Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Identification and evaluation of novel protective antigens for the development of a candidate TB subunit vaccine

The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), is urgently needed. The only currently available vaccine, BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognised during the course of human infection. A replication deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually and these vectors were evaluated for protective efficacy in murine M.tb challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4+ and CD8+ CXCR3+ KLRG1- T cells, previously associated with M.tb protection, were enriched in vaccinated compared to control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models is now merited, together with the identification of further novel protective antigens using this selection strategy

Identification and evaluation of novel protective antigens for the development of a candidate TB subunit vaccine

The development of a vaccine against tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (M.tb), is urgently needed. The only currently available vaccine, BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognised during the course of human infection. A replication deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually and these vectors were evaluated for protective efficacy in murine M.tb challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4+ and CD8+ CXCR3+ KLRG1- T cells, previously associated with M.tb protection, were enriched in vaccinated compared to control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models is now merited, together with the identification of further novel protective antigens using this selection strategy

Postnatal Expansion, Maturation, and Functionality of MR1T Cells in Humans

MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR α-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, including Mycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labeling and of the TRAV1-2^{+} MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2^{+}CD161^{++}CD26^{++} cells). We analyzed postnatal expansion, maturation, and functionality of peripheral blood MR1-5-OP-RU tetramer^{+} MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection with M. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer^{+} MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4^{+} and TRAV1-2^{−} population in neonates, to a predominantly TRAV1-2^{+}CD161^{++}CD26^{++}CD8^{+} population. We also observed that tetramer^{+} MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ~10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer^{+}TRAV1-2^{+} and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naïve T cell markers on tetramer^{+} TRAV1-2^{+} MR1T cells more rapidly than tetramer^{+}TRAV1-2^{−} MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer^{+}TRAV1-2^{+} population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood