Publications

BACKGROUND

Vital sign instability on discharge could be a clinically objective means of assessing readiness and safety for discharge; however, the association between vital sign instability on discharge and post-hospital outcomes is unclear.

OBJECTIVE

To assess the association between vital sign instability at hospital discharge and post-discharge adverse outcomes.

DESIGN

Multi-center observational cohort study using electronic health record data. Abnormalities in temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation were assessed within 24 hours of discharge. We used logistic regression adjusted for predictors of 30-day death and readmission.

PARTICIPANTS

Adults (≥18 years) with a hospitalization to any medicine service in 2009-2010 at six hospitals (safety-net, community, teaching, and non-teaching) in north Texas.

MAIN MEASURES

Death or non-elective readmission within 30 days after discharge.

KEY RESULTS

Of 32,835 individuals, 18.7 % were discharged with one or more vital sign instabilities. Overall, 12.8 % of individuals with no instabilities on discharge died or were readmitted, compared to 16.9 % with one instability, 21.2 % with two instabilities, and 26.0 % with three or more instabilities (p < 0.001). The presence of any (≥1) instability was associated with higher risk-adjusted odds of either death or readmission (AOR 1.36, 95 % CI 1.26-1.48), and was more strongly associated with death (AOR 2.31, 95 % CI 1.91-2.79). Individuals with three or more instabilities had nearly fourfold increased odds of death (AOR 3.91, 95 % CI 1.69-9.06) and increased odds of 30-day readmission (AOR 1.36, 95 % 0.81-2.30) compared to individuals with no instabilities. Having two or more vital sign instabilities at discharge had a positive predictive value of 22 % and positive likelihood ratio of 1.8 for 30-day death or readmission.

CONCLUSIONS

Vital sign instability on discharge is associated with increased risk-adjusted rates of 30-day mortality and readmission. These simple vital sign criteria could be used to assess safety for discharge, and to reduce 30-day mortality and readmissions.

Type I interferons (including IFNαβ) are innate cytokines that may contribute to pathogenesis during Mycobacterium tuberculosis (Mtb) infection. To induce IFNβ, Mtb must gain access to the host cytosol and trigger stimulator of interferon genes (STING) signaling. A recently proposed model suggests that Mtb triggers STING signaling through bacterial DNA binding cyclic GMP-AMP synthase (cGAS) in the cytosol. The aim of this study was to test the generalizability of this model using phylogenetically distinct strains of the Mtb complex (MTBC). We infected bone marrow derived macrophages with strains from MTBC Lineages 2, 4 and 6. We found that the Lineage 6 strain induced less IFNβ, and that the Lineage 2 strain induced more IFNβ, than the Lineage 4 strain. The strains did not differ in their access to the host cytosol and IFNβ induction by each strain required both STING and cGAS. We also found that the three strains shed similar amounts of bacterial DNA. Interestingly, we found that the Lineage 6 strain was associated with less mitochondrial stress and less mitochondrial DNA (mtDNA) in the cytosol compared with the Lineage 4 strain. Treating macrophages with a mitochondria-specific antioxidant reduced cytosolic mtDNA and inhibited IFNβ induction by the Lineage 2 and 4 strains. We also found that the Lineage 2 strain did not induce more mitochondrial stress than the Lineage 4 strain, suggesting that additional pathways contribute to higher IFNβ induction. These results indicate that the mechanism for IFNβ by Mtb is more complex than the established model suggests. We show that mitochondrial dynamics and mtDNA contribute to IFNβ induction by Mtb. Moreover, we show that the contribution of mtDNA to the IFNβ response varies by MTBC strain and that additional mechanisms exist for Mtb to induce IFNβ.

Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCε), occurs in male but not in female rats. However, activation of second messengers downstream of PKCε, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females. The lowest dose of ryanodine able to induce priming in females (1 pg) is 1/100,000(th) that needed in males (100 ng), an effect dependent on the activation of ryanodine receptors. Treatment of female rats with antisense to estrogen receptor alpha (ERα), but not beta (ERβ), mRNA, prevented the induction of priming by low dose ryanodine, and the ERα agonist, PPT, induced ryanodine receptor-dependent priming. In vitro application of ryanodine in low concentration (2 nM) to small DRG neurons cultured from females, significantly potentiated calcium release via ryanodine receptors induced by caffeine. This effect was only observed in IB4+ neurons, cultured in the presence of β-estradiol or PPT. Our results demonstrate a profound regulatory role of ERα in ryanodine receptor-dependent transition to chronic pain.

BACKGROUND

Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS).

OBJECTIVE

To evaluate efficacy and safety of abatacept in RRMS.

METHODS

ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks.

RESULTS

No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated.

CONCLUSION

The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.