-represented among respondents. However, for questions related to pay for performance, there was no systematic association between response rates and questionnaire scores. Two questions which triggered payments to general practitioners were reliable measures of practice performance, with average practice-level reliability coefficients of 93.2% and 95.0%. Less than 3% and 0.5% of practices had fewer than the number of responses required to achieve conventional reliability levels of 90% and 70%. A change to the payment formula in 2009 resulted in an increase in the average impact of random variation in patient scores on payments to general practitioners compared with payments made in 2007 and 2008. \n CONCLUSIONS There is little evidence to support the concern of some general practitioners that low response rates and selective non-response bias have led to systematic unfairness in payments attached to questionnaire scores. The study raises issues relating to the validity and reliability of payments based on patient surveys and provides lessons for the UK and for other countries considering the use of patient experience as part of pay for performance schemes." }, { "docid": "80522346", "title": "Variables Affecting Kinetics of Minimal Residual Disease Clearance in Children with Lymphoblastic Leukaemia; Results of the United Kingdom Medical Research Council (UK MRC) Protocols ALL97, ALL97/99 and ALL2003.", "text": "We studied the influence of patient, leukaemia and treatment characteristics on the kinetics of Minimal Residual Disease (MRD) clearance in children with lymphoblastic leukaemia treated using an intensive risk stratified approach. UK MRC protocol ALL97 (1997–1999), and its amended version ALL 97/99 (1999–2002), compared the efficacy and toxicity of dexamethasone (DEX) with prednisolone (PRED), and 6-thioguanine (TG) with 6-Mercaptopurine (MP) in a randomised fashion. The trial produced a 5 year event-free survival (EFS) of 80%, with better systemic and Central Nervous System outcomes in DEX compared with PRED recipients but no difference between TG and MP recipients. Several changes to the risk stratification and treatment regimens during the period of the trial provided an opportunity to determine their impact on MRD clearance. We compared this with clearance in those treated on the successor trial ALL 2003 (more intensive induction containing DEX and Pegylated Asparaginase). The variables investigated for their potential influence on MRD status at the end of induction (EOI) were: NCI Risk; Asparaginase intensity (Erwinia Asparaginase [ERW] in ALL 97 and early part of ALL97/99 vs native or Pegylated E. Coli Asparaginase [E. Coli] in later part of ALL 97/99 and ALL2003); DEX vs PRED; and marrow response at day 8/15 of induction (Slow Early Response [SER] >25% blasts vs Rapid Early Response [RER] ⩽ 25% blasts). MRD was assessed using either a semi-quantitative sequence-specific PCR (ALL97) or Real-Time Quantitative PCR (ALL99 and ALL 2003) of antigen receptor gene re-arrangements at EOI. MRD status was defined as NEG if no MRD was detected by two markers sensitive to 10 −4 ; POS if > 10 −4 , and Positive Outside Quantitative Range (POQR) if positive −4 . Results were available from retrospective testing in 66 ALL97 and 76 ALL97/99 patients, and 204 ALL2003 patients monitored prospectively. There was no significant difference in the proportions of patients MRD NEG, POS or POQR in steroid or NCI sub-groups. Significantly more ERW Asparaginase recipients were MRD POS compared with E.Coli (p −4 at EOI have the same low risk of relapse as those who have undetectable MRD." }, { "docid": "9547722", "title": "Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care.", "text": "BACKGROUND Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis. \n METHODS Incidence and survival data from 1975-2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. population. \n RESULTS As of January 1, 2012, approximately 13.7 million cancer survivors were living in the United States with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37% to 11.9 million. \n CONCLUSIONS A coordinated agenda for research and practice is needed to address cancer survivors' long-term medical, psychosocial, and practical needs across the survivorship trajectory. IMPACT Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population." }, { "docid": "21616324", "title": "Systemic arterial hypertension in children following renal transplantation: prevalence and risk factors.", "text": "BACKGROUND Control of blood pressure (BP) following renal transplantation may improve allograft and patient survival. Our aims were (i) to describe the distribution of BP and the prevalence of systolic and/or diastolic hypertension in children over the first 5 years following renal transplantation and (ii) to evaluate clinical risk factors and centre-specific factors associated with hypertension in this population. \n METHODS We conducted a retrospective case note review of all current paediatric kidney transplant patients in the UK, with data collected at 6 months, 1, 2 and 5 years following transplantation in subjects with hypertension (systolic and/or diastolic BP > 95th > ) and non-hypertensive subjects BP ≤ 95th > . \n RESULTS In total, 27.3% (117/428), 27.6% (118/428), 26.0% (95/365) and 25.6% (50/195) of the patients were hypertensive (systolic and/or diastolic BP > 95th > ) at 6 months, 1, 2 and 5 years following transplantation, respectively. A total of 58.4% of the patients at 6 months, 52.8% at 1 year, 48.2% at 2 years and 48.2% at 5 years were receiving anti-hypertensive therapy, of whom 31.6-36.6% remained hypertensive. When subjects were identified as being hypertensive, on anti-hypertensive medication or had untreated hypertension (systolic and/or diastolic BP > 95th > ), 66.4, 61.0, 56.4 and 55.9% of patients were hypertensive at 6 months, 1, 2 and 5 years, respectively. In a multivariate model, odds ratios for systolic hypertension were 4.16 (deceased versus living donor), 2.65 (lowest versus highest quartile of height z-score) and 2.07 (if on anti-hypertensive; yes versus no). There was significant variation in prevalent rates of hypertension between centres (P < 0.0001) that remained significant (P = 0.003) after adjustment for all the factors in the multivariate model. \n CONCLUSIONS Control of BP after kidney transplantation remains sub-optimal in paediatric centres in the UK. Just over 25% of patients remain hypertensive 5 years following transplantation. Significant differences between centres remain unexplained and may reflect differences in assessment and management of hypertension." }, { "docid": "40164383", "title": "Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.", "text": "CONTEXT Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. \n OBJECTIVE To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. \n DESIGN, SETTING, AND PATIENTS A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. \n INTERVENTION Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. \n MAIN OUTCOME MEASURES Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. \n RESULTS Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. \n CONCLUSIONS In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. \n TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01087996." }, { "docid": "15476777", "title": "Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial", "text": "BACKGROUND Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. \n METHODS We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. \n FINDINGS 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU. \n INTERPRETATION FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. \n FUNDING Cancer Research UK and the Medical Research Council." }, { "docid": "18199839", "title": "Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies", "text": "BACKGROUND Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. \n METHODS In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. \n FINDINGS The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. \n INTERPRETATION Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. \n FUNDING British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation." }, { "docid": "42240424", "title": "The effects of prion protein proteolysis and disaggregation on the strain properties of hamster scrapie.", "text": "Native mammalian prions exist in self-propagating strains that exhibit distinctive clinical, pathological and biochemical characteristics. Prion strain diversity is associated with variations in PrP(Sc) conformation, but it remains unknown precisely which physical properties of the PrP(Sc) molecules are required to encipher mammalian prion strain phenotypes. In this study, we subjected prion-infected brain homogenates derived from three different hamster scrapie strains to either (i) proteinase K digestion or (ii) sonication, and inoculated the modified samples into normal hamsters. The results show that the strain-specific clinical features and neuropathological profiles of inoculated animals were not affected by either treatment. Similarly, the strain-dependent biochemical characteristics of the PrP(Sc) molecules (including electrophoretic mobility, glycoform composition, conformational stability and susceptibility to protease digestion) in infected animals were unaffected by either proteolysis or sonication of the original inocula. These results indicate that the infectious strain properties of native prions do not appear to be altered by PrP(Sc) disaggregation, and that maintenance of such properties does not require the N-domain (approximately residues 23-90) of the protease-resistant PrP(Sc) molecules or protease-sensitive PrP(Sc) molecules." }, { "docid": "17333231", "title": "The sheddase ADAM10 is a potent modulator of prion disease", "text": "The prion protein (PrP(C)) is highly expressed in the nervous system and critically involved in prion diseases where it misfolds into pathogenic PrP(Sc). Moreover, it has been suggested as a receptor mediating neurotoxicity in common neurodegenerative proteinopathies such as Alzheimer's disease. PrP(C) is shed at the plasma membrane by the metalloprotease ADAM10, yet the impact of this on prion disease remains enigmatic. Employing conditional knockout mice, we show that depletion of ADAM10 in forebrain neurons leads to posttranslational increase of PrP(C) levels. Upon prion infection of these mice, clinical, biochemical, and morphological data reveal that lack of ADAM10 significantly reduces incubation times and increases PrP(Sc) formation. In contrast, spatiotemporal analysis indicates that absence of shedding impairs spread of prion pathology. Our data support a dual role for ADAM10-mediated shedding and highlight the role of proteolytic processing in prion disease." }, { "docid": "11718220", "title": "Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial", "text": "BACKGROUND Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. \n METHODS In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and, when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533. \n FINDINGS All patients were included in the analyses. The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to 2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI 2.40-7.27). \n INTERPRETATION These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results. \n FUNDING Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network." }, { "docid": "9167230", "title": "Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis", "text": "BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. \n METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. \n FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. \n INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. \n FUNDING WHO." }, { "docid": "32481310", "title": "Abnormal hemoglobins in a quarter million people.", "text": "Hemolysates of erythrocytes from more than a quarter million people in Alabama were electrophoresed on cellulose acetate, pH 8.4, and those samples exhibiting an abnormality were also electrophoresed in citrate agar, pH 6.0. The globin chains of mutants other than Hb S and C were electrophoresed in urea-mercaptoethanol buffers at both pH 8.9 and pH 6.0, and 60 of them were also analyzed structurally. Of about 6000 samples from whites, only three contained abnormal hemoglobins--Hb D Los Angeles, Hb J Baltimore, and one unidentified. Of 249,000 samples from blacks, about 29,000 contained electrophoretically detectable abnormalities, most of them associated with Hb S or C, present in a frequency of about 9% and 3%, respectively. About 1000 samples resolved into patterns of potential clinical significance. Twenty other mutant hemoglobins were detected, in various genetic combinations in 164 kindreds; four of these-Hb Alabama, Montgomery, Titusville, and Mobile--were previously unknown. The methods used are rapid, economical, and well suited for large scale surveys. They provide highly specific characterizations of many mutant hemoglobins, and no discrepancies were found between the presumptive identifications based on these characterizations and the definitive identifications obtained from structural analyses." } ]

[ { "docid": "22942787", "title": "Relation between Medicare screening reimbursement and stage at diagnosis for older patients with colon cancer.", "text": "CONTEXT Medicare's reimbursement policy was changed in 1998 to provide coverage for screening colonoscopies for patients with increased colon cancer risk, and expanded further in 2001 to cover screening colonoscopies for all individuals. \n OBJECTIVE To determine whether the Medicare reimbursement policy changes were associated with an increase in either colonoscopy use or early stage colon cancer diagnosis. \n DESIGN, SETTING, AND PARTICIPANTS Patients in the Surveillance, Epidemiology, and End Results Medicare linked database who were 67 years of age and older and had a primary diagnosis of colon cancer during 1992-2002, as well as a group of Medicare beneficiaries who resided in Surveillance, Epidemiology, and End Results areas but who were not diagnosed with cancer. \n MAIN OUTCOME MEASURES Trends in colonoscopy and sigmoidoscopy use among Medicare beneficiaries without cancer were assessed using multivariate Poisson regression. Among the patients with cancer, stage was classified as early (stage I) vs all other (stages II-IV). Time was categorized as period 1 (no screening coverage, 1992-1997), period 2 (limited coverage, January 1998-June 2001), and period 3 (universal coverage, July 2001-December 2002). A multivariate logistic regression (outcome = early stage) was used to assess temporal trends in stage at diagnosis; an interaction term between tumor site and time was included. \n RESULTS Colonoscopy use increased from an average rate of 285/100,000 per quarter in period 1 to 889 and 1919/100,000 per quarter in periods 2 (P<.001) and 3 (P vs 2<.001), respectively. During the study period, 44,924 eligible patients were diagnosed with colorectal cancer. The proportion of patients diagnosed at an early stage increased from 22.5% in period 1 to 25.5% in period 2 and 26.3% in period 3 (P<.001 for each pairwise comparison). The changes in Medicare coverage were strongly associated with early stage at diagnosis for patients with proximal colon lesions (adjusted relative risk period 2 vs 1, 1.19; 95% confidence interval, 1.13-1.26; adjusted relative risk period 3 vs 2, 1.10; 95% confidence interval, 1.02-1.17) but weakly associated, if at all, for patients with distal colon lesions (adjusted relative risk period 2 vs 1, 1.07; 95% confidence interval, 1.01-1.13; adjusted relative risk period 3 vs 2, 0.97; 95% confidence interval, 0.90-1.05). \n CONCLUSIONS Expansion of Medicare reimbursement to cover colon cancer screening was associated with an increased use of colonoscopy for Medicare beneficiaries, and for those who were diagnosed with colon cancer, an increased probability of being diagnosed at an early stage. The selective effect of the coverage change on proximal colon lesions suggests that increased use of whole-colon screening modalities such as colonoscopy may have played a pivotal role." } ]

[ { "docid": "1387104", "title": "Malignancies, prothrombotic mutations, and the risk of venous thrombosis.", "text": "CONTEXT Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life. \n OBJECTIVE To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations. \n DESIGN, SETTING, AND PATIENTS A large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3220 consecutive patients aged 18 to 70 years, with a first deep venous thrombosis of the leg or pulmonary embolism, between March 1, 1999, and May 31, 2002, at 6 anticoagulation clinics in the Netherlands, and separate 2131 control participants (partners of the patients) reported via a questionnaire on acquired risk factors for venous thrombosis. Three months after discontinuation of the anticoagulant therapy, all patients and controls were interviewed, a blood sample was taken, and DNA was isolated to ascertain the factor V Leiden and prothrombin 20210A mutations. \n MAIN OUTCOME MEASURE Risk of venous thrombosis. \n RESULTS The overall risk of venous thrombosis was increased 7-fold in patients with a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2-8.6) vs persons without malignancy. Patients with hematological malignancies had the highest risk of venous thrombosis, adjusted for age and sex (adjusted OR, 28.0; 95% CI, 4.0-199.7), followed by lung cancer and gastrointestinal cancer. The risk of venous thrombosis was highest in the first few months after the diagnosis of malignancy (adjusted OR, 53.5; 95% CI, 8.6-334.3). Patients with cancer with distant metastases had a higher risk vs patients without distant metastases (adjusted OR, 19.8; 95% CI, 2.6-149.1). Carriers of the factor V Leiden mutation who also had cancer had a 12-fold increased risk vs individuals without cancer and factor V Leiden (adjusted OR, 12.1; 95% CI, 1.6-88.1). Similar results were indirectly calculated for the prothrombin 20210A mutation in patients with cancer. \n CONCLUSIONS Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk." }, { "docid": "24980622", "title": "Hypoxia in relation to vasculature and proliferation in liver metastases in patients with colorectal cancer.", "text": "PURPOSE To investigate hypoxia measured by pimonidazole binding, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CA-IX) expression, proliferation, and vascularity in liver metastases of colorectal cancer and to compare GLUT1 and CA-IX expression in corresponding primary tumors. \n METHODS AND MATERIALS Twenty-five patients with liver metastases of colorectal cancer, planned for metastasectomy, were included. The hypoxia marker pimonidazole and proliferation marker iododeoxyuridine were administered before surgery. After immunofluorescent staining of the frozen metastases, pimonidazole binding, vascularity, and proliferation were analyzed quantitatively. Thirteen paraffin-embedded primary tumors were stained immunohistochemically for GLUT1 and CA-IX expression, which was analyzed semiquantitatively in primary tumors and corresponding liver metastases. \n RESULTS In liver metastases, pimonidazole binding showed a pattern consistent with diffusion-limited hypoxia. The mean pimonidazole-positive fraction was 0.146; the mean distance from vessels to pimonidazole-positive areas was 80 microm. When expressed, often co-localization was observed between pimonidazole binding and GLUT1 or CA-IX expression, but microregional areas of mismatch were also observed. No correlation between the level of pimonidazole binding and GLUT1 or CA-IX expression was observed. In some patients, a large fraction (up to 30%) of proliferating cells was present in pimonidazole-stained areas. Expression of CA-IX in primary tumors and metastases showed a significant correlation, which was absent for GLUT1 expression. \n CONCLUSIONS Compared with other tumor types, liver metastases of colorectal cancer contain large amounts of hypoxic cells. The lack of correlation with pimonidazole binding brings into question the value of GLUT1 and CA-IX as endogenous markers of hypoxia." }, { "docid": "10958594", "title": "Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases", "text": "The aim of this study was to determine trends in incidence, treatment and survival of colorectal cancer (CRC) patients with synchronous metastases (Stage IV) in the Netherlands. This nationwide population-based study included 160,278 patients diagnosed with CRC between 1996 and 2011. We evaluated changes in stage distribution, location of synchronous metastases and treatment in four consecutive periods, using Chi square tests for trend. Median survival in months was determined, using Kaplan–Meier analysis. The proportion of Stage IV CRC patients (n = 33,421) increased from 19 % (1996–1999) to 23 % (2008–2011, p < 0.001). This was predominantly due to a major increase in the incidence of lung metastases (1.7–5.0 % of all CRC patients). During the study period, the primary tumor was resected less often in Stage IV patients (65–46 %) and the use of systemic treatment has increased (29–60 %). Also an increase in metastasectomy was found in patients with one metastatic site, especially in patients with liver-only disease (5–18 %, p < 0.001). Median survival of all Stage IV CRC patients increased from 7 to 12 months. Especially in patients with metastases confined to the liver or lungs this improvement in survival was apparent (9–16 and 12–24 months respectively, both p < 0.001). In the last two decades, more lung metastases were detected and an increasing proportion of Stage IV CRC patients was treated with systemic therapy and/or metastasectomy. Survival of patients has significantly improved. However, the prognosis of Stage IV patients becomes increasingly diverse." }, { "docid": "5641851", "title": "Social and geographical factors affecting access to treatment of colorectal cancer: a cancer registry study", "text": "OBJECTIVE Cancer outcomes vary between and within countries with patients from deprived backgrounds known to have inferior survival. The authors set out to explore the effect of deprivation in relation to the accessibility of hospitals offering diagnostic and therapeutic services on stage at presentation and receipt of treatment. \n DESIGN Analysis of a Cancer Registry Database. Data included stage and treatment details from the first 6 months. The socioeconomic status of the immediate area of residence and the travel time from home to hospital was derived from the postcode. \n SETTING Population-based study of patients resident in a large area in the north of England. \n PARTICIPANTS 39 619 patients with colorectal cancer diagnosed between 1994 and 2002. \n OUTCOMES MEASURED Stage of diagnosis and receipt of treatment in relation to deprivation and distance from hospital. \n RESULTS Patients in the most deprived quartile were significantly more likely to be diagnosed at stage 4 for rectal cancer (OR 1.516, p<0.05) but less so for colonic cancer. There was a trend for both sites for patients in the most deprived quartile to be less likely to receive chemotherapy for stage 4 disease. Patients with colonic cancer were very significantly less likely to receive any treatment if they came from any but the most affluent area (ORs 0.639, 0.603 and 0.544 in increasingly deprived quartiles), this may have been exacerbated if the hospital was distant from their residence (OR for forth quartile for both travel and deprivation 0.731, not significant). The effect was less for rectal cancer and no effect of distance was seen. \n CONCLUSIONS Residing in a deprived area is associated with tendencies to higher stage at diagnosis and especially in the case of colonic cancer to reduced receipt of treatment. These observations are consistent with other findings and indicate that access to diagnosis requires further investigation." }, { "docid": "52188256", "title": "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.", "text": "This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society." }, { "docid": "18062308", "title": "Operable non-small cell lung cancer diagnosed by transpleural techniques : do they affect relapse and prognosis?", "text": "STUDY OBJECTIVE We assessed whether transpleural methods for diagnosing peripheral lung cancer, such as needle aspiration or tumor excision, affect relapse and prognosis, because these techniques have potential to spread malignant cells from the tumor. \n DESIGN A retrospective study. \n SETTING National referral hospital. \n PATIENTS We reviewed 239 patients who underwent surgery between 1990 and 1998 and for whom non-small cell lung cancer (NSCLC) of < 3 cm in maximum diameter was completely resected. The duration of postoperative follow-up ranged from 12 to 105 months, with a median period of 45 months. \n INTERVENTIONS We defined the transbronchial method as using a bronchoscope, and the transpleural method as using needle aspiration cytology or tumor excision. Dichotomous variables included gender, histologic type of squamous cell carcinoma or other type of carcinoma, pathologic stage, and whether the diagnostic method was the transbronchial type only (first-line method) or the transpleural type (second-line method). \n RESULTS NSCLC was diagnosed in 45 patients by the transpleural technique and in 194 patients by the transbronchial technique. There were no significant statistical differences in age of patients, gender, histologic type, pathologic stage, and tumor size. There were 42 relapses, 7 in the transpleural technique group and 35 in the transbronchial technique group (p = 0.90). Of the 7 patients in the transpleural group, there were 4 distant metastasis and 3 local relapses; of the 35 patients in the transbronchial group, there were 20 distant metastasis and 15 local relapses (p = 0.99). Pleural carcinomatosis occurred in none of the 45 patients in the transpleural group and in 1 case (0.5%) in the 194 patients in the transbronchial group (p = 0.99). Patients in the transpleural group had a statistically better 5-year survival rate than patients in the transbronchial group (79.4% vs 60.3%, p = 0.04). This is also confirmed as an independent prognostic factor in a multivariate analysis. \n CONCLUSIONS Transpleural methods seem to be an advisable way to diagnose operable lung cancer that is difficult to diagnose using bronchoscopy, because these methods did not affect relapse and prognosis in the patients in our study." }, { "docid": "9831859", "title": "Pancreatic stellate cells: partners in crime with pancreatic cancer cells.", "text": "Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression." }, { "docid": "39580129", "title": "Elevated expression of miR-24-3p is a potentially adverse prognostic factor in colorectal adenocarcinoma.", "text": "OBJECTIVES Several miRNAs are aberrantly expressed in cancer. miR-24-3p is involved in cancer-related cellular processes, including cell cycle control, cell growth, proliferation, and apoptosis. In this study, we examined the potential diagnostic and prognostic significance of miR-24-3p expression in colorectal adenocarcinoma. \n DESIGN AND METHODS Total RNA was isolated from 182 colorectal adenocarcinoma specimens and 86 paired non-cancerous colorectal mucosae. After polyadenylation of 2μg total RNA and reverse transcription into first-strand cDNA using an oligo-dT-adapter primer, miR-24-3p expression was quantified using an in-house-developed reverse-transcription real-time quantitative PCR method, based on the SYBR Green chemistry. SNORD43 (RNU43) was used as a reference gene. \n RESULTS miR-24-3p levels do not significantly differ between colorectal adenocarcinoma and non-cancerous colorectal mucosae. Thus, miR-24-3p expression cannot be used for diagnostic purposes. However, high miR-24-3p expression predicts poor disease-free survival (DFS) and overall survival (OS) of colorectal adenocarcinoma patients. Multivariate Cox regression analysis confirmed that miR-24-3p overexpression is a significant predictor of relapse in colorectal adenocarcinoma and that its prognostic significance is independent of other established prognostic factors and treatment of patients. Of note, miR-24-3p overexpression retains its rather unfavorable prognostic value in the subgroup of patients with advanced yet locally restricted colorectal adenocarcinoma (T3) and in those without distant metastasis (M0). Moreover, miR-24-3p overexpression is a potentially unfavorable prognosticator for patients who were not treated with radiotherapy. \n CONCLUSIONS Strong expression of miR-24-3p predicts poor DFS and OS of colorectal adenocarcinoma patients, independently of clinicopathological parameters that are currently used for prognosis in this human malignancy." }, { "docid": "13030852", "title": "Identification of bone and liver metastases from breast cancer by measurement of plasma alkaline phosphatase isoenzyme activity.", "text": "Plasma alkaline phosphatase isoenzyme activities were determined in patients with breast cancer to diagnose and monitor bone and liver metastases. Bone alkaline phosphatase activity was increased in 21 of 50 patients (42%) with radiologically confirmed bone metastases, while total alkaline phosphatase activity was increased in only 10 of 50 (20%); liver alkaline phosphatase activity was raised in 12 of 25 patients (48%) with liver metastases. All patients with liver metastases had bone metastases. Bone alkaline phosphatase activity was significantly higher in patients with symptomatic bone disease. Isoenzyme determination provided additional information that would have changed patient management in five of 20 patients who were monitored serially. Measurement of alkaline phosphatase isoenzyme activity, though less sensitive than imaging procedures, can assist in screening for, and in early detection of, a high proportion of bone and liver metastases, and can provide useful objective evidence of their response to treatment." }, { "docid": "3329824", "title": "Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.", "text": "BACKGROUND Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. \n METHODS Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. \n RESULTS A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. \n CONCLUSIONS Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients." }, { "docid": "2058909", "title": "Colorectal cancer survival in socioeconomic groups in England: variation is mainly in the short term after diagnosis.", "text": "UNLABELLED The objective of this study was to examine differences in cancer survival between socioeconomic groups in England, with particular attention to survival in the short term of follow-up. \n PATIENTS AND METHODS Individuals diagnosed with colorectal cancer between 1996 and 2004 in England were identified from cancer registry records. Five-year cumulative relative survival and excess death rates were computed. \n RESULTS For colon cancer there was a very high excess death rate in the first month of follow-up, and the excess death rate was highest in the socioeconomically deprived groups. In subsequent periods, excess mortality rates were much lower and there was less socioeconomic variation. The pattern of variation in excess death rates was generally similar in rectal cancer but the socioeconomic difference in death rates persisted several years longer. If the excess death rates in the entire colorectal cancer patient population were the same as those observed in the most affluent socioeconomic quintile, the annual reduction would be 360 deaths in colon cancer and 336 deaths in rectal cancer patients. These deaths occurred almost entirely in the first month and the first year after diagnosis. \n CONCLUSION Recent developments in the national cancer control agenda have included an increasing emphasis on outcome measures, with short-term cancer survival an operational measure of variation and progress in cancer control. In providing clues to the nature of the survival differences between socioeconomic groups, the results presented here give strong support for this strategy." }, { "docid": "23639838", "title": "Surgical Resection for Patients with Solid Brain Metastases: Current Status", "text": "Brain metastases occur in up to 40% of patients with cancer. Their management has been revolutionized in the last decade by three developments: improved imaging and detection of metastases, better treatment of systemic disease with the result that metastases occur more often; and improved surgical techniques including image-guided surgery to treat metastatic lesions. Class 1 data suggest that surgery is a better treatment for metastases than whole brain radiation. Other data suggest that metastases even in eloquent cortex can be removed safely. The complication rate is low and the recurrence rate is less than 10%. In general, indications for surgery include a mass with an unknown primary; a symptomatic mass including one in eloquent areas; a mass with considerable edema requiring high dose steroids; a mass greater than 3 cm; or patient preference when radiosurgery may also be an option. The question of radiosurgery or whole brain radiation as adjunct to surgical removal requires further evaluation." }, { "docid": "15476777", "title": "Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial", "text": "BACKGROUND Elderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer. \n METHODS We undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452. \n FINDINGS 459 patients were randomly assigned (115 to each of groups A-C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3-7·5] vs 4·5 months [2·8-6·4]; hazard ratio 0·84, 95% CI 0·69-1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14-1·52), less widespread disease (1·51, 1·05-2·19), and use of oxaliplatin (0·57, 0·39-0·82) were predictive of better OTU. \n INTERPRETATION FOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit. \n FUNDING Cancer Research UK and the Medical Research Council." }, { "docid": "825728", "title": "Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1.", "text": "The epithelial-mesenchymal transition (EMT) is required in the embryo for the formation of tissues for which cells originate far from their final destination. Carcinoma cells hijack this program for tumor dissemination. The relevance of the EMT in cancer is still debated because it is unclear how these migratory cells colonize distant tissues to form macrometastases. We show that the homeobox factor Prrx1 is an EMT inducer conferring migratory and invasive properties. The loss of Prrx1 is required for cancer cells to metastasize in vivo, which revert to the epithelial phenotype concomitant with the acquisition of stem cell properties. Thus, unlike the classical EMT transcription factors, Prrx1 uncouples EMT and stemness, and is a biomarker associated with patient survival and lack of metastasis." }, { "docid": "17482507", "title": "Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer.", "text": "OBJECTIVE To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases. \n DATA SOURCES Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included. STUDY SELECTION Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity. \n RESULTS 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates. \n CONCLUSIONS In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant." }, { "docid": "4429932", "title": "Lysyl oxidase is essential for hypoxia-induced metastasis", "text": "Metastasis is a multistep process responsible for most cancer deaths, and it can be influenced by both the immediate microenvironment (cell–cell or cell–matrix interactions) and the extended tumour microenvironment (for example vascularization). Hypoxia (low oxygen) is clinically associated with metastasis and poor patient outcome, although the underlying processes remain unclear. Microarray studies have shown the expression of lysyl oxidase (LOX) to be elevated in hypoxic human tumour cells. Paradoxically, LOX expression is associated with both tumour suppression and tumour progression, and its role in tumorigenesis seems dependent on cellular location, cell type and transformation status. Here we show that LOX expression is regulated by hypoxia-inducible factor (HIF) and is associated with hypoxia in human breast and head and neck tumours. Patients with high LOX-expressing tumours have poor distant metastasis-free and overall survivals. Inhibition of LOX eliminates metastasis in mice with orthotopically grown breast cancer tumours. Mechanistically, secreted LOX is responsible for the invasive properties of hypoxic human cancer cells through focal adhesion kinase activity and cell to matrix adhesion. Furthermore, LOX may be required to create a niche permissive for metastatic growth. Our findings indicate that LOX is essential for hypoxia-induced metastasis and is a good therapeutic target for preventing and treating metastases." }, { "docid": "16390264", "title": "Social variations in access to hospital care for patients with colorectal, breast, and lung cancer between 1999 and 2006: retrospective analysis of hospital episode statistics", "text": "OBJECTIVES To determine the extent to which type of hospital admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. \n DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. \n SETTING Hospital episode statistics (HES) dataset. \n PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. \n MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. \n RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care." }, { "docid": "25915873", "title": "Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.", "text": "PURPOSE Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation. \n RESULTS Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release. EXPERIMENTAL DESIGN We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases. \n CONCLUSION Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases." }, { "docid": "5372432", "title": "Geographical access to healthcare in Northern England and post-mortem diagnosis of cancer.", "text": "BACKGROUND There is some previous evidence that diagnosis of cancer at death, recorded as registry death certificate only records, is associated with problems of access to care. \n METHODS Records from the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung, ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time to general practitioner and hospital services, and social deprivation. Logistic regression was used to identify predictors of records where diagnosis was at death. \n RESULTS There was no association between the odds diagnosis at death and access to primary care. For all sites except breast, the highest odds of being a cancer diagnosed at death fell among those living in the highest quartile of hospital travel time, although it was only statistically significant for colorectal and ovary tumours. Those in the most deprived and furthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death case compared with those in the most affluent and proximal areas. \n CONCLUSIONS There is some evidence that poorer geographical access to tertiary care, in particular when coupled with social disadvantages, may be associated with increased odds of diagnosis at death." } ]

[ { "docid": "2613775", "title": "Sudden infant death syndrome.", "text": "Despite declines in prevalence during the past two decades, sudden infant death syndrome (SIDS) continues to be the leading cause of death for infants aged between 1 month and 1 year in developed countries. Behavioural risk factors identified in epidemiological studies include prone and side positions for infant sleep, smoke exposure, soft bedding and sleep surfaces, and overheating. Evidence also suggests that pacifier use at sleep time and room sharing without bed sharing are associated with decreased risk of SIDS. Although the cause of SIDS is unknown, immature cardiorespiratory autonomic control and failure of arousal responsiveness from sleep are important factors. Gene polymorphisms relating to serotonin transport and autonomic nervous system development might make affected infants more vulnerable to SIDS. Campaigns for risk reduction have helped to reduce SIDS incidence by 50-90%. However, to reduce the incidence even further, greater strides must be made in reducing prenatal smoke exposure and implementing other recommended infant care practices. Continued research is needed to identify the pathophysiological basis of SIDS." } ]

[ { "docid": "35521287", "title": "Cardiorespiratory adaptation during sleep in infants and children.", "text": "The cardiorespiratory control system undergoes functional maturation after birth. Until this process is completed, the cardiorespiratory system is unstable, placing infants at risk for cardiorespiratory disturbances, especially during sleep. The profound influence of states of alertness on respiratory and cardiac control has been the focus of intense scrutiny during the last decade. The effects of rapid-eye movement (REM) sleep on various mechanisms involved in cardiorespiratory control are of particular significance during the postnatal period since newborns spend much of their time in this sleep state. In fullterm newborns, REM sleep occupies more than 50% of total sleep time, and this percentage is even greater in preterm newborns. From term to six months of age, the proportion of REM sleep decreases. Since respiratory and cardiac disturbances are known to occur selectively during REM sleep, the predominance of REM sleep may be a risk factor for abnormal sleep-related events during early infancy. Awareness of these developmental changes in sleep patterns is important for clinicians dealing with problems such as apparent life-threatening events (ALTE), sudden infant death syndrome (SIDS), and/or cardiorespiratory responses to respiratory disorders. Our current understanding of respiratory and cardiac control rests mainly on studies conducted during the first months of life. There is a paucity of data on late infancy and early childhood. The present paper will review available data on how sleep affects 1) ventilatory mechanics, in particular of the upper airways and the chest wall; ventilation and apnea; gas exchange; chemoreceptor function; and arousal responses; 2) changes in heart rate and heart rate variability, and the occurrence and mechanisms of bradycardia." }, { "docid": "23117378", "title": "Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach.", "text": "The definition of sudden infant death syndrome (SIDS) originally appeared in 1969 and was modified 2 decades later. During the following 15 years, an enormous amount of additional information has emerged, justifying additional refinement of the definition of SIDS to incorporate epidemiologic features, risk factors, pathologic features, and ancillary test findings. An expert panel of pediatric and forensic pathologists and pediatricians considered these issues and developed a new general definition of SIDS for administrative and vital statistics purposes. The new definition was then stratified to facilitate research into sudden infant death. Another category, defined as unclassified sudden infant deaths, was introduced for cases that do not meet the criteria for a diagnosis of SIDS and for which alternative diagnoses of natural or unnatural conditions were equivocal. It is anticipated that these new definitions will be modified in the future to accommodate new understanding of SIDS and sudden infant death." }, { "docid": "20240998", "title": "Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five major case–control studies", "text": "OBJECTIVE To resolve uncertainty as to the risk of Sudden Infant Death Syndrome (SIDS) associated with sleeping in bed with your baby if neither parent smokes and the baby is breastfed. \n DESIGN Bed sharing was defined as sleeping with a baby in the parents' bed; room sharing as baby sleeping in the parents' room. Frequency of bed sharing during last sleep was compared between babies who died of SIDS and living control infants. Five large SIDS case-control datasets were combined. Missing data were imputed. Random effects logistic regression controlled for confounding factors. \n SETTING Home sleeping arrangements of infants in 19 studies across the UK, Europe and Australasia. \n PARTICIPANTS 1472 SIDS cases, and 4679 controls. Each study effectively included all cases, by standard criteria. Controls were randomly selected normal infants of similar age, time and place. \n RESULTS In the combined dataset, 22.2% of cases and 9.6% of controls were bed sharing, adjusted OR (AOR) for all ages 2.7; 95% CI (1.4 to 5.3). Bed sharing risk decreased with increasing infant age. When neither parent smoked, and the baby was less than 3 months, breastfed and had no other risk factors, the AOR for bed sharing versus room sharing was 5.1 (2.3 to 11.4) and estimated absolute risk for these room sharing infants was very low (0.08 (0.05 to 0.14)/1000 live-births). This increased to 0.23 (0.11 to 0.43)/1000 when bed sharing. Smoking and alcohol use greatly increased bed sharing risk. \n CONCLUSIONS Bed sharing for sleep when the parents do not smoke or take alcohol or drugs increases the risk of SIDS. Risks associated with bed sharing are greatly increased when combined with parental smoking, maternal alcohol consumption and/or drug use. A substantial reduction of SIDS rates could be achieved if parents avoided bed sharing." }, { "docid": "21050357", "title": "Research Priorities in Sudden Unexpected Infant Death: An International Consensus.", "text": "Despite the success of safe sleep campaigns and the progress in understanding risk factors, the rate of reduction in the cases of sudden infant death syndrome has now slowed and it remains a leading cause of postneonatal mortality in many developed countries. Strategic action is needed to tackle this problem and it is now vital to identify how the sudden infant death research community may best target its efforts. The Global Action and Prioritization of Sudden Infant Death Project was an international consensus process that aimed to define and direct future research by investigating the priorities of expert and lay members of the sudden unexpected infant death (SUID) community across countries. The aim was to identify which areas of research should be prioritized to reduce the number of SUID deaths globally. Scientific researchers, clinicians, counselors, educators, and SUID parents from 25 countries took part across 2 online surveys to identify potential research priorities. Workshops subsequently took place in the United Kingdom, United States, and Australia to reach consensus and 10 priority areas for research were established. Three main themes among the priorities emerged: (1) a better understanding of mechanisms underlying SUID, (2) ensuring best practice in data collection, management and sharing, and (3) a better understanding of target populations and more effective communication of risk. SUID is a global problem and this project provides the international SUID community with a list of shared research priorities to more effectively work toward explaining and reducing the number of sudden infant deaths." }, { "docid": "30292811", "title": "Swaddling: a systematic review.", "text": "Swaddling was an almost universal child-care practice before the 18th century. It is still tradition in certain parts of the Middle East and is gaining popularity in the United Kingdom, the United States, and The Netherlands to curb excessive crying. We have systematically reviewed all articles on swaddling to evaluate its possible benefits and disadvantages. In general, swaddled infants arouse less and sleep longer. Preterm infants have shown improved neuromuscular development, less physiologic distress, better motor organization, and more self-regulatory ability when they are swaddled. When compared with massage, excessively crying infants cried less when swaddled, and swaddling can soothe pain in infants. It is supportive in cases of neonatal abstinence syndrome and infants with neonatal cerebral lesions. It can be helpful in regulating temperature but can also cause hyperthermia when misapplied. Another possible adverse effect is an increased risk of the development of hip dysplasia, which is related to swaddling with the legs in extension and adduction. Although swaddling promotes the favorable supine position, the combination of swaddling with prone position increases the risk of sudden infant death syndrome, which makes it necessary to warn parents to stop swaddling if infants attempt to turn. There is some evidence that there is a higher risk of respiratory infections related to the tightness of swaddling. Furthermore, swaddling does not influence rickets onset or bone properties. Swaddling immediately after birth can cause delayed postnatal weight gain under certain conditions, but does not seem to influence breastfeeding parameters." }, { "docid": "19332616", "title": "Coronary plaque disruption.", "text": "Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.1 2 3 4 5 Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.6 This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.7 8 Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment9 10 11 12 13 14 ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis15 16 ; degeneration, with lipid accumulation17 18 ; necrosis, possibly related to the cytotoxic effect of oxidized lipid19 ; calcification/ossification, which may represent an active rather than a dystrophic process20 21 ; and thrombosis, with platelet recruitment and fibrin formation.1 22 23 Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis. ### Mature Plaques: Atherosis and Sclerosis As the name atherosclerosis implies, mature …" }, { "docid": "29253460", "title": "Sex-related differences in the presentation, treatment and outcomes among patients with acute coronary syndromes: the Global Registry of Acute Coronary Events.", "text": "OBJECTIVE To assess whether sex differences exist in the angiographic severity, management and outcomes of acute coronary syndromes (ACS). \n METHODS The study comprised 7638 women and 19 117 men with ACS who underwent coronary angiography and were included in GRACE (Global Registry of Acute Coronary Events) from 1999-2006. Normal vessels/mild disease was defined as <50% stenosis in all epicardial vessels; advanced disease was defined as >or=one vessel with >or=50% stenosis. \n RESULTS Women were older than men and had higher rates of cardiovascular risk factors. Men and women presented equally with chest pain; however, jaw pain and nausea were more frequent among women. Women were more likely to have normal/mild disease (12% vs 6%, p<0.001) and less likely to have left-main and three-vessel disease (27% vs 32%, p<0.001) or undergo percutaneous coronary intervention (65% vs 68%, p<0.001). Women and men with normal and mild disease were treated less aggressively than those with advanced disease. Women with advanced disease had a higher risk of death (4% vs 3%, p<0.01). After adjustment for age and extent of disease, women were more likely to have adverse outcomes (death, myocardial infarction, stroke and rehospitalisation) at six months compared to men (odds ratio 1.24, 95% confidence interval 1.14 to 1.34); however, sex differences in mortality were no longer statistically significant. \n CONCLUSIONS Women with ACS were more likely to have cardiovascular disease risk factors and atypical symptoms such as nausea compared with men, but were more likely to have normal/mild angiographic coronary artery disease. Further study regarding sex differences related to disease severity is warranted." }, { "docid": "24150328", "title": "Peroxisome proliferator-activated receptor gamma agonists for the Prevention of Adverse events following percutaneous coronary Revascularization--results of the PPAR study.", "text": "BACKGROUND Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator-activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). \n METHODS A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. \n RESULTS There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (-35.4% vs -15.8%, P = .059) and 12 months (-40.0% vs -20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (-13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. \n CONCLUSIONS Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator-activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted." }, { "docid": "16204011", "title": "Care Seeking for Neonatal Illness in Low- and Middle-Income Countries: A Systematic Review", "text": "BACKGROUND Despite recent achievements to reduce child mortality, neonatal deaths continue to remain high, accounting for 41% of all deaths in children under five years of age worldwide, of which over 90% occur in low- and middle-income countries (LMICs). Infections are a leading cause of death and limitations in care seeking for ill neonates contribute to high mortality rates. As estimates for care-seeking behaviors in LMICs have not been studied, this review describes care seeking for neonatal illnesses in LMICs, with particular attention to type of care sought. \n METHODS AND FINDINGS We conducted a systematic literature review of studies that reported the proportion of caregivers that sought care for ill or suspected ill neonates in LMICs. The initial search yielded 784 studies, of which 22 studies described relevant data from community household surveys, facility-based surveys, and intervention trials. The majority of studies were from South Asia (n = 17/22), set in rural areas (n = 17/22), and published within the last 4 years (n = 18/22). Of the 9,098 neonates who were ill or suspected to be ill, 4,320 caregivers sought some type of care, including care from a health facility (n = 370) or provider (n = 1,813). Care seeking ranged between 10% and 100% among caregivers with a median of 59%. Care seeking from a health care provider yielded a similar range and median, while care seeking at a health care facility ranged between 1% and 100%, with a median of 20%. Care-seeking estimates were limited by the few studies conducted in urban settings and regions other than South Asia. There was a lack of consistency regarding illness, care-seeking, and care provider definitions. \n CONCLUSIONS There is a paucity of data regarding newborn care-seeking behaviors; in South Asia, care seeking is low for newborn illness, especially in terms of care sought from health care facilities and medically trained providers. There is a need for representative data to describe care-seeking patterns in different geographic regions and better understand mechanisms to enhance care seeking during this vulnerable time period." }, { "docid": "9167230", "title": "Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis", "text": "BACKGROUND The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010. \n METHODS We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies. \n FINDINGS We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals. \n INTERPRETATION Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities. \n FUNDING WHO." }, { "docid": "25028913", "title": "Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease.", "text": "BACKGROUND In patients with unstable coronary artery disease, there is a relation between the short-term risk of death and blood levels of troponin T (a marker of myocardial damage) and C-reactive protein and fibrinogen (markers of inflammation). Using information obtained during an extension of the follow-up period in the Fragmin during Instability in Coronary Artery Disease trial, we evaluated the usefulness of troponin T, C-reactive protein, and fibrinogen levels and other indicators of risk as predictors of the long-term risk of death from cardiac causes. \n METHODS Levels of C-reactive protein and fibrinogen at enrollment and the maximal level of troponin T during the first 24 hours after enrollment were analyzed in 917 patients included in a clinical trial of low-molecular-weight heparin in unstable coronary artery disease. The patients were followed for a mean of 37.0 months (range, 1.6 to 50.6). \n RESULTS During follow-up, 1.2 percent of the 173 patients with maximal blood troponin T levels of less than 0.06 microg per liter died of cardiac causes, as compared with 8.7 percent of the 367 patients with levels of 0.06 to 0.59 microg per liter and 15.4 percent of the 377 patients with levels of at least 0.60 microg per liter (P=0.007 and P=0.001, respectively). The rates of death from cardiac causes were 5.7 percent among the 314 patients with blood C-reactive protein levels of less than 2 mg per liter, 7.8 percent among the 294 with levels of 2 to 10 mg per liter, and 16.5 percent among the 309 with levels of more than 10 mg per liter (P=0.29 and P=0.001, respectively). The rates of death from cardiac causes were 5.4 percent among the 314 patients with blood fibrinogen levels of less than 3.4 g per liter, 12.0 percent among the 300 with levels of 3.4 to 3.9 g per liter, and 12.9 percent among the 303 with levels of at least 4.0 g per liter (P=0.004 and P=0.69, respectively). In a multivariate analysis, levels of troponin T and C-reactive protein were independent predictors of the risk of death from cardiac causes. \n CONCLUSIONS In unstable coronary artery disease, elevated levels of troponin T and C-reactive protein are strongly related to the long-term risk of death from cardiac causes. These markers are independent risk factors, and their effects are additive with respect to each other and other clinical indicators of risk." }, { "docid": "4791384", "title": "Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis of Progress, Projections, and Priorities", "text": "BACKGROUND Historically, the main focus of studies of childhood mortality has been the infant and under-five mortality rates. Neonatal mortality (deaths <28 days of age) has received limited attention, although such deaths account for about 41% of all child deaths. To better assess progress, we developed annual estimates for neonatal mortality rates (NMRs) and neonatal deaths for 193 countries for the period 1990-2009 with forecasts into the future. \n METHODS AND FINDINGS We compiled a database of mortality in neonates and children (<5 years) comprising 3,551 country-years of information. Reliable civil registration data from 1990 to 2009 were available for 38 countries. A statistical model was developed to estimate NMRs for the remaining 155 countries, 17 of which had no national data. Country consultation was undertaken to identify data inputs and review estimates. In 2009, an estimated 3.3 million babies died in the first month of life-compared with 4.6 million neonatal deaths in 1990-and more than half of all neonatal deaths occurred in five countries of the world (44% of global livebirths): India 27.8% (19.6% of global livebirths), Nigeria 7.2% (4.5%), Pakistan 6.9% (4.0%), China 6.4% (13.4%), and Democratic Republic of the Congo 4.6% (2.1%). Between 1990 and 2009, the global NMR declined by 28% from 33.2 deaths per 1,000 livebirths to 23.9. The proportion of child deaths that are in the neonatal period increased in all regions of the world, and globally is now 41%. While NMRs were halved in some regions of the world, Africa's NMR only dropped 17.6% (43.6 to 35.9). \n CONCLUSIONS Neonatal mortality has declined in all world regions. Progress has been slowest in the regions with high NMRs. Global health programs need to address neonatal deaths more effectively if Millennium Development Goal 4 (two-thirds reduction in child mortality) is to be achieved." }, { "docid": "7111021", "title": "Integration of antiretroviral therapy with tuberculosis treatment.", "text": "BACKGROUND We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, the timing for the initiation of ART during tuberculosis treatment remains unresolved. \n METHODS We conducted a three-group, open-label, randomized, controlled trial in South Africa involving 642 ambulatory patients, all with tuberculosis (confirmed by a positive sputum smear for acid-fast bacilli), human immunodeficiency virus infection, and a CD4+ T-cell count of less than 500 per cubic millimeter. Findings in the earlier-ART group (ART initiated within 4 weeks after the start of tuberculosis treatment, 214 patients) and later-ART group (ART initiated during the first 4 weeks of the continuation phase of tuberculosis treatment, 215 patients) are presented here. \n RESULTS At baseline, the median CD4+ T-cell count was 150 per cubic millimeter, and the median viral load was 161,000 copies per milliliter, with no significant differences between the two groups. The incidence rate of the acquired immunodeficiency syndrome (AIDS) or death was 6.9 cases per 100 person-years in the earlier-ART group (18 cases) as compared with 7.8 per 100 person-years in the later-ART group (19 cases) (incidence-rate ratio, 0.89; 95% confidence interval [CI], 0.44 to 1.79; P=0.73). However, among patients with CD4+ T-cell counts of less than 50 per cubic millimeter, the incidence rates of AIDS or death were 8.5 and 26.3 cases per 100 person-years, respectively (incidence-rate ratio, 0.32; 95% CI, 0.07 to 1.13; P=0.06). The incidence rates of the immune reconstitution inflammatory syndrome (IRIS) were 20.1 and 7.7 cases per 100 person-years, respectively (incidence-rate ratio, 2.62; 95% CI, 1.48 to 4.82; P<0.001). Adverse events requiring a switching of antiretroviral drugs occurred in 10 patients in the earlier-ART group and 1 patient in the later-ART group (P=0.006). \n CONCLUSIONS Early initiation of ART in patients with CD4+ T-cell counts of less than 50 per cubic millimeter increased AIDS-free survival. Deferral of the initiation of ART to the first 4 weeks of the continuation phase of tuberculosis therapy in those with higher CD4+ T-cell counts reduced the risks of IRIS and other adverse events related to ART without increasing the risk of AIDS or death. (Funded by the U.S. President's Emergency Plan for AIDS Relief and others; SAPIT ClinicalTrials.gov number, NCT00398996.)." }, { "docid": "13900610", "title": "Self-harm in prisons in England and Wales: an epidemiological study of prevalence, risk factors, clustering, and subsequent suicide", "text": "BACKGROUND Self-harm and suicide are common in prisoners, yet robust information on the full extent and characteristics of people at risk of self-harm is scant. Furthermore, understanding how frequently self-harm is followed by suicide, and in which prisoners this progression is most likely to happen, is important. We did a case-control study of all prisoners in England and Wales to ascertain the prevalence of self-harm in this population, associated risk factors, clustering effects, and risk of subsequent suicide after self-harm. \n METHODS Records of self-harm incidents in all prisons in England and Wales were gathered routinely between January, 2004, and December, 2009. We did a case-control comparison of prisoners who self-harmed and those who did not between January, 2006, and December, 2009. We also used a Bayesian approach to look at clustering of people who self-harmed. Prisoners who self-harmed and subsequently died by suicide in prison were compared with other inmates who self-harmed. \n FINDINGS 139,195 self-harm incidents were recorded in 26,510 individual prisoners between 2004 and 2009; 5-6% of male prisoners and 20-24% of female inmates self-harmed every year. Self-harm rates were more than ten times higher in female prisoners than in male inmates. Repetition of self-harm was common, particularly in women and teenage girls, in whom a subgroup of 102 prisoners accounted for 17,307 episodes. In both sexes, self-harm was associated with younger age, white ethnic origin, prison type, and a life sentence or being unsentenced; in female inmates, committing a violent offence against an individual was also a factor. Substantial evidence was noted of clustering in time and location of prisoners who self-harmed (adjusted intra-class correlation 0·15, 95% CI 0·11-0·18). 109 subsequent suicides in prison were reported in individuals who self-harmed; the risk was higher in those who self-harmed than in the general prison population, and more than half the deaths occurred within a month of self-harm. Risk factors for suicide after self-harm in male prisoners were older age and a previous self-harm incident of high or moderate lethality; in female inmates, a history of more than five self-harm incidents within a year was associated with subsequent suicide. \n INTERPRETATION The burden of self-harm in prisoners is substantial, particularly in women. Self-harm in prison is associated with subsequent suicide in this setting. Prevention and treatment of self-harm in prisoners is an essential component of suicide prevention in prisons. \n FUNDING Wellcome Trust, National Institute for Health Research, National Offender Management Service, and Department of Health." }, { "docid": "3944632", "title": "Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.", "text": "CONTEXT In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. \n OBJECTIVE To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. \n DESIGN, SETTING, AND PATIENTS Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. \n INTERVENTIONS Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). \n MAIN OUTCOME MEASURES The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. \n RESULTS The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. \n CONCLUSIONS Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. \n TRIAL REGISTRATION umin.ac.jp/ctr Identifier: C000000412." }, { "docid": "27099731", "title": "Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants.", "text": "IMPORTANCE There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. \n OBJECTIVE To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. \n DESIGN, SETTING, AND PARTICIPANTS Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES Early screening echocardiography before day 3 of life. \n MAIN OUTCOMES AND MEASURES The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). \n RESULTS Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. \n CONCLUSIONS AND RELEVANCE In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity." }, { "docid": "52072815", "title": "Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016", "text": "Summary Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2·2% (95% uncertainty interval [UI] 1·5–3·0) of age-standardised female deaths and 6·8% (5·8–8·0) of age-standardised male deaths. Among the population aged 15–49 years, alcohol use was the leading risk factor globally in 2016, with 3·8% (95% UI 3·2–4·3) of female deaths and 12·2% (10·8–13·6) of male deaths attributable to alcohol use. For the population aged 15–49 years, female attributable DALYs were 2·3% (95% UI 2·0–2·6) and male attributable DALYs were 8·9% (7·8–9·9). The three leading causes of attributable deaths in this age group were tuberculosis (1·4% [95% UI 1·0–1·7] of total deaths), road injuries (1·2% [0·7–1·9]), and self-harm (1·1% [0·6–1·5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27·1% (95% UI 21·2–33·3) of total alcohol-attributable female deaths and 18·9% (15·3–22·6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0·0–0·8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption. Funding Bill & Melinda Gates Foundation." }, { "docid": "25182647", "title": "Maternal and perinatal outcome in severe pregnancy-related liver disease.", "text": "Acute fatty liver of pregnancy (AFLP) and the syndrome of hemolysis, elevated liver enzyme levels, and low platelet count (HELLP) are rare but major disorders of the third trimester of pregnancy. Over a 10-year period, 46 women (median age, 30 years; range, 17-41 years) developed hepatic dysfunction severe enough to require transfer to our Liver Failure Unit. Three quarters of the women were nulliparous, and 5 had twin pregnancies; the median gestational age was 35 weeks (range, 24-40 weeks). At admission, 32 patients (70%) were preeclamptic and 21 (46%) were encephalopathic and/or ventilated. Thirty-two patients (70%) had clinical features and laboratory values consistent with AFLP, and 7 (15%) had HELLP syndrome. One patient had preeclamptic liver rupture requiring liver transplantation. In 6 other patients, causes of severe liver dysfunction unrelated to pregnancy were found. Infectious complications occurred in 17 of the patients with AFLP (53%) and in 2 of those with HELLP syndrome (29%). Major intra-abdominal bleeding occurred in 12 women (10 with AFLP), 9 of whom required laparotomies for clot evacuation. Four patients with AFLP (12.5%) had a fatal outcome, with a corresponding perinatal mortality rate of 9%. There were no maternal or perinatal deaths associated with HELLP syndrome. In contrast to results of many previous studies, the results of this large series suggest a relatively favorable maternal and perinatal outcome in severe AFLP and HELLP syndrome. Further improvements in outcome are likely to be achieved through the prevention of the bleeding and infectious complications associated with these disorders." }, { "docid": "18256197", "title": "Homocysteine and the risk of ischemic stroke in a triethnic cohort: the NOrthern MAnhattan Study.", "text": "BACKGROUND AND PURPOSE The level of total homocysteine (tHcy) that confers a risk of ischemic stroke is unsettled, and no prospective cohort studies have included sufficient elderly minority subjects. We investigated the association between mild to moderate fasting tHcy level and the incidence of ischemic stroke, myocardial infarction, and vascular death in a multiethnic prospective study. \n METHODS A population-based cohort was followed for vascular events (stroke, myocardial infarction, and vascular death). Baseline values of tHcy and methylmalonic acid were measured among 2939 subjects (mean age, 69+/-10; 61% women, 53% Hispanics, 24% blacks, and 20% whites). Cox proportional models were used to calculate hazard ratios (HRs) and 95% CIs in tHcy categories after adjusting for age, race, education, renal insufficiency, B12 deficiency, and other risk factors. \n RESULTS The adjusted HR for a tHcy level > or =15 micromol/L compared with <10 micromol/L was greatest for vascular death (HR=6.04; 95% CI, 3.44 to 10.60), followed by combined vascular events (HR=2.27; 95% CI, 1.51 to 3.43), ischemic stroke (HR=2.01; 95% CI, 1.00 to 4.05), and nonvascular death (HR=2.02; 95% CI, 1.31 to 3.14). Mild to moderate elevations of tHcy of 10 to 15 micromol/L were not significantly predictive of ischemic stroke, but increased the risk of vascular death (2.27; 95% CI, 1.44 to 3.60) and combined vascular events (1.42; 95% CI, 1.06 to 1.88). The effect of tHcy was stronger among whites and Hispanics, but not a significant risk factor for blacks. \n CONCLUSIONS Total Hcy elevations above 15 micromol/L are an independent risk factor for ischemic stroke, whereas mild elevations of tHcy of 10 to 15 micromol/L are less predictive. The vascular effects of tHcy are greatest among whites and Hispanics, and less among blacks." } ]

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