Effectiveness of multidisciplinary care teams in reducing major amputation rate in adults with diabetes: A systematic review & meta-analysis.

AIMS: To determine the pooled effectiveness of multidiscipinary care teams (MCTs) in reducing major amputation rates in adults with diabetes. METHODS: A systematic review and meta-analysis was performed, searching databases MEDLINE, EMBASE, Google Scholar, Cochrane Library, and Clinicaltrials.gov thru October 2018. We included only before-after studies comparing amputation rates before and after the implementation of a MCT for the prevention of major amputation in adults with diabetes. Our primary outcome was relative risk of major amputation. Risk ratios and 95% confidence intervals were calculated using a fixed effects model. RESULTS: Twenty studies met the inclusion criteria. Nine studies were included in the meta-analysis, and eleven were included in a qualitative analysis. Exposure to a MCT resulted in a protective effect ranging from a RR of 0.44 [p-value < 0.00001 (95% CI 0.38, 0.51) I2 = 67%] to a RR of 0.61 [p-value < 0.0001, (95% CI 0.50, 0.75) I2 = 0%] after sensitivity analysis, and remained robust in qualitative analysis. CONCLUSIONS: Healthcare systems can expect a 39-56% amputation rate reduction after implementing an MCT amputation prevention program. These findings may justify the use of additional resources needed for program implementation by helping healthcare systems predict the anticipated benefit these teams have on "possible limbs saved". FUNDING: None.

IL-1ß associations with posttraumatic epilepsy development: A genetics and biomarker cohort study.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1ß) gene, Il-1ß levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1ß ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1ß tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1ß levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1ß gene variants, and also PTE. Temporally matched CSF/serum IL-1ß ratios were also generated to reflect the relative contribution of serum IL-1ß to CSF IL-1ß. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1ß ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1ß levels (p = 0.014) and higher IL-1ß CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1ß gene variability in PTE risk and linking (1) IL-1ß gene variation with serum IL-1ß levels observed after TBI and (2) IL-1ß ratios with PTE risk. Given these findings, we propose that genetic and IL-1ß ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1ß production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1ß CSF/serum associations with PTE, and (3) evaluating targeted IL-1ß therapies that reduce PTE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development.

OBJECTIVE: Determine if genetic variation in enzymes/transporters influencing extracellular adenosine homeostasis, including adenosine kinase (ADK), [ecto-5'-nucleotidase (NT5E), cluster of differentiation 73 (CD73)], and equilibrative nucleoside transporter type-1 (ENT-1), is significantly associated with epileptogenesis and posttraumatic epilepsy (PTE) risk, as indicated by time to first seizure analyses. METHODS: Nine ADK, three CD73, and two ENT-1 tagging single nucleotide polymorphisms (SNPs) were genotyped in 162 white adults with moderate/severe traumatic brain injury (TBI) and no history of premorbid seizures. Kaplan-Meier models were used to screen for genetic differences in time to first seizure occurring >1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model. RESULTS: Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27-15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) . SIGNIFICANCE: Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development.

IL-1ß associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1ß) gene, IL-1ß levels in cerebrospinal fluid (CSF) and serum, and CSF/serum IL-1ß ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1ß tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1ß levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1ß gene variants, and also PTE. Temporally matched CSF/serum IL-1ß ratios were also generated to reflect the relative contribution of serum IL-1ß to CSF IL-1ß. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1ß ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1ß levels (p = 0.014) and higher IL-1ß CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1ß gene variability in PTE risk and linking (1) IL-1ß gene variation with serum IL-1ß levels observed after TBI and (2) IL-1ß ratios with PTE risk. Given these findings, we propose that genetic and IL-1ß ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1ß production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1ß CSF/serum associations with PTE, and (3) evaluating targeted IL-1ß therapies that reduce PTE.