BackgroundIn addition to acute hospital mortality, sepsis is associated with higher risk of death following hospital discharge. We assessed the strength of epidemiological evidence supporting a causal link between sepsis and mortality after hospital discharge by systematically evaluating the available literature for strength of association, bias, and techniques to address confounding.MethodsWe searched Medline and Embase using the following ‘mp’ terms, MESH headings and combinations thereof - sepsis, septic shock, septicemia, outcome. Studies published since 1992 where one-year post-acute mortality in adult survivors of acute sepsis could be calculated were included. Two authors independently selected studies and extracted data using predefined criteria and data extraction forms to assess risk of bias, confounding, and causality. The difference in proportion between cumulative one-year mortality and acute mortality was defined as post-acute mortality. Meta-analysis was done by sepsis definition categories with post-acute mortality as the primary outcome.ResultsThe literature search identified 11,156 records, of which 59 studies met our inclusion criteria and 43 studies reported post-acute mortality. In patients who survived an index sepsis admission, the post-acute mortality was 16.1 % (95 % CI 14.1, 18.1 %) with significant heterogeneity (p < 0.001), on random effects meta-analysis. In studies reporting non-sepsis control arm comparisons, sepsis was not consistently associated with a higher hazard ratio for post-acute mortality. The additional hazard associated with sepsis was greatest when compared to the general population. Older age, male sex, and presence of comorbidities were commonly reported independent predictors of post-acute mortality in sepsis survivors, challenging the causality relationship. Sensitivity analyses for post-acute mortality were consistent with primary analysis.ConclusionsEpidemiologic criteria for a causal relationship between sepsis and post-acute mortality were not consistently observed. Additional epidemiologic studies with recent patient level data that address the pre-illness trajectory, confounding, and varying control groups are needed to estimate sepsis-attributable additional risk and modifiable risk factors to design interventional trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1276-7) contains supplementary material, which is available to authorized users.

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The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria AbstractBackground: Mefloquine and artesunate combination therapy is the recommended first-line treatment for uncomplicated malaria throughout much of south-east Asia. Concerns have been raised about the potential central nervous system (CNS) effects of both drug components and there are no detailed reports in very young children.

An impaired capacity of muscle to regenerate after critical illness results in long-term functional disability. We previously described in a long-term rat peritonitis model that gastrocnemius displays near-normal histology whereas soleus demonstrates a necrotizing phenotype. We thus investigated the link between the necrotizing phenotype of critical illness myopathy and proteasome activity in these two limb muscles. We studied male Wistar rats that underwent an intraperitoneal injection of the fungal cell wall constituent zymosan or n-saline as a sham-treated control. Rats ( n = 74) were killed at 2, 7, and 14 days postintervention with gastrocnemius and soleus muscle removed and studied ex vivo. Zymosan-treated animals displayed an initial reduction of body weight but a persistent decrease in mass of both lower hindlimb muscles. Zymosan increased chymotrypsin- and trypsin-like proteasome activities in gastrocnemius at days 2 and 7 but in soleus at day 2 only. Activated caspases-3 and -9, polyubiquitin proteins, and 14-kDa fragments of myofibrillar actin (proteasome substrates) remained persistently increased from day 2 to day 14 in soleus but not in gastrocnemius. These results suggest that a relative proteasome deficiency in soleus is associated with a necrotizing phenotype during long-term critical illness. Rescuing proteasome clearance may offer a potential therapeutic option to prevent long-term functional disability in critically ill patients.