Long-term outcomes of patients admitted to an intensive care unit with intentional self-harm.

Self-harm is one of the most common reasons for admission to an intensive care unit (ICU). While most patients with self-harm survive the ICU admission, little is known about their outcomes after hospital discharge. We conducted a retrospective cohort study of patients in the Barwon region in Victoria admitted to the ICU with self-harm (between 1998 and 2018) who survived to hospital discharge. The primary objective was to determine mortality after hospital discharge, and secondarily estimate relative survival, years of potential life lost, cause of death and factors associated with death. Over the 20-year study period, there were 710 patients in the cohort. The median patient age was 37 years (interquartile range (IQR) 26-48 years). A total of 406 (57%) were female, and 527 (74%) had a prior psychiatric diagnosis. The incidence of ICU admission increased over time (incidence rate ratio 1.05; 95% confidence interval (CI) 1.03-1.06 per annum). There were 105 (15%) patients who died after hospital discharge. Relative survival decreased each year after discharge, with the greatest decrement during the first 12 months. At ten years, relative survival was 0.85 (95% CI 0.81-0.88). The median years of potential life lost was 35 (IQR 22-45). Cause of death was self-harm in 27%, possible self-harm in 32% and medical disease in 41%. The only factors associated with mortality were male sex, older age and re-admission to ICU with self-harm. Further population studies are required to confirm these findings, and to understand what interventions may improve long-term survival in this relatively young group of critically ill patients.

HIV-1 infection induces changes in expression of cellular splicing factors that regulate alternative viral splicing and virus production in macrophages.

BACKGROUND: Macrophages are important targets and long-lived reservoirs of HIV-1, which are not cleared of infection by currently available treatments. In the primary monocyte-derived macrophage model of infection, replication is initially productive followed by a decline in virion output over ensuing weeks, coincident with a decrease in the levels of the essential viral transactivator protein Tat. We investigated two possible mechanisms in macrophages for regulation of viral replication, which appears to be primarily regulated at the level of tat mRNA: 1) differential mRNA stability, used by cells and some viruses for the rapid regulation of gene expression and 2) control of HIV-1 alternative splicing, which is essential for optimal viral replication. RESULTS: Following termination of transcription at increasing times after infection in macrophages, we found that tat mRNA did indeed decay more rapidly than rev or nef mRNA, but with similar kinetics throughout infection. In addition, tat mRNA decayed at least as rapidly in peripheral blood lymphocytes. Expression of cellular splicing factors in uninfected and infected macrophage cultures from the same donor showed an inverse pattern over time between enhancing factors (members of the SR family of RNA binding proteins) and inhibitory factors (members of the hnRNP family). While levels of the SR protein SC35 were greatly up-regulated in the first week or two after infection, hnRNPs of the A/B and H groups were down-regulated. Around the peak of virus production in each culture, SC35 expression declined to levels in uninfected cells or lower, while the hnRNPs increased to control levels or above. We also found evidence for increased cytoplasmic expression of SC35 following long-term infection. CONCLUSION: While no evidence of differential regulation of tat mRNA decay was found in macrophages following HIV-1 infection, changes in the balance of cellular splicing factors which regulate alternative viral pre-mRNA splicing were observed. These changes correlated with changes in Tat expression and virus production and could play an important role in viral persistence in macrophages. This mechanism could provide a novel target for control of infection in this critical cell type, which would be necessary for eventual eradication of the virus from infected individuals.