An evaluation of the effectiveness of the institutional mechanism to manage substance abuse in South Africa

Includes bibliographical references.This mixed method study of the effectiveness of the management of substance abuse in South Africa explored the way policies are formulated and implemented. A governance lens used coordination and public participation as indicators to measure the efficacy of the coordinating substance abuse structures (the Central Drug Authority, Provincial Substance Abuse Forums and Local Drug Action Committees) to implement the National Drug Master Plan 2006-2011. Coordinated governance, which include empowerment and resourcing of structures at the provincial and municipal levels will be helpful to provide necessary resources, expertise and skills to the "whole of society" for the implementation of future strategies

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

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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Preliminary Insights on the Spatial Ecology, Population Demography, and Sexual Dimorphism of the Critically Endangered Sulawesi Forest Turtle (Leucocephalon yuwonoi)

Sulawesi Forest Turtles (Leucocephalon yuwonoi) are critically endangered and endemic to the island of Sulawesi. We conducted radiotelemetry and capture-mark-recapture to study their spatial ecology, habitat selection, activity patterns, and demography in February-April and June-July, 2019. The average area occupied by 14 turtles using the minimum convex polygon (MCP) method was 0.49 ± 0.42 ha (standard deviation [SD]), whereas using the fixed 50% kernel density method averaged 0.076 ± 0.061 ha (SD). Males (mean = 0.53 ± 0.40 ha, N = 7) occupied a larger area (MCP method) than females (mean = 0.44 ± 0.46 ha, N = 7) but the difference was not statistically significant. Turtles took refuge in habitat containing significantly more canopy cover, broadleaf plant cover, and more and deeper ground cover than that in random plots. Males were predominantly active at night and females were exclusively so. We caught 25 adult females, 16 adult males, and 38 unsexed juveniles in two stream sections. Estimated population size (95% confidence intervals) in the lower stream was 17 turtles (15-28) in the wet season and 10 turtles (8-21) in the dry season. The population estimate in the upper stream was 25 (24-33) and 13 (9-28) turtles in the wet and dry seasons, respectively. Our study provides important baseline ecological data that can be used to inform future conservation and recovery programs for the species.</p

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings In 2016, there were 27.08 million (95% uncertainty interval [UI] 24.30-30.30 million) new cases of TBI and 0.93 million (0.78-1.16 million) new cases of SCI, with age-standardised incidence rates of 369 (331-412) per 100 000 population for TBI and 13 (11-16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55.50 million (53.40-57.62 million) and of SCI was 27.04 million (24 .98-30 .15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8.4% (95% UI 7.7 to 9.2), whereas that of SCI did not change significantly (-0.2% [-2.1 to 2.7]). Age-standardised incidence rates increased by 3.6% (1.8 to 5.5) for TBI, but did not change significantly for SCI (-3.6% [-7.4 to 4.0]). TBI caused 8.1 million (95% UI 6. 0-10. 4 million) YLDs and SCI caused 9.5 million (6.7-12.4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82-141) per 100 000 for TBI and 130 (90-170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. Interpretation TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

The conservation status of the world’s reptiles

Effective and targeted conservation action requires detailed information about species, their distribution, systematics and ecology as well as the distribution of threat processes which affect them. Knowledge of reptilian diversity remains surprisingly disparate, and innovative means of gaining rapid insight into the status of reptiles are needed in order to highlight urgent conservation cases and inform environmental policy with appropriate biodiversity information in a timely manner. We present the first ever global analysis of extinction risk in reptiles, based on a random representative sample of 1500 species (16% of all currently known species). To our knowledge, our results provide the first analysis of the global conservation status and distribution patterns of reptiles and the threats affecting them, highlighting conservation priorities and knowledge gaps which need to be addressed urgently to ensure the continued survival of the world’s reptiles. Nearly one in five reptilian species are threatened with extinction, with another one in five species classed as Data Deficient. The proportion of threatened reptile species is highest in freshwater environments, tropical regions and on oceanic islands, while data deficiency was highest in tropical areas, such as Central Africa and Southeast Asia, and among fossorial reptiles. Our results emphasise the need for research attention to be focussed on tropical areas which are experiencing the most dramatic rates of habitat loss, on fossorial reptiles for which there is a chronic lack of data, and on certain taxa such as snakes for which extinction risk may currently be underestimated due to lack of population information. Conservation actions specifically need to mitigate the effects of human-induced habitat loss and harvesting, which are the predominant threats to reptiles

Search for intermediate mass black hole binaries in the first observing run of Advanced LIGO

International audienceDuring their first observational run, the two Advanced LIGO detectors attained an unprecedented sensitivity, resulting in the first direct detections of gravitational-wave signals produced by stellar-mass binary black hole systems. This paper reports on an all-sky search for gravitational waves (GWs) from merging intermediate mass black hole binaries (IMBHBs). The combined results from two independent search techniques were used in this study: the first employs a matched-filter algorithm that uses a bank of filters covering the GW signal parameter space, while the second is a generic search for GW transients (bursts). No GWs from IMBHBs were detected; therefore, we constrain the rate of several classes of IMBHB mergers. The most stringent limit is obtained for black holes of individual mass 100  M⊙, with spins aligned with the binary orbital angular momentum. For such systems, the merger rate is constrained to be less than 0.93  Gpc−3 yr−1 in comoving units at the 90% confidence level, an improvement of nearly 2 orders of magnitude over previous upper limits