The burden of severe hypoglycemia in type 1 diabetes

Aims: Approximately 1.25 million people in the US have type 1 diabetes mellitus (T1DM), a chronic metabolic disease that develops from the body’s inability to produce insulin, and requires life-long insulin therapy. Poor insulin adherence may cause severe hypoglycemia (SHO), leading to hospitalization and long-term complications; these, in turn, drive up costs of SHO and T1DM overall. This study’s objective was to estimate the prevalence and costs of SHO-related hospitalizations and their additional longer-term impacts on patients with T1DM using basal-bolus insulin.

Methods: Using Truven MarketScan claims, we identified adult T1DM patients using basal-bolus insulin regimens who were hospitalized for SHO (inpatient SHO patients) during 2010–2015. Two comparison groups were defined: those with outpatient SHO-related encounters only, including emergency department (ED) visits without hospitalization (outpatient SHO patients), and those with no SHO- or acute hyperglycemia-related events (comparison patients). Lengths of stay and SHO-related hospitalization costs were estimated and propensity score and inverse probability weighting methods were used to adjust for baseline differences across the groups to evaluate longer-term impacts.

Results: We identified 8,734 patients, of which 4.2% experienced at least one SHO-related hospitalization. Among those who experienced SHO (i.e. of those in the inpatient and outpatient SHO groups), 31% experienced at least one SHO-related hospitalization, while 9% were treated in the ED without subsequent hospitalization. Approximately 79% of patients were admitted directly to the hospital; the remainder were first assessed or treated in the ED. The inpatient SHO patients stayed in the hospital, including time in the ED, for 1.7 days and incurred $3551 in costs. About one-third of patients were hospitalized again for SHO. Inpatient SHO patients incurred significantly higher monthly costs after their initial SHO-related hospitalization than patients in the two other groups ($2084 vs $1313 and $1372), corresponding to 59% or 52% higher monthly costs for inpatient SHO patients.

Limitations: These analyses excluded patients who did not seek ED or hospital care when faced with SHO; events may have been miscoded; and we were not able to account for clinical characteristics associated with SHO, such as insulin dose and duration of diabetes, or unmeasured confounders.

Conclusions: The burden associated with SHO is not negligible. About 4% of T1DM patients using basal-bolus insulin regimens are hospitalized at least once due to SHO. Not only did those patients incur the costs of their SHO hospitalization, but they also incur red at least $712 (52%) more in costs per month after their hospitalization than outpatient SHO or comparison patients. Reducing SHO events can help decrease the burden associated with SHO among patients with T1DM.     

Nasal Administration of Cationic Nanoemulsions as Nucleic Acids Delivery Systems Aiming at Mucopolysaccharidosis Type I Gene Therapy

Purpose

This study demonstrates the nasal administration (NA) of nanoemulsions complexed with the plasmid encoding for IDUA protein (pIDUA) as an attempt to reach the brain aiming at MPS I gene therapy.

Methods

Formulations composed of DOPE, DOTAP, MCT (NE), and DSPE-PEG (NE-PEG) were prepared by high-pressure homogenization, and assessed in vitro on human fibroblasts from MPS I patients and in vivo on MPS I mice for IDUA production and gene expression.

Results

The physicochemical results showed that the presence of DSPE-PEG in the formulations led to smaller and more stable droplets even when submitted to dilution in simulated nasal medium (SNM). In vitro assays showed that pIDUA/NE-PEG complexes were internalized by cells, and led to a 5% significant increase in IDUA activity, besides promoting a two-fold increase in IDUA expression. The NA of pIDUA/NE-PEG complexes to MPS I mice demonstrated the ability to reach the brain, promoting increased IDUA activity and expression in this tissue, as well as in kidney and spleen tissues after treatment. An increase in serum IL-6 was observed after treatment, although with no signs of tissue inflammatory infiltrate according to histopathology and CD68 assessments.

Conclusions

These findings demonstrated that pIDUA/NE-PEG complexes could efficiently increase IDUA activity in vitro and in vivo after NA, and represent a potential treatment for the neurological impairment present in MPS I patients.

     

Sustained Release from Ionic-Gradient Liposomes Significantly Decreases ETIDOCAINE Cytotoxicity

Purpose

Etidocaine (EDC) is a long lasting local anesthetic, which alleged toxicity has restricted its clinical use. Liposomes can prolong the analgesia time and reduce the toxicity of local anesthetics. Ionic gradient liposomes (IGL) have been proposed to increase the upload and prolong the drug release, from liposomes.

Methods

First, a HPLC method for EDC quantification was validated. Then, large unilamellar vesicles composed of hydrogenated soy phosphatidylcholine:cholesterol with 250 mM (NH₄)₂SO₄ - inside gradient - were prepared for the encapsulation of 0.5% EDC. Dynamic light scattering, nanotracking analysis, transmission electron microscopy and electron paramagnetic resonance were used to characterize: nanoparticles size, polydispersity, zeta potential, concentration, morphology and membrane fluidity. Release kinetics and in vitro cytotoxicity tests were also performed.

Results

IGL_EDC showed average diameters of 172.3?±?2.6 nm, low PDI (0.12?±?0.01), mean particle concentration of 6.3?±?0.5?×?10¹²/mL and negative zeta values (?10.2?±?0.4 mV); parameters that remain stable during storage at 4°C. The formulation, with 40% encapsulation efficiency, induced the sustained release of EDC (ca. 24 h), while reducing its toxicity to human fibroblasts.

Conclusion

A novel formulation is proposed for etidocaine that promotes sustained release and reduces its cytotoxicity. IGL_EDC can come to be a tool to reintroduce etidocaine in clinical use.

     

The Internet and lifestyle drugs: an analysis of demographic characteristics,methods, and motives of online purchasers of illicit lifestyle drugs in the Netherlands

Abstract

Aims: The Internet has marked a revolution in the supply of illegal drugs, while at the same time, new types of illegal and semilegal drugs increasingly are becoming available. In order to deepen our understanding of the demand and supply of these new drugs on the Internet, this study focuses on the demographic characteristics, methods and preferences of people who purchase ‘lifestyle drugs’ through the surface web.

Methods: Data were obtained through the following two surveys: a prevalence study of 50,848 Dutch respondents and an in-depth study of 153 people who have purchased lifestyle drugs online.

Findings: At least 10.2% of the Dutch adult population has bought medicines online; the majority being lifestyle drugs (5.2%). In addition, an estimated 1.6% of the Dutch population has purchased medicines illicitly, with the majority of products concerning lifestyle drugs (0.9%). Illicit lifestyle drugs are primarily purchased through e-commerce sites and online pharmacies, and users report high satisfaction rates.

Conclusion: Purchasing lifestyle drugs is characterised by specific online dynamics, as the drugs are often openly accessible and the boundaries between legal and illegal sale blurred. As new types of drugs become available, it is important to further monitor customers’ preferences and experiences.     

AN INTERIM ANALYSIS OF A DOUBLE-BLIND SHAM-CONTROLLED STUDY ON THE ACUTE EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION IN OBSESSIVE-COMPULSIVE DISORDER

We describe the interim analysis of a double-blind sham controlled quasi-randomized study on the acute effects of transcranial direct current stimulation (tDCS) for individuals with obsessive-compulsive disorder (OCD). Twenty OCD patients were assigned to receive a single session of sham (n=10) or active (2mA) tDCS (n=10) for 30 minutes, with the cathode placed over the central supplementary motor area (SMA) and the anode on the supraorbital region. Assessments of outcome were made at baseline and one hour following tDCS using: a dot-probe task comprising images illustrating different OCD-related scenarios, the Positive and Negative Affect Schedule (PANAS), and the Yale-Brown Obsessive-Compulsive Challenge Scale (YBOCCS; a measure of symptoms in the preceding hour). Active and sham tDCS groups did not differ in terms of age, gender, medication use and baseline severity of OCD, depression and anxiety symptoms. Though a significant time-effect (before vs. after tDCS) was observed on YBOCCS, PANAS and dot-probe scores, there was no interaction between groups. However, exploratory analyses revealed that sham tDCS led to a significant decrease in OCD symptoms in the past hour, while active tDCS failed to do so. Although we did not observe acute effects of tDCS on OCD symptoms, this interim analysis suggests that inhibition of the SMA may interfere with sham response in OCD, probably through increasing vigilance towards OCD-related environmental stimuli.     

Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches

This work investigated the impact of formulation including in vitro release profile, repeated dosing, and nail poration on the ex vivo nail delivery performance of antifungal formulations. Chitosan coated and uncoated tioconazole-loaded nanocapsules and a nano-based film-forming vehicle were assessed via in vitro release and in vitro permeation tests using an artificial membrane and human nail clippings, respectively. The later involved single and daily dosing experiments with intact and porated nails. Additional experiments with Nile Red-loaded formulations evaluated the depth of penetration of the fluorescent marker into the nail by laser scanning confocal microscopy. The nanocapsule formulations prolonged release of tioconazole for longer than the control solutions and this ability was related to an enhanced nail penetration of the drug. Further, the new film-forming formulation delivered its drug payload more efficiently than a marketed product. Daily dosing of the formulations doubled the amount of drug recovered from the nails. Porating the nails enhanced tioconazole delivery in single dose experiments only. The depth of penetration of Nile Red into the nails clippings ranged between 90–160?μm. This research suggests that ensuring prolonged release of a drug is fundamental to develop efficacious topical nail formulations.     

Changes in income-related inequalities in cervical cancer screening during the Spanish economic crisis: a decomposition analysis

Background

Cervical cancer is one of the most prevalent cancers, but it may be prevented by early detection. Social inequalities in the use of cytology testing have been identified in the literature. However, the degree of income-related inequality has not been quantified and determinants of inequality changes during the economic crisis remain unknown.

Methods

Using the Spanish National Health Surveys (2006–07 / 2011–12), we analyzed how income-related inequalities in the use of cervical cancer screening for women aged 25–64 changed across the economic crisis. We used corrected concentration indices (CCI) which were further decomposed in order to compute the contribution of the explanatory variables. An Oaxaca-type approach was employed to investigate the origin of changes over time.

Results

Our final sample consisted of 10,743 observations in 2006–07 and 6587 in 2011–12. Despite the higher prevalence of screening over time (from 73.9 to 77.9%), pro-rich inequality significantly increased (from CCI?=?0.1726 to CCI?=?0.1880, p <?0.001). Income was the main determinant of inequality in cervical screening, although its contribution decreased over time, as well as the contribution of the type of health insurance, mainly due to changes in elasticity. Other factors, such as nationality or the educational level, seem to have played an important role in the increase of pro-rich inequality of cytology testing.

Conclusions

Reducing cervical screening inequalities would require actions focused on most vulnerable groups such as migrants, low income and low educated population. The implementation of population-based screening programs would also help to cope with income-related inequalities in cytology testing.

     

Spatial analyzes of HLA data in Rio Grande do Sul,south Brazil: genetic structure and possible correlation with autoimmune diseases

Background

HLA genes are the most polymorphic of the human genome and have distinct allelic frequencies in populations of different geographical regions of the world, serving as genetic markers in ancestry studies. In addition, specific HLA alleles may be associated with various autoimmune and infectious diseases. The bone marrow donor registry in Brazil is the third largest in the world, and it counts with genetic typing of HLA-A, -B, and -DRB1. Since 1991 Brazil has maintained the DATASUS database, a system fed with epidemiological and health data from compulsory registration throughout the country.

Methods

In this work, we perform spatial analysis and georeferencing of HLA genetic data from more than 86,000 bone marrow donors from Rio Grande do Sul (RS) and data of hospitalization for rheumatoid arthritis, multiple sclerosis and Crohn’s disease in RS, comprising the period from 1995 to 2016 obtained through the DATASUS system. The allele frequencies were georeferenced using Empirical Bayesian Kriging; the diseases prevalence were georeferenced using Inverse Distance Weighted and cluster analysis for both allele and disease were performed using Getis-Ord Gi* method. Spearman’s test was used to test the correlation between each allele and disease.

Results

The results indicate a HLA genetic structure compatible with the history of RS colonization, where it is possible to observe differentiation between regions that underwent different colonization processes. Spatial analyzes of autoimmune disease hospitalization data were performed revealing clusters for different regions of the state for each disease analyzed. The correlation test between allelic frequency and the occurrence of autoimmune diseases indicated a significant correlation between the HLA-B*08 allele and rheumatoid arthritis.

Conclusions

Genetic mapping of populations and the spatial analyzes such as those performed in this work have great economic relevance and can be very useful in the formulation of public health campaigns and policies, contributing to the planning and adjustment of clinical actions, as well as informing and educating professionals and the population.