Hypothesizing Synergy between Acupuncture/ Auriculotherapy and Natural Activation of Mesolimbic Dopaminergic Pathways: Putative Natural Treatment Modalities for the Reduction of Drug Hunger and Relapse

Acupuncture is a very ancient form of healing which predates recorded history. The philosophy is rooted in the Taoist tradition which goes back over 8000 years. To date this practice although used world-wide to treat addictive behaviors has not been generally accepted or scientifically proven. There are however many positive reports in the literature in its effectiveness in reducing symptoms of withdrawal from alcohol, heroin and cocaine. In addition, due to known neuro-chemical mechanisms associated with acupuncture, especially its role in pain relief and endogenous opioid function, clinical benefits in reward dependence behaviors seem parsimonious. In this review article we are hypothesizing synergy between acupuncture/auriculotherapy and natural activation of mesolimbic dopaminergic pathways to reduce drug hunger and prevent relapse. Following a review of the literature involving both of these modalities the scientific and clinical community is encouraged to carry out translational research in large randomized double-blinded placebo controlled investigations coupling these two anti-craving treatment modalities

Tropomyosin 1: multiple roles in the developing heart and in the formation of congenital heart defects

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1 + 2T > C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1 + 2T > C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Decrease in Healthcare Utilization and Costs for Opioid Users Following Residential Integrated Treatment for Co-Occurring Disorders

Background: Opioid use results in higher healthcare utilization and costs, particularly among those with co-occurring mental health disorders. Presumably, effective treatment would result in a reduction in healthcare utilization and costs. To date, research has not examined this question. As such, the purpose of this study was to estimate and compare pre- and post-treatment healthcare utilization and costs for individuals receiving residential integrated treatment for co-occurring mental health and opioid use disorders. Methods: A single-group, repeated measures design was used to examine changes in pre- and post-treatment healthcare utilization and costs among a sample of individuals with co-occurring mental health and opioid use disorders who received residential, integrated treatment. Results: Significant reductions in emergency rooms visits, inpatient admissions, and resulting costs were observed in the six months following treatment. Conclusions: Residential, integrated treatment of co-occurring mental health and opioid use disorders can significantly decrease both utilization and cost of healthcare among opioid users with co-occurring mental health disorders

Decrease in Healthcare Utilization and Costs for Opioid Users Following Residential Integrated Treatment for Co-Occurring Disorders

Background: Opioid use results in higher healthcare utilization and costs, particularly among those with co-occurring mental health disorders. Presumably, effective treatment would result in a reduction in healthcare utilization and costs. To date, research has not examined this question. As such, the purpose of this study was to estimate and compare pre- and post-treatment healthcare utilization and costs for individuals receiving residential integrated treatment for co-occurring mental health and opioid use disorders. Methods: A single-group, repeated measures design was used to examine changes in pre- and post-treatment healthcare utilization and costs among a sample of individuals with co-occurring mental health and opioid use disorders who received residential, integrated treatment. Results: Significant reductions in emergency rooms visits, inpatient admissions, and resulting costs were observed in the six months following treatment. Conclusions: Residential, integrated treatment of co-occurring mental health and opioid use disorders can significantly decrease both utilization and cost of healthcare among opioid users with co-occurring mental health disorders

Forecasting the risk of vector-borne diseases at different time scales: an overview of the CLIMate SEnsitive DISease (CLIMSEDIS) Forecasting Tool project for the Horn of Africa.

Vector-borne diseases are transmitted by a range of arthropod insects that are climate sensitive. Arthropods are ectothermic; hence air temperature has a significant impact on their biting and development rates. In addition, higher temperatures shorten the extrinsic incubation period of pathogens, namely the time required for an insect vector to become infectious once it has been infected. Rainfall also creates suitable conditions for breeding sites. The latest IPCC-AR6 report unequivocally concluded that recent climate change already had an impact on the distribution of important human and animal diseases and their vectors. For example, dengue is now transmitted in temperate regions of Europe, and malaria vectors are now found at higher altitudes and latitudes in the Tropics. Different streams of climate forecasts, ranging from short range numerical weather prediction (NWP) models to seasonal forecasting systems, to future climate change ensembles can be used to forecast the risk posed by key vector-borne diseases at different time scales. This work will first introduce vector-borne disease forecasting system prototypes developed for different time scales and applications. Three examples will be presented; first a NWP driven model to forecast the risk of the animal disease Bluetongue in the UK, second the skill of the Liverpool malaria model simulations driven by seasonal forecasts in Botswana, and third the impact of RCP-SSP climate change scenarios on the risk posed by dengue and malaria at global scale. In addition, the use of mathematical disease models in anticipating disease risk will be presented, highlighting the limited uptake by policy makers. To bridge the academic/policy making gap, novel participatory approaches which include all actors need to be developed. The CLIMate SEnsitive DISease Forecasting Tool (CLIMSEDIS) project aims to bridge that gap. The overall aim of CLIMSEDIS is to develop and build capacity in the use of an innovative user-friendly digital tool. CLIMSEDIS will allow end-user stakeholders to utilise forecasts and delineate sub-national risk of multiple climate sensitive diseases to inform timely and targeted intervention strategies in eight countries across the Horn of Africa. Disease prioritization exercise, scoping reviews and interactive workshops with stakeholders will be carried out. The final deliverable will consist in a web-based portal and a phone application that will be used, maintained, and developed further by key African regional partners. A presentation of the CLIMSEDIS project phases and its overall strategy will be presented