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Batman by Grant Morrison omnibus
\"One of the greatest storytellers of his generation, Grant Morrison's arrival onto the Dark Knight was one of the most hyped debuts in industry history. This collection includes time-spanning epic graphic novels featuring the cataclysmic events of FINAL CRISIS and the introduction of Batman's son, Damian Wayne! These blockbuster stories featured a deconstruction of super hero comics like never before, with challenging, thought-provoking takes on the modern, four-color icons.\"-- Provided by publisher.
Book
Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients
Abstract Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m, $847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.
Journal Article
Hypertension in older adults
Since the last review of hypertension in older patients in this journal in 1999, there has been an enormous expansion in the available evidence for management of hypertension. Blood pressure treatment is only one part in an overall strategy of cardiovascular risk reduction. The actual prevalence of hypertension depends on the level of blood pressure used to define when treatment should be started and thus varies between patients depending on their degree of risk. A publication from the University of York NHS Centre for Reviews and Dissemination quoted a figure of over 50% of older people as being hypertensive in 1999. Newer guidelines tend to be encouraging treatment at lower blood pressure levels than previously and some authors now suggest that around 70% of the elderly population could be considered as hypertensive.
Journal Article
The Happy Burden of History
Germans are often accused of failing to take responsibility for Nazi crimes, but what precisely should ordinary people do differently? Indeed, scholars have yet to outline viable alternatives for how any of us should respond to terror and genocide. And because of the way they compartmentalize everyday life, our discipline-bound analyses often disguise more than they illuminate. Written by a historian, literary critic, philosopher, and theologian, The Happy Burden of History takes an integrative approach to the problem of responsible selfhood. Exploring the lives and letters of ordinary and intellectual Germans who faced the ethical challenges of the Third Reich, it focuses on five typical tools for cultivating the modern self: myths, lies, non-conformity, irony, and modeling. The authors carefully dissect the ways in which ordinary and intellectual Germans excused their violent claims to mastery with a sense of 'sovereign impunity.' They then recuperate the same strategies of selfhood for our contemporary world, but in ways that are self-critical and humble. The book shows how viewing this problem from within everyday life can empower and encourage us to bear the burden of historical responsibility ? and be happy doing so.
eBook
Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients
Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m, $847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.
Journal Article
Antibody–Drug Conjugates for Cancer Therapy
Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
Journal Article
Spatial and temporal patterns of mass bleaching of corals in the Anthropocene
Coral bleaching occurs when stressful conditions result in the expulsion of the algal partner from the coral. Before anthropogenic climate warming, such events were relatively rare, allowing for recovery of the reef between events. Hughes et al. looked at 100 reefs globally and found that the average interval between bleaching events is now less than half what it was before. Such narrow recovery windows do not allow for full recovery. Furthermore, warming events such as El Niño are warmer than previously, as are general ocean conditions. Such changes are likely to make it more and more difficult for reefs to recover between stressful events. Science , this issue p. 80 Coral reefs in the present day have less time than in earlier periods to recover from bleaching events. Tropical reef systems are transitioning to a new era in which the interval between recurrent bouts of coral bleaching is too short for a full recovery of mature assemblages. We analyzed bleaching records at 100 globally distributed reef locations from 1980 to 2016. The median return time between pairs of severe bleaching events has diminished steadily since 1980 and is now only 6 years. As global warming has progressed, tropical sea surface temperatures are warmer now during current La Niña conditions than they were during El Niño events three decades ago. Consequently, as we transition to the Anthropocene, coral bleaching is occurring more frequently in all El Niño–Southern Oscillation phases, increasing the likelihood of annual bleaching in the coming decades.
Journal Article
Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas
Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the “genomic recipe” for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.
Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.
Journal Article
Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells
Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR–ABL. Direct inhibition of BCR–ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR–ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show—using proteomics, transcriptomics and network analyses—that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR–ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.
Leukaemic stem cells (LSCs) are responsible for BCR–ABL-driven chronic myeloid leukaemia relapse; here, p53 and MYC signalling networks are shown to regulate LSCs concurrently, and targeting both these pathways has a synergistic effect in managing the disease.
Dual targeting of p53 and c-Myc pathways
Tyrosine kinase inhibitors are a first-line therapy in patients with chronic myeloid leukaemia (CML), where they target the oncogenic
BCR-ABL
fusion gene. However, relapse inevitably occurs, probably driven by a drug-resistant population of leukaemic stem cells (LSCs). This study uncovers the concurrent involvement of p53 and Myc signalling networks in regulating LSCs. The authors demonstrate that genetic and/or pharmacological targeting of both the p53 and c-Myc pathways achieves more effective disease neutralization in mouse and human cell models of CML.
Journal Article