Global strategies to reduce the price of antiretroviral medicines: evidence from transactional databases

Objective

To estimate the impact of global strategies, such as pooled procurement arrangements, third-party price negotiation and differential pricing, on reducing the price of antiretrovirals (ARVs), which currently hinders universal access to HIV/AIDS treatment.

Methods

We estimated the impact of global strategies to reduce ARV prices using data on 7253 procurement transactions (July 2002–October 2007) from databases hosted by WHO and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

Findings

For 19 of 24 ARV dosage forms, we detected no association between price and volume purchased. For the other five ARVs, high-volume purchases were 4–21% less expensive than medium- or low-volume purchases. Nine of 13 generic ARVs were priced 6–36% lower when purchased under the Clinton Foundation HIV/AIDS Initiative (CHAI). Fifteen of 18 branded ARVs were priced 23–498% higher for differentially priced purchases compared with non-CHAI generic purchases. However, two branded, differentially priced ARVs were priced 63% and 73% lower, respectively, than generic non-CHAI equivalents.

Conclusion

Large purchase volumes did not necessarily result in lower ARV prices. Although current plans for pooled procurement will further increase purchase volumes, savings are uncertain and should be balanced against programmatic costs. Third-party negotiation by CHAI resulted in lower generic ARV prices. Generics were less expensive than differentially priced branded ARVs, except where little generic competition exists. Alternative strategies for reducing ARV prices, such as streamlining financial management systems, improving demand forecasting and removing barriers to generics, should be explored.     

Availability of Safe Childbirth Supplies in 284 Facilities in Uttar Pradesh,India

Maternal and Child Health Journal - Objectives Vital to implementation of the World Health Organization (WHO) Safe Childbirth Checklist (SCC), designed to improve delivery of 28 essential birth...     

Dietary Intake over a 7-Day Training and Game Period in Female Varsity Rugby Union Players

This study estimated the daily energy intake (EI) and energy expenditure (TDEE) in female varsity rugby union players during a weekly training/game cycle. Fifteen (nine forwards, six backs) players (20.5 ± 0.4 y, 167.1 ± 1.8 cm, 74.9 ± 2.9 kg) were monitored for a 7-day period (one fitness, two heavy training, one light training, one game, and two recovery days) during their regular season. The average EI throughout the week for all 15 players was 2158 ± 87 kcal. There were no significant differences between days, but the lowest EI (1921 ± 227 kcal) occurred on the mid-week recovery day and the highest on game day (2336 ± 231 kcal). The average TDEE was 2286 ± 168 kcal (~6% > EI). The mean energy availability (EA) over the 7-day period was 31.1 ± 3.6 kcal/kg FFM/day for the group. Of the players, 14% were in the optimal EA range (>45 kcal/kg FFM/day); 34% were in the moderate range (≥30–45 kcal/kg FFM/day); and 52% had a poor EA of <30 kcal/kg FFM/day. Carbohydrate (3.38 ± 0.36 g/kg/day, 45% of EI); fat (1.27 ± 0.12 g/kg/day, 37% of EI); and protein (1.38 ± 0.12 g/kg/day, 18% of EI) consumption remained similar throughout the week (p > 0.05). The players consumed 6% less energy than they expended, providing poor to moderate EA; therefore, daily carbohydrate intake recommendations were not met.     

Animal soundscapes reveal key markers of Amazon forest degradation from fire and logging

Safeguarding tropical forest biodiversity requires solutions for monitoring ecosystem structure over time. In the Amazon, logging and fire reduce forest carbon stocks and alter habitat, but the long-term consequences for wildlife remain unclear, especially for lesser-known taxa. Here, we combined multiday acoustic surveys, airborne lidar, and satellite time series covering logged and burned forests (n = 39) in the southern Brazilian Amazon to identify acoustic markers of forest degradation. Our findings contradict expectations from the Acoustic Niche Hypothesis that animal communities in more degraded habitats occupy fewer “acoustic niches” defined by time and frequency. Instead, we found that aboveground biomass was not a consistent proxy for acoustic biodiversity due to the divergent patterns of “acoustic space occupancy” between logged and burned forests. Ecosystem soundscapes highlighted a stark, and sustained reorganization in acoustic community assembly after multiple fires; animal communication networks were quieter, more homogenous, and less acoustically integrated in forests burned multiple times than in logged or once-burned forests. These findings demonstrate strong biodiversity cobenefits from protecting burned Amazon forests from recurrent fire. By contrast, soundscape changes after logging were subtle and more consistent with acoustic community recovery than reassembly. In both logged and burned forests, insects were the dominant acoustic markers of degradation, particularly during midday and nighttime hours, which are not typically sampled by traditional biodiversity field surveys. The acoustic fingerprints of degradation history were conserved across replicate recording locations, indicating that soundscapes may offer a robust, taxonomically inclusive solution for digitally tracking changes in acoustic community composition over time.

Biological diversity is disappearing rapidly in response to human activity, especially in tropical forests, which are home to well over half of Earth’s terrestrial species (1). Global concern over greenhouse gas emissions from tropical forests (2) has led to international efforts to Reduce Emissions from Deforestation and Forest Degradation (REDD+) (3). Retention of diverse ecosystems supports climate change mitigation and adaptation (4); yet, carbon-focused conservation may not result in a commensurate win for tropical forest biodiversity (5). Longstanding data gaps on species distributions and uncertainty regarding the direct and indirect impacts of human activity on biodiversity complicate efforts to quantify the interplay between carbon and biodiversity (6, 7).Across the tropics, the Brazilian Amazon has the highest rates of deforestation (8), and forest degradation from fire and logging may double biodiversity loss from deforestation alone (9). However, the long-term impacts of human activity on Amazon biodiversity remain highly uncertain due, in part, to the spatial heterogeneity among degraded forests from differences in the timing, frequency, extent, and severity of disturbances (10). Time-varying heterogeneity in the biodiversity of degraded forests may also explain some of the apparent contradictions in previous studies of degradation impacts on birds, the most well-studied Amazonian taxa. Many nectarivorous birds, for example, increase in abundance immediately after logging but ultimately decline. Yet, many insectivorous birds show immediate sensitivity to changes in habitat from logging but continue to decline in abundance over time (11). Time dependence also complicates efforts to measure the effects of degradation on insects, a problem confounded by limited research (12).Addressing the tropical biodiversity extinction crisis, therefore, requires an efficient, distributed, long-term monitoring system to assess ecosystem structure (13). Traditional, ground-based biodiversity inventories are logistically prohibitive to conduct at scale, and limited taxonomic expertise perpetuates large data discrepancies for lesser-known taxa, such as insects, which constitute the bulk of tropical biodiversity (7). Advances in the emerging discipline of acoustic remote sensing, or ecoacoustics, may permit large-scale biodiversity monitoring for multiple taxa, including unidentifiable species, based on the aggregate sound signature of the animal community, or soundscape (14–16). Since multiple sites can be recorded simultaneously over time, sound surveys reduce the effort and cost associated with routine monitoring and facilitate standardized assessments of community variation and ecosystem recovery. Most previous efforts to utilize acoustic data for biodiversity monitoring have focused on detecting known vocalizations associated with individual species (17, 18), but there is increasing interest in evaluating the entire collection of signals in a given soundscape to derive measures of ecosystem intactness that include all sound-generating taxa without definitive species identification (15, 16, 19, 20).The Acoustic Niche Hypothesis (ANH) (21) is a core premise of ecoacoustics and the prevailing organizing principle for assessing diversity (16), community similarity (22), and human impacts (23, 24) using soundscape data. The ANH posits that more intact habitats support more biodiverse communities that occupy more “acoustic niches.” Greater niche partitioning of available acoustic space, defined by frequency and time of day, is posited to minimize communication interference among coexisting species. The ANH implies a positive linear relationship between habitat intactness (i.e., biomass) and acoustic niche infilling or acoustic space occupancy (ASO) by the “animal orchestra.” The corollary is that more degraded habitats support less acoustic infilling due to vacant acoustic niches from local species extirpations (25). Ecoacoustic approaches have great potential to extend monitoring capabilities in the hyperdiverse tropics, where competition for acoustic space is strongest (16, 26). Still, large uncertainties remain as to whether soundscape infilling can be used as a robust proxy for ecosystem intactness to monitor landscapes altered by human activity (27).Here, we test the ANH across logged and burned Amazon forests to identify acoustic markers of forest degradation (Fig. 1). We collected coincident high-density airborne lidar data and multiday acoustic recordings (214 24-h surveys) during September and October 2016 in 39 forests with different times since logging (4 to 23 y) and histories of fire activity (1 to 5 fires), stratified based on a 33-y time series of annual Landsat imagery (10). We used space-for-time substitution and two complementary analytic approaches to characterize threshold effects and time dependence for changes in the structure of animal soundscapes along gradients of degradation history (see Materials and Methods). First, we calculated ASO for each site at hourly and 1-min time steps to test the ANH and to quantify the magnitude, persistence, and variability in the infilling of acoustic space following forest degradation. Second, we developed a network-based approach to capture additional complexity from the soundscape data to track the composition and co-occurrences of “acoustic pseudotaxa” (defined as the community components that occupy the same acoustic niche) along degradation and recovery pathways. Our findings demonstrate that soundscapes encode digital markers of the history of degradation from human activity, revealing distinct patterns of community change following logging and fire. This study paves the way for more widespread use of ecoacoustics to benchmark and monitor changes in acoustic community composition in human-altered tropical forest landscapes, especially in remote regions with many unknown species.Open in a separate windowFig. 1.Acoustic recording sites in logged and burned forests (n = 39) were distributed across 9,400 km² in northern Mato Grosso, Brazil (Upper Left). Colored boxes identify subsets of the study domain to illustrate how the triplicate sampling scheme was designed to capture the heterogeneity in habitat structure and acoustic community composition in logged (yellow) and burned (black) forests. False-color composites of Landsat imagery (2014, 543-RGB) in each panel show deforested areas in magenta and gradients of forest cover in shades of green.     

A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.     

The GIST of Targeted Therapy for Malignant Melanoma

The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF^V600E melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.     

A mixture of pesticides at environmental concentrations induces oxidative stress and cholinergic effects in the neotropical fish Rhamdia quelen

The insecticides imidacloprid (IMI), a neonicotinoid, and propoxur (PRO), an N-methylcarbamate compound, are pesticides widely used throughout the world. Although they are not used together to combat pests, both are often found in freshwater near agricultural areas. Thereby, the goal of this study was to evaluate the additive effects of IMI and PRO mixtures at environmental concentrations in relation to isolated compounds on Rhamdia quelen, a neotropical fish. The fish was exposed to IMI (0.11 µg/L), PRO (0.039 µg/L), or Mix (0.11 µg/L IMI plus 0.039 µg/L PRO) during 96 h. Glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), acetylcholinesterase (AChE) activities were determined. To verify oxidative damage thiobarbituric acid reactive substances (TBARS), protein carbonyl (PC), reactive oxygen species contents (ROS), antioxidant capacity against peroxides (ACAP) were determined in gills, liver, brain and muscle. The results shows that a mixture of these pesticides at environmental concentrations inhibited acetylcholinesterase activity in the brain and induced oxidative damage in all analyzed tissues. These results reinforce the hypothesis that mixture of contaminants present in environment could induce additive or synergistic effects on fish species.