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

Differential Regulation of Synaptic Vesicle Protein Genes by Target and Synaptic Activity

Differentiation of presynaptic nerve terminals involves changes in gene expression; these may be regulated by synaptic transmission and/or by contact with the target muscle. To gain insight into the control of presynaptic differentiation, we examined the regulation by target and synaptic activity of synaptic vesicle protein (SVP) genes in the chick ciliary ganglion (CG). In the CG, two SVP genes, synaptotagmin I (syt I) and synaptophysin II (syp II), are coordinately upregulated at the time of target contact. To test the hypothesis that this upregulation is induced by target contact, we examined mRNA levels of syt I and syp II in CGs from embryos in which one eye had been removed before axon outgrowth. As expected, target removal prevented the normal upregulation of syt I mRNA in the deprived ganglion. In contrast, and unexpectedly, syp II mRNA upregulation was not affected. The target dependence of syt I upregulation was not attributable to nerve–muscle transmission, because blockade of this transmission had no effect on SVP mRNA levels. Surprisingly, blockade of synapses onto CG neurons from the brain also did not affect syt I mRNA levels but increased levels of syp II mRNA. We conclude that contact with target induces upregulation of syt I mRNA, which is the case for spinal motor neurons. However, the normal upregulation of syp II mRNA is not controlled by the same signal(s). Instead, our results suggest that these two SVP genes are differentially regulated, both by target contact and by blockade of synaptic transmission

Swimming ability improves over a period of eight weeks after a complete spinal cord transection in adult zebrafish.

<p>(A) Examples of swimming path recorded in a five-min period at two- (“2 wpl”) and eight (“8 wpl”) weeks post-lesion. (B) Boxplot diagram demonstrating the median distance swam and confidence interval of the median during the five-min period. Asterisks indicate significant differences between groups (Kruskal-Wallis test, followed by Mann-Whitney U test with Bonferroni correction, p significant if ≤0.003). Two weeks post-lesion group is significantly different from all other groups. Normal (unlesioned) group is significantly different from all other groups. (C) A cumulative distribution plot illustrating the differences in the distribution of data between individual groups. (unlesioned (n = 19), sham-injured (n = 20), 2 wpl (n = 20), 4 wpl (n = 33), 6 wpl (n = 34), 8 wpl (n = 35).</p

Cerebrospinal axon regeneration is correlated with swimming ability.

<p>(A) Rank of number of FE-positive neurons in the whole brain is correlated with the rank of average distance swam in all analyzed zebrafish (n = 132) and, specifically, at (C) four (n = 32) and (D) six (n = 32) weeks post-lesion. No correlation was observed at (B) two (n = 15) and (E) eight (n = 34) weeks post-lesion and in (F) normal (unlesioned) zebrafish (n = 19). Spearman’s rho correlation, differences considered significant with p<0.05.</p

The number of cerebrospinal axons regenerated into the caudal spinal cord increases in time after the lesion.

<p>(A–E) Retrogradely labeled neurons in RT (A–E), MaON (F–J), and NMLF (K–O) at two (A, F, K, respectively), four (B, G, L, respectively), six (C, H, M, respectively), and eight (D, I, N, respectively) weeks post-lesion and in unlesioned zebrafish (E, J, O, respectively). Boxplot diagrams demonstrating the median number (and confidence interval of median) of FE-labeled neurons in zebrafish at two, four, six, and eight weeks post-lesion and in unlesioned zebrafish in the whole brain (P), RT (Q), MaON (R), and NMLF (S). Asterisks indicate significant differences between groups (Kruskal-Wallis test, followed by Mann-Whitney U test with Bonferroni correction, p significant if ≤0.005). The numbers of total FE-positive neurons and FE-positive neurons in RT are significantly different between two weeks post-lesion and six weeks post-lesion. The number of FE-positive neurons in normal (unlesioned) group is not significantly different from six weeks post-lesion in the whole brain and in each of the examined nuclei. 2 wpl (n = 20); 4 wpl (n = 21); 6 wpl (n = 20); 8 wpl (n = 20), unlesioned (n = 19). Bar = 100 µm in A–O.</p

New tissue forms within the spinal cord transection site in adult zebrafish.

<p>(A) Percentage of zebrafish with (white) and without (black) a tissue bridge at the different time points post-lesion. (B) Photographs of dissected spinal cord showing the new tissue in the transection site (asterisks) and bridging the spinal cord stumps. Bar = 1 mm.</p

GFAP-positive cells form a tissue bridge at the spinal cord transection site.

<p>(A) Distribution and orientation of GFAP-positive cells and processes at two weeks post-lesion in zebrafish without the tissue bridge. Distribution and orientation of GFAP-positive cells and processes in zebrafish with the tissue bridge at two weeks post-lesion (B), four weeks post-lesion (C), six weeks post-lesion (D) and eight weeks post-lesion (E). (B’) Enlarged view of the newly formed tissue from box in B. Arrowheads point at the longitudinally oriented GFAP-positive processes. (E’) Enlarged view of the newly formed tissue from box in E. (F) Distribution of GFAP-positive cells and processes in normal (unlesioned) tissue. Arrows point at the radially oriented GFAP-positive processes. Transection site is denoted with asterisks. Bar = 100 µm in A–E and 50 µm in B’, E’, F.</p

Axonal regeneration from specific brain nuclei is correlated with swimming ability.

<p>In all analyzed zebrafish, the rank of average distance swam is correlated with the rank of number of FE-positive neurons in the (A) RT, (B) MaON, and the (C) NMLF. Spearman’s rho correlation, differences considered significant with p<0.05, n = 92.</p

Schematic representation of the: (A) spinal cord transection, (B) open-field testing system, (C) retrograde tracing procedure, (D) transcardial perfusion.

<p>The spinal cord was cut between 8^th and 9^th vertebra. At different time points after transection (“survival”), average distance swam was measured for each fish using an open-field testing system. One day after swimming assessment Fluoroemerald was injected 4 mm caudally from the transection site. Unlesioned zebrafish were traced at the same level as lesioned zebrafish. A week after tracing, zebrafish were transcardially perfused and tissue collected for analysis. 1 d, 1 day; 1 wk, 1 week.</p

Effects of Interleukin-10 (IL-10) on Pain Behavior and Gene Expression Following Excitotoxic Spinal Cord Injury in the Rat

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized that QUIS-induced inflammation and subsequent gene expression contribute to the development and progression of pain-related behaviors and that blockade of inflammation-related gene expression leads to the amelioration of these behaviors. Using the QUIS model of spinal cord injury, we examined whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to reduce mRNA levels of inflammatory and cell death-related genes leading to a reduction of pain behaviors. The results demonstrate that animals receiving systemic injection of IL-10, 30 minutes following QUIS-induced SCI, showed a significant delay in the onset of excessive grooming behavior, a significant reduction in grooming severity, and a significant reduction in the longitudinal extent of a pattern of neuronal loss within the spinal cord characterized as “grooming-type damage.” QUIS injections also resulted in an increase in mRNA levels of interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), CD95 ligand (CD95-L, also called FAS-L/APO-1L), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Results of QUIS injury plus IL-10 treatment resulted in a significant downregulation of IL1-β and iNOS mRNA and these results were supported by Western blot analysis of protein levels following IL-10 treatment. These data suggest that IL-10 reduces inflammation and that targeting injury-induced inflammation is an effective strategy for limiting the extent of neuronal damage following excitotoxic SCI and thus the onset and progression of injury-induced pain behaviors