Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)alpha-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFalpha levels before MCAO and that TNFalpha is required for subsequent reduction in damage, as mice lacking TNFalpha are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.

Osteopontin (OPN), a large secreted glycoprotein with an arginine, glycine, aspartate (RGD) motif, can bind and signal through cellular integrin receptors. We have shown previously that OPN enhances neuronal survival in the setting of ischemia. Here, we sought to increase the neuroprotective potency of OPN and improve the method of delivery with the goal of identifying a treatment for stroke in humans. We show that thrombin cleavage of OPN improves its ability to ligate integrin receptors and its neuroprotective capacity in models of ischemia. Thrombin-cleaved OPN is a twofold more effective neuroprotectant than the untreated molecule. We also tested whether OPN could be administered intranasally and found that it is efficiently targeted to the brain via intranasal delivery. Furthermore, intranasal administration of thrombin-treated OPN confers protection against ischemic brain injury. Osteopontin mimetics based on the peptide sequences located either N or C terminal to the thrombin cleavage site were generated and tested in models of ischemia. Treatment with successively shorter N-terminal peptides and a phosphorylated C-terminal peptide provided significant neuroprotection against ischemic injury. These findings show that OPN mimetics offer promise for development into new drugs for the treatment of stroke.

Background and Purpose-Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T 1 AM) and thyronamine (T 0 AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T 1 AM-and T 0 AM-induced hypothermia protects against brain injury from experimental stroke. Methods-We tested T 1 AM and T 0 AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T 1 AM and T 0 AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented. Results-T 1 AM and T 0 AM administration reduced body temperature from 37°C to 31°C. Mice given T 1 AM or T 0 AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T 1 AM before ischemia displayed significantly smaller infarcts compared with controls. Pre-and postischemia treatments required the induction of hypothermia. T 1 AM and T 0 AM treatment in vitro failed to confer neuroprotection against ischemia. Conclusions-T 1 AM and T 0 AM, are potent neuroprotectants in acute stroke and T 1 AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T 1 AM and T 0 AM may underlie neuroprotection. T 1 AM and T 0 AM offer promise as treatments for brain injury.

Background Determining risk factors for opioid abuse or dependence will help clinicians practice informed prescribing and may help mitigate opioid abuse or dependence. The purpose of this study is to identify variables predicting opioid abuse or dependence. Methods A retrospective cohort study using de-identified integrated pharmacy and medical claims between October 2009 and September 2013. Patients with at least one opioid prescription claim during the index period (index claim) were identified. We ascertained risk factors using data from 12 months prior to index claim (pre-period) and captured abuse or dependency diagnosis using data from 12 months post index claim (post-period). We included continuously eligible (pre- and post-period) commercially insured patients aged 18 or older. We excluded patients with cancer, residence in a long-term care facility, or previous diagnosis of opioid abuse or dependence (identified by International Classification of Diseases-9th revision (ICD-9) code or buprenorphine/naloxone claim in the pre-period). The outcome was a diagnosis of opioid abuse (ICD9 code 304.0×) or dependence (305.5). Results The final sample consisted of 694,851 patients. Opioid abuse or dependence was observed in 2,067 patients (0.3%). Several factors predicted opioid abuse or dependence: younger age [per decade (older) odds ratio (OR) 0.68], being a chronic opioid user [OR 4.39], history of mental illness [OR 3.45], non-opioid substance abuse [OR 2.82], alcohol abuse [OR 2.37], high morphine equivalent dose per day user [OR 1.98], tobacco use [OR 1.80], obtaining opioids from multiple prescribers [OR 1.71], residing in the South [OR 1.65], West [OR 1.49], or Midwest [OR 1.24], using multiple pharmacies [OR 1.59], male gender [OR 1.43], and increased 30-day adjusted opioid prescriptions [OR 1.05]. Conclusions Readily available demographic, clinical, behavioral, pharmacy and geographic information can be used to predict likelihood of opioid abuse or dependence.

BackgroundThere is limited literature about physician handoffs between the intensive care unit (ICU) and the ward, and best practices have not been described. These patients are uniquely vulnerable given their medical complexity, diagnostic uncertainty and reduced monitoring intensity. We aimed to characterise the structure, perceptions and processes of ICU–ward handoffs across three teaching hospitals using multimodal methods: by identifying the handoff components involved in communication failures and describing common processes of patient transfer.MethodsWe conducted a study at three academic medical centres using two methods to characterise the structure, perceptions and processes of ICU–ward transfers: (1) an anonymous resident survey characterising handoff communication during ICU–ward transfer, and (2) comparison of process maps to identify similarities and differences between ICU–ward transfer processes across the three hospitals.ResultsOf the 295 internal medicine residents approached, 175 (59%) completed the survey. 87% of the respondents recalled at least one adverse event related to communication failure during ICU–ward transfer. 95% agreed that a well-structured handoff template would improve ICU–ward transfer. Rehabilitation needs, intravenous access/hardware and risk assessments for readmission to the ICU were the most frequently omitted or incorrectly communicated components of handoff notes. More than 60% of the respondents reported that notes omitted or miscommunicated pending results, active subspecialty consultants, nutrition and intravenous fluids, antibiotics, and healthcare decision-maker information at least twice per month. Despite variable process across the three sites, all process maps demonstrated flaws and potential for harm in critical steps of the ICU–ward transition.ConclusionIn this multisite study, despite significant process variation across sites, almost all resident physicians recalled an adverse event related to the ICU–ward handoff. Future work is needed to determine best practices for ICU–ward handoffs at academic medical centres.