847 research outputs found

    Using data to understand outcomes for cancer surgery in low- and middle-income countries

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    BACKGROUND: Of the 15.2 million individuals diagnosed with cancer worldwide in 2015, 80% had a need for surgery. Yet little comparative data globally exist on early outcomes, particularly within low-income and middle-income countries (LMICs). I designed and delivered an international, prospective cohort study to provide comprehensive data across income settings on early outcomes in patients undergoing surgery for three common cancers. METHODS: I determined the early outcomes following cancer surgery through standardised and prospective methodology to gather contemporaneous and comprehensive data across multiple countries. Next, I validated this data to ensure accuracy and high case ascertainment. Finally, I determined the patient- and hospital-level factors which influence early outcomes following cancer surgery, to identify potential interventions which may improve surgical cancer care worldwide. RESULTS: In an international cohort of 15 958 patients from 428 hospitals and 82 countries undergoing surgery for breast, colorectal, or gastric cancer, case ascertainment and data accuracy were high. Higher postoperative mortality was seen in patients receiving surgery in LMICs, despite equivalent complication rates. The capacity to rescue patients from death after the development of common postoperative complications explains some of the disproportionate mortality burden experienced in LMICs. I demonstrated improvements in hospital facilities, which correlate with a hospital’s ability to perform safe, high-quality operations and aid the early identification and treatment of postoperative complications, are likely to prevent up to three early surgical deaths for every 100 patients undergoing cancer surgery worldwide. CONCLUSIONS: Perioperative mortality is disproportionately greater in LMICs, which contributes to worse cancer survival in these settings. Excess early mortality following cancer surgery is avoidable, but improving access to surgical care alone is unlikely to significantly reduce cancer-associated mortality. Urgent assessment of pragmatic perioperative interventions led by investigators in LMICs is needed to avert avoidable mortality after the development of common complications after cancer surgery

    Total Hip Arthroplasty - over 100 years of operative history

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    Total hip arthroplasty (THA) has completely revolutionized the nature in which the arthritic hip is treated, and is considered to be one of the most successful orthopaedic interventions of its generation. With over 100 years of operative history, this review examines the progression of the operation from its origins, together with highlighting the materials and techniques that have contributed to its development. Knowledge of its history contributes to a greater understanding of THA, such as the reasons behind selection of prosthetic materials in certain patient groups, while demonstrating the importance of critically analyzing research to continually determine best operative practice. Finally, we describe current areas of research being undertaken to further advance techniques and improve outcomes

    Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

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    Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies

    Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis.

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    OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART

    The Impossibility of a Perfectly Competitive Labor Market

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    Using the institutional theory of transaction cost, I demonstrate that the assumptions of the competitive labor market model are internally contradictory and lead to the conclusion that on purely theoretical grounds a perfectly competitive labor market is a logical impossibility. By extension, the familiar diagram of wage determination by supply and demand is also a logical impossibility and the neoclassical labor demand curve is not a well-defined construct. The reason is that the perfectly competitive market model presumes zero transaction cost and with zero transaction cost all labor is hired as independent contractors, implying multi-person firms, the employment relationship, and labor market disappear. With positive transaction cost, on the other hand, employment contracts are incomplete and the labor supply curve to the firm is upward sloping, again causing the labor demand curve to be ill-defined. As a result, theory suggests that wage rates are always and everywhere an amalgam of an administered and bargained price. Working Paper 06-0
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