Embolic protection device use and its association with procedural safety and long‐term outcomes following saphenous vein graft intervention: An analysis from the British Columbia Cardiac registry

• Coronary stents are commonly deployed using high pressure. However, the duration time of balloon inflation during deployment is still to be determined.
• Vallurupalli and coworkers, in this issue of CCI, show that the stent system takes an average of 33 sec to “accommodate” its pressure during in vitro deployment. In patients, the mean stent inflation time to achieve pressure stability was 104 seconds, ranging from 30 to 380 sec.
• These results challenge a rapid inflation/deflation approach for stent deployment. It is suggested that the duration of the inflation might be individualized, in a case‐by‐case approach.
• However, the findings must be interpreted with caution, as they cannot be directly extrapolated to more diverse clinical, angiographic, and interventional scenarios.

     

Pharmacokinetics of LFF571 and Vancomycin in Patients with Moderate Clostridium difficile Infections

Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C. difficile that is comparable to or greater than that of other clinically used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. This multicenter, randomized, evaluator-blind, and active-controlled study evaluated the safety, efficacy, and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The PK parameters were calculated from drug concentrations measured in serum and fecal samples. The systemic exposure following oral administration of 200 mg of LFF571 four times per day for 10 days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/ml, whereas the levels in feces at the end of treatment were between 107 and 12,900 μg/g. In comparison, the peak vancomycin level observed in serum was considerably higher, at 2.73 μg/ml; the levels of vancomycin in feces were not measured. Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571. These results are consistent with the retention of LFF571 in the lumen of the gastrointestinal tract. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01232595","term_id":"NCT01232595"}}NCT01232595.)     

Thalassaemia major and infectious risk: High Mobility Group Box‐1 represents a novel diagnostic and prognostic biomarker

High mobility group box ‐1 (HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in β‐thalassemia major (TM) by evaluating its diagnostic and prognostic role. Fifty‐one TM patients and 30 healthy subjects (HS) were enrolled. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1 to determine the best cut‐off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14·6 ± 8·7 vs. 2·08 ± 0·9 ng/ml, P < 0·0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10·2 ± 8 vs. 19·1 ± 7 ng/ml, P = 0·004). ROC analyses revealed an AUC for serum HMGB1 of 0·801, with a sensitivity and specificity of 92·3% and 68·2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events (HR: 0·81; P = 0·006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events.     

Axonal fusion via conduit-based delivery of hydrophilic polymers

Background

Hydrophilic polymers have been shown to improve physiologic recovery following repair of transected nerves with microsutures. Our study was designed to combine hydrophilic polymer therapy with nerve tubes (NT) to enhance polymer delivery to the site of nerve injury.

Methods

Using a rat sciatic nerve injury model, a single transection injury was repaired in an end-to-end fashion with NT + polyethylene glycol (PEG) to NT alone. Compound action potentials (CAPs) were recorded before nerve transection and after repair. Behavioral testing was performed for 5 weeks.

Results

PEG therapy restored CAPS in all, but one, animals, while no CAPS were recorded in animals not receiving PEG. Behavioral nerve function was measured using the standardized functional assessment technique and foot fault asymmetry scores (FF). FF scores were improved for the PEG therapy groups on postoperative days 7, 14, and 21. However, after expected eventual axonal outgrowth, the benefit was less noticeable at days 28 and 35. Immunohistochemistry of the distal axon segments showed an increase number of sensory and motor axons in the NT + PEG group as compared to NT alone.

Conclusion

These data suggest that PEG delivery via a conduit may provide a simple, effective way to fuse severed axons and regain early nerve function. For proximal nerve injuries in large animals, recovery of axonal continuity could dramatically improve outcomes, even if fusion only occurs in a small percentage of axons.     

Feasibility and acceptability of mobile phone short message service as a support for patients receiving antiretroviral therapy in rural Uganda: a cross-sectional study

Introduction

Mobile phone technologies have been promoted to improve adherence to antiretroviral therapy (ART). We studied the receptiveness of patients in a rural Ugandan setting to the use of short messaging service (SMS) communication for such purposes.

Methods

We performed a cross-sectional analysis measuring mobile phone ownership and literacy amongst patients of The AIDS Support Organisation (TASO) in Jinja, Uganda. We performed bivariate and multivariate logistic regression analyses to examine associations between explanatory variables and a composite outcome of being literate and having a mobile phone.

Results

From June 2012 to August 2013, we enrolled 895 participants, of whom 684 (76%) were female. The median age was 44 years. A total of 576 (63%) were both literate and mobile phone users. Of these, 91% (527/ 576) responded favourably to the potential use of SMS for health communication, while only 38.9% (124/319) of others were favourable to the idea (p<0.001). A lower proportion of literate mobile phone users reported optimal adherence to ART (86.4% vs. 90.6%; p=0.007). Male participants (AOR=2.81; 95% CI 1.83–4.30), sub-optimal adherence (AOR=1.76; 95% CI 1.12–2.77), those with waged or salaried employment (AOR=2.35; 95% CI 1.23–4.49), crafts/trade work (AOR=2.38; 95% CI 1.11–5.12), or involved in petty trade (AOR=1.85; 95% CI 1.09–3.13) (in comparison to those with no income) were more likely to report mobile phone ownership and literacy.

Conclusions

In a rural Ugandan setting, we found that over 60% of patients could potentially benefit from a mobile phone-based ART adherence support. However, support for such an intervention was lower for other patients.     

Nitric oxide modulates μ‐opioid receptor function in vitro

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that develops as a consequence of prolonged hyperglycaemia‐induced injury to the long nerves. Apart from pain, PDN is also characterized by morphine hyposensitivity. Intriguingly, in streptozotocin (STZ)‐induced diabetic rats exhibiting marked morphine hyposensitivity, dietary administration of the nitric oxide (NO) precursor, L‐arginine at 1 g/d, progressively rescued morphine efficacy and potency over an 8‐week treatment period. In earlier work, single bolus doses of the furoxan nitric oxide (NO) donor, PRG150 (3‐methylfuroxan‐4‐carbaldehyde), evoked dose‐dependent pain relief in STZ‐diabetic rats but the efficacious doses were 3‐4 orders of magnitude higher in advanced diabetes than that required in early STZ diabetes. Together, these findings suggested a role for NO in the modulation of μ‐opioid (MOP) receptor signalling. Therefore, the present study was designed to assess a role for NO released from PRG150, in modulating MOP receptor function in vitro. Here, we show an absolute requirement for the MOP receptor, but not the δ‐opioid (DOP) or the κ‐opioid (KOP) receptor, to transduce the cellular effects of PRG150 on forskolin‐stimulated cAMP responses in vitro. PRG150 did not interact with the classical naloxone‐sensitive binding site of the MOP receptor, and its effects on cAMP responses in HEK‐MOP cells were also naloxone‐insensitive. Nevertheless, the inhibitory effects of PRG150 on forskolin‐stimulated cAMP responses in HEK‐MOP cells were dependent upon pertussis toxin (PTX)‐sensitive G_i/o proteins as well as membrane lipid rafts and src kinase. Together, our findings implicate a role for NO in modulating MOP receptor function in vivo.     

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.     

Alcohol outlet density and intimate partner violence-related emergency department visits

Background: Previous research has identified risk factors for intimate partner violence (IPV) severity, injury, and emergency department (ED) visits. These risk factors have been shown at both the individual level (heavy drinking and other substance use on the part of 1 or both partners) and the neighborhood level (residence in an area characterized by poverty and social disadvantage). Alcohol outlet density has been linked with assaultive violence in community settings, but has not been analyzed in relation to IPV‐related ED visits. This study examined the effects of outlet densities on IPV‐related ED visits throughout California between July 2005 and December 2008. Methods: Half‐yearly counts of ED visits related to IPV (E‐code 967.3) were computed for each zip code from patient‐level public data sets. Alcohol outlet density measures, calculated separately for bars, off‐premise outlets, and restaurants, were derived from California Alcohol Beverage Control records. Census‐based neighborhood demographic characteristics previously shown to be related to health disparities and IPV (percent black, percent Hispanic, percentage below 150% of poverty line, percent unemployed) were included in models. This study used Bayesian space–time models that allow longitudinal analysis at the zip code level despite frequent boundary redefinitions. These spatial misalignment models control for spatial variation in geographic unit definitions over time and account for spatial autocorrelation using conditional autoregressive (CAR) priors. The model incorporated data from between 1,686 (2005) and 1,693 (2008) zip codes across California for 7 half‐year time periods from 2005 through 2008 (n = 11,836). Results: Density of bars was positively associated with IPV‐related ED visits. Density of off‐premise outlets was negatively associated with IPV‐related ED visits; this association was weaker and smaller than the bar association. There was no association between density of restaurants and IPV‐related ED visits. Conclusions: Further research is needed to understand the mechanisms by which environmental factors, such as alcohol outlet density, affect IPV behaviors resulting in ED visits.     

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE)

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.