The impact of international benchmarking on the price of immunosuppressive medicines for transplant recipients in South Africa

Background. External reference pricing (ERP) is an internationally applied pricing policy to regulate the price of medicines. In 2005, the South African (SA) Minister of Health published a Government Gazette of regulations relating to a transparent pricing system for medicines and scheduled substances, stating that the Minister must publish a methodology for conforming to international benchmarks. In May 2014, the most recent proposed benchmark methodology was published, detailing that international benchmarking of medicines (IBM) requires that the lowest price in a selected basket of countries (Australia, Canada, New Zealand, Spain and SA) be used as the ultimate price for the purposes of benchmarking of originator products.Objectives. To provide a broad observational basis for the use of IBM and the proposed countries as a pricing tool; the feasibility of using BRICS countries (Brazil, Russia, India, China and SA) as comparator countries; and a small sample comparison of local state tender pricing in relation to the IBM proposed basket of comparator country pricing. Immunosuppressant medicines for organ transplant patients were used for this comparison, as they are relatively expensive and there is reluctance to implement pricing and reimbursement policy options to contain their costs.Methods. Ex-manufacturer medicine pricing information for 2016, 2017 and 2018 was sourced for immunosuppressive medicines for SA (public and private sectors), Australia, New Zealand, Canada, Spain, Brazil and Russia. Unit prices were compared for products with the same international non-proprietary name (INN), strength, formulation and manufacturer. In most cases the products were matched on product name, bearing translation nuances in mind.Results. Across all 3 years, in the majority of products, ERP using the proposed basket of comparator countries Australia, New Zealand, Canada and Spain lowered the local private sector ex-manufacturer price of medicine. Similarly, for the majority of products comparing local pricing with that of available BRICS country pricing data, the comparison lowered the price. For 92% of products where a comparison could be made, the SA state tender price was the lowest available price.Conclusions. Conducting an ERP analysis consumes time and resources. However, it may prove to reduce a current or proposed medicine price and may be considered as one of a range of medicine pricing policies employed by a country. It should not be used in isolation from other medicine pricing and reimbursement policies.

Amyloid Precursor Proteins Are Dynamically Trafficked and Processed during Neuronal Development

Proteolytic processing of the Amyloid Precursor Protein (APP) produces beta-amyloid (Aβ) peptide fragments that accumulate in Alzheimer’s Disease (AD), but APP may also regulate multiple aspects of neuronal development, albeit via mechanisms that are not well understood. APP is a member of a family of transmembrane glycoproteins expressed by all higher organisms, including two mammalian orthologs (APLP1 and APLP2) that have complicated investigations into the specific activities of APP. By comparison, insects express only a single APP-related protein (APP-Like, or APPL) that contains the same protein interaction domains identified in APP. However, unlike its mammalian orthologs, APPL is only expressed by neurons, greatly simplifying an analysis of its functions in vivo. Like APP, APPL is processed by secretases to generate a similar array of extracellular and intracellular cleavage fragments, as well as an Aβ-like fragment that can induce neurotoxic responses in the brain. Exploiting the complementary advantages of two insect models (Drosophila melanogaster and Manduca sexta), we have investigated the regulation of APPL trafficking and processing with respect to different aspects of neuronal development. By comparing the behavior of endogenously expressed APPL with fluorescently tagged versions of APPL and APP, we have shown that some full-length protein is consistently trafficked into the most motile regions of developing neurons both in vitro and in vivo. Concurrently, much of the holoprotein is rapidly processed into N- and C-terminal fragments that undergo bi-directional transport within distinct vesicle populations. Unexpectedly, we also discovered that APPL can be transiently sequestered into an amphisome-like compartment in developing neurons, while manipulations targeting APPL cleavage altered their motile behavior in cultured embryos. These data suggest that multiple mechanisms restrict the bioavailability of the holoprotein to regulate APPL-dependent responses within the nervous system. Lastly, targeted expression of our double-tagged constructs (combined with time-lapse imaging) revealed that APP family proteins are subject to complex patterns of trafficking and processing that vary dramatically between different neuronal subtypes. In combination, our results provide a new perspective on how the regulation of APP family proteins can be modulated to accommodate a variety of cell type-specific responses within the embryonic and adult nervous system

Genetic diversity and dynamics of the Noir Marron settlement in French Guyana : A study combining mitochondrial DNA, Y chromosome and HTLV-1 genotyping [Abstract]

The Noir Marron are the direct descendants of thousands of African slaves deported to the Guyanas during the Atlantic Slave Trade and later escaped mainly from Dutch colonial plantations. Six ethnic groups are officially recognized, four of which are located in French Guyana: the Aluku, the Ndjuka, the Saramaka, and the Paramaka. The aim of this study was: (1) to determine the Noir Marron settlement through genetic exchanges with other communities such as Amerindians and Europeans; (2) to retrace their origins in Africa. Buffy-coat DNA from 142 Noir Marron, currently living in French Guyana, were analyzed using mtDNA (typing of SNP coding regions and sequencing of HVSI/II) and Y chromosomes (typing STR and SNPs) to define their genetic profile. Results were compared to an African database composed by published data, updated with genotypes of 82 Fon from Benin, and 128 Ahizi and 63 Yacouba from the Ivory-Coast obtained in this study for the same markers. Furthermore, the determination of the genomic subtype of HTLV-1 strains (env gp21 and LTR regions), which can be used as a marker of migration of infected populations, was performed for samples from 23 HTLV-1 infected Noir Marron and compared with the corresponding database. MtDNA profiles showed a high haplotype diversity, in which 99% of samples belonged to the major haplogroup L, frequent in Africa. Each haplotype was largely represented on the West African coast, but notably higher homologies were obtained with the samples present in the Gulf of Guinea. Y Chromosome analysis revealed the same pattern, i.e. a conservation of the African contribution to the Noir Marron genetic profile, with 98% of haplotypes belonging to the major haplogroup E1b1a, frequent in West Africa. The genetic diversity was higher than those observed in African populations, proving the large Noir Marron’s fatherland, but a predominant identity in the Gulf of Guinea can be suggested. Concerning HTLV-1 genotyping, all the Noir Marron strains belonged to the large Cosmopolitan A subtype. However, among them 17/23 (74%) clustered with the West African clade comprizing samples originating from Ivory-Coast, Ghana, Burkina-Fasso and Senegal, while 3 others clustered in the Trans-Sahelian clade and the remaining 3 were similar to strains found in individuals in South America. Through the combined analyses of three approaches, we have provided a conclusive image of the genetic profile of the Noir Marron communities studied. The high degree of preservation of the African gene pool contradicts the expected gene flow that would correspond to the major cultural exchanges observed between Noir Marron, Europeans and Amerindians. Marital practices and historical events could explain these observations. Corresponding to historical and cultural data, the origin of the ethnic groups is widely dispatched throughout West Africa. However, all results converge to suggest an individualization from a major birthplace in the Gulf of Guinea

A lunar occultation and direct imaging survey of multiplicity in the Ophiuchus and Taurus star-forming regions

We present an IR lunar occultation and direct imaging search for companions in the Ophiuchus star-forming region and update a similar search of the Taurus region. The search is sensitive to companions in the angular separation range 0.005-10 sec. In Ophiuchus, we surveyed 35 young star targets; this sample contains at least 10 binaries, two triples, and one quadruple. Ten of the companion stars are newly discovered. In Taurus, the survey now includes 47 systems among which there are at least 22 binaries and four triples. Only two companion stars are newly identified because there is strong overlap with prior work. All the triples and quadruple are hierarchical. The observed binary frequency in Ophiuchus, in the 3-1400 AU range of separations, is at least 1.1 +/- 0.3 that of the nearby solar-like stars. This value is a lower bound because we make no corrections for incompleteness. In Taurus, in the same range of separations, the observed binary frequency is at least 1.6 +/- 0.3 that of the nearby solar-like stars. This value extends Ghez et al.'s (1993) and Leinert's et al.'s (1993) determination of an excess binary frequency to 3 AU separation. We used the weak-line T Tauri star/T Tauri star (WT/TT) type and the K-L color index to distinguish between systems with and without inner disks. We find no convincing difference in the binary frequency or distribution of separations of the systems with and without inner disks. The 1.3 mm continuum emission of the single systems exceeds that of the multiples suggesting that their extensive outer disks are more massive. The specific angular momenta of the binaries overlap those of molecular cloud cores measured by Goodman et al. (1993)

Atmospheric aerosols at the Pierre Auger Observatory and environmental implications

The Pierre Auger Observatory detects the highest energy cosmic rays. Calorimetric measurements of extensive air showers induced by cosmic rays are performed with a fluorescence detector. Thus, one of the main challenges is the atmospheric monitoring, especially for aerosols in suspension in the atmosphere. Several methods are described which have been developed to measure the aerosol optical depth profile and aerosol phase function, using lasers and other light sources as recorded by the fluorescence detector. The origin of atmospheric aerosols traveling through the Auger site is also presented, highlighting the effect of surrounding areas to atmospheric properties. In the aim to extend the Pierre Auger Observatory to an atmospheric research platform, a discussion about a collaborative project is presented.Comment: Regular Article, 16 pages, 12 figure

Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis.

BACKGROUND: Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction. METHODS AND FINDINGS: We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24-6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03-28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33-7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02-5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32-8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13-14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased. CONCLUSIONS: To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-maker