General Practitioner perspectives on and attitudes toward the Methadone Treatment Programme in Ireland

Background: Methadone maintenance treatment in Ireland is provided in addiction clinics, and in primary community care settings by Level 1 and 2 specialist trained general practitioners (GPs). The Irish College of General Practitioners (ICGP) provides training and regulates the Methadone Treatment Programme (MTP). Aim: The study aimed to assess and compare GP perceptions of the scale of local illicit drug use, attitudes toward and obstacles in the provision of methadone treatment and preferred adjunct modalities. Methods: In 2006 and 2015, an online survey was undertaken with all Level 1 and 2 registered GPs in the MTP. Results: The majority of participants were male, aged between 35 and 60 years, treated between 1 and 25 patients in urban areas. In 2015, 44.7% with registered methadone patients reported no obstacles to taking on more (32% in 2006). In relation to GPs with no current methadone patients, reasons for not taking patients in 2015 were similar to 2006, and centred on no referrals or demand, and concern for negative affect on private patients. Majority attitudes toward the MTP remained positive, with one exception relating to greater disagreement in 2015 with the statement that supervised daily dispensing prevents patients from working (p < .05). Preferred adjunct services remained constant; addiction counselling, in-patient detoxification, employment schemes and consultant psychiatric services. Conclusions: The study illustrates a generally positive attitude toward the Irish MTP. Efficient referral mechanisms for stabilised patients to primary care settings, and greater psycho-social, vocational and detoxification supports are warranted

Irish General Practitioner (GP) Perspectives Toward Decriminalisation, Legalisation and Cannabis for Therapeutic Purposes (CTP)

Cannabis is the most prevalent illicit drug used globally. Regulatory debate in Ireland on the decriminalisation of cannabis and legalisation for therapeutic purposes (CTP) is on-going. The study aimed to investigate Irish general practitioner (GP) attitudes toward decriminalisation of cannabis and assess levels of support for CTP. An online survey was administered to all GPs in the Irish College of General Practitioner (ICGP) database. A content analysis was conducted on open-ended survey questions, with five themes emerging. GPs were concerned around early onset of use and intergenerational impacts, vulnerabilities to drug induced psychosis, patient self-medication with cannabis and potential for misuse of prescribed cannabis. The study reflects concerns around the mental health consequences of cannabis use and potential for misuse in the event of legalisation, and the need for product regulation and an enhanced evidence base to support treatment decision making. Further research and medical education is warranted. © 2016, Springer Science+Business Media New York

Comparative population structure of <i>Plasmodium malariae</i> and <i>Plasmodium falciparum</i> under different transmission settings in Malawi

&lt;b&gt;Background:&lt;/b&gt; Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns - one seasonal, one perennial - to explore the effects of transmission on population structures. &lt;BR/&gt; &lt;b&gt;Methods:&lt;/b&gt; Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI), population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. &lt;BR/&gt; &lt;b&gt;Results:&lt;/b&gt; Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008) and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11) and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission setting. &lt;BR/&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The extent of similarity between P. falciparum and P. malariae population structure described by the high level of multiple infection, the lack of significant population differentiation or haplotype clustering and lack of linkage disequilibrium is surprising given the differences in the biological features of these species that suggest a reduced potential for out-crossing and transmission in P. malariae. The absence of a rise in P. malariae MOI with increased transmission or a reduction in MOI with age could be explained by differences in the duration of infection or degree of immunity compared to P. falciparum

Characteristics of methadone related overdose deaths and comparisons between those dying on and off methadone substitution treatment: a national cohort study.

Background: Opioid users, particularly those with a history of injecting and dependence, have a high risk of fatal polysubstance and methadone related overdose. Aim: To describe characteristics of methadone related overdose deaths and assess if differences exist between those dying on and off opioid agonist treatment (OAT). Methods: A descriptive study of all persons dying of drug overdose involving methadone on the Irish National Drug Related Deaths Index (NDRDI) in 2012 and 2013. Results: A total of 182 methadone implicated deaths were recorded . 78% (n=142) were male; with a mean age of 36 years. Of the cohort, 61% (n=111) were not in receipt of opiate agonist treatment (OAT) at the time of death, 15.9% (n=29) had a previous history of non-fatal overdose and 24.7% (n=45) a history of alcohol dependence. Analysis and interpretations are limited by incomplete data on other characteristics but where available show that 89% (n=73) were injecting drug users, with 57.8% (n=26) injecting drugs at the time of death. History of mental illness was recorded in 96.3% (n=77) of cases, with 94.7% (n=107) having history of substance dependency treatment. Polysubstances were implicated in 86.8% (n=158) of deaths. The majority died in a private dwelling (74.7% n= 127) and were not alone 67.4% (n=114). Conclusions: Methadone related fatal overdose is a significant cause of death in young Irish, who share many characteristics with other drug related deaths. Improved monitoring, risk assessment and OAT retention strategies is warranted to inform national drug overdose plans and overdose prevention

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Enhancement of electroporation facilitated immunogene therapy via T-reg depletion

Regulatory T cells (T-regs) can negatively impact tumor antigen-specific immune responses after infiltration into tumor tissue. However, depletion of T-regs can facilitate enhanced anti-tumor responses, thus augmenting the potential for immunotherapies. Here we focus on treating a highly aggressive form of cancer using a murine melanoma model with a poor prognosis. We utilize a combination of T-reg depletion and immunotherapy plasmid DNA delivered into the B16F10 melanoma tumor model via electroporation. Plasmids encoding murine granulocyte macrophage colony-stimulating factor and human B71 were transfected with electroporation into the tumor and transient elimination of T-regs was achieved with CD25-depleting antibodies (PC61). The combinational treatment effectively depleted T-regs compared to the untreated tumor and significantly reduced lung metastases. The combination treatment was not effective in increasing the survival, but only effective in suppression of metastases. These results indicate the potential for combining T-reg depletion with immunotherapy-based gene electrotransfer to decrease systemic metastasis and potentially enhance survival

MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons

The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression and splicing. However, the functional impact on neurons of such expression differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation of induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures to obtain cultures expressing all six adult tau protein isoforms. After 6 months of maturation, levels of exon 3+ and exon 10+ transcripts approach those of adult brain. Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. This work links haplotype-specific MAPT expression with a biologically functional outcome relevant for PD

Bullying and cyberbullying studies in the school-aged population on the island of Ireland : a meta-analysis

Background. Bullying research has gained a substantial amount of interest in recent years because of the implications for child and adolescent development. Aim and sample. We conducted a meta-analysis of traditional and cyberbullying studies in the Republic and North of Ireland to gain an understanding of prevalence rates and associated issues (particularly psychological correlates and intervention strategies) among young people (primary and secondary school students). Method. Four electronic databases were searched (PsychArticles, ERIC, PsychInfo and Education Research Complete) for studies of traditional bullying and cyberbullying behaviours (perpetrators, victims or both) published between January 1997 and April 2016. Results. Afinal sample of 39 articles fit our selection criteria.CMAsoftware was used to estimate a pooled prevalence rate for traditional/cyberbullying victimization and perpetration. A systematic review on the psychological impacts for all types of bullying and previously used interventions in an Irish setting is also provided. Conclusions. The results demonstrate the influence moderating factors (e.g., assessment tools, answer scale, time frame) have on reported prevalence rates. These results are discussed in light of current studies, and points for future research are considered