Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases

Comparative phylogenetic methods and the cultural evolution of medicinal plant use

Human life depends on plant biodiversity and the ways in which plants are used are culturally determined. Whilst anthropologists have used phylogenetic comparative methods (PCMs) to gain an increasingly sophisticated understanding of the evolution of political, religious, social, and material culture, plant use has been almost entirely neglected. Medicinal plants are of special interest because of their role in maintaining people’s health across the world. PCMs in particular, and cultural evolutionary theory in general, provide a framework in which to study the diversity of medicinal plant applications cross-culturally, and to infer changes in plant use through time. These methods can be applied to single medicinal plants as well as the entire set of plants used by a culture for medicine, and they account for the non-independence of data when testing for floristic, cultural or other drivers of plant use. With cultural, biological, and linguistic diversity under threat, gaining a deeper and broader understanding of the variation of medicinal plant use through time and space is pressing

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Mortality Measurement Matters: Improving Data Collection and Estimation Methods for Child and Adult Mortality

Colin Mathers and Ties Boerma discuss three research articles in PLoS Medicine that address the measurement and analysis of child and adult mortality data collected through death registration, censuses, and household surveys

Insomnia and its associations in patients with recurrent glial neoplasms

BACKGROUND: Patient with neurological disorders and cancer can develop sleep disturbance, in particular insomnia. Etiology of insomnia is multi-factorial in primary brain tumour patients with possible causes including corticosteroids, psychoactive medications, co-morbid psychiatric/medical conditions, and damage to neuronal tissue. FINDINGS: To understand better insomnia in recurrent glioma patients, a single-center retrospective analysis was performed looking at recurrent glioma patients from January 2004 to May 2009. Data was extracted and included demographics, clinical factors, psychoactive medications, and co-morbid symptoms. Presence and absence of insomnia complaints was evaluated with other co-morbidities using Chi square and Wilcoxon analyses. Records from 340 recurrent glioma patients were evaluated and 46.8 % (n = 159) indicated presence of insomnia with 20 % (n = 66) actively using medications for sleep. Use of corticosteroids were significantly associated with insomnia (p = 0.0003). Age, gender, tumour location, use of stimulants, antipsychotics, and antidepressants were not significantly associated with insomnia in recurrent glioma patients. There was a trend towards a possible significant association with insomnia to fatigue complaints and use of anti-epileptics, p-values of 0.0501 and 0.0725 respectively. CONCLUSIONS: In conclusion, insomnia is commonly encountered in patients with recurrent glial tumors. Corticosteroid use is associated with insomnia in this population. In light of the frequency of insomnia and its associations, future analysis is warranted into sleep complaints in recurrent glioma patients and its impact on quality of life

Programmatic Evaluation of a Combined Antigen and Antibody Test for Rapid HIV Diagnosis in a Community and Sexual Health Clinic Screening Programme

Background A substantial proportion of HIV-infected individuals in the UK are unaware of their status and late presentations continue, especially in low prevalence areas. Fourth generation antigen/antibody rapid test kits could facilitate earlier diagnosis of HIV in non-clinical settings but lack data on performance under programmatic conditions. Methods and Findings We evaluated the performance of Determine HIV-1/2 Ag/Ab Combo Test (Determine Combo), a rapid test with indicators for both HIV antibodies and p24 antigen, in participants recruited from community outreach and hospital-based sexual health clinics. HIV infection was confirmed using laboratory enzyme-linked immunosorbent assay (EIA), Line Immuno Assay (LIA) and quantitative polymerase chain reaction (PCR). In total, 953 people underwent HIV testing. HIV antibody (Ab) prevalence was 1.8% (17/953). Four false positive rapid tests were identified: two antibody and two p24 antigen (Ag) reactions. Of participants diagnosed as HIV Ab positive, 2/17 (12%) were recent seroconverters based on clinical history and HIV antibody avidity test results. However, none of these were detected by the p24 antigen component of the rapid test kit. There were no other true positive p24 Ag tests. Conclusion These data lend support to an increasing body of evidence suggesting that 4th generation rapid HIV tests have little additional benefit over 3rd generation HIV kits for routine screening in low prevalence settings and have high rates of false positives. In order to optimally combine community-based case-finding among hard-to-reach groups with reliable and early diagnosis 3rd generation kits should be primarily used with laboratory testing of individuals thought to be at risk of acute HIV infection. A more reliable point of care diagnostic is required for the accurate detection of acute HIV infection under programmatic conditions

Breeding systems of floral colour forms in the Drosera cistiflora species complex

The study was supported by the National Research Foundation of South Africa (Grant 46372 to SDJ).Variation in plant breeding systems has implications for pollinator‐mediated selection on floral traits and the ecology of populations. Here we evaluate pollinator contribution to seed production, self‐compatibility and pollen limitation in different floral colour forms of Drosera cistiflora sensu lato (Droseraceae). These insectivorous perennial plants are endemic to fynbos and renosterveld vegetation in the Cape Floristic Region of South Africa, and the species complex includes five floral colour forms (pink, purple, red, white and yellow), some of which are known to be pollinated by beetles. Controlled hand‐pollination experiments were conducted in 15 populations of D. cistiflora s.l. (two to four populations per floral colour form) to test whether the colour forms vary in their degree of self‐compatibility and their ability to produce seeds through autonomous self‐fertilization. Yellow‐flowered forms were highly self‐incompatible, while other floral colour forms exhibited partial self‐compatibility. Seed set resulting from autonomous selfing was very low, and pollinator dependence indices were high in all populations. Since hand cross‐pollination resulted in greater seed set than open pollination in 13 of the 15 populations, we inferred that seed production is generally pollen‐limited.Drosera cistiflora s.l. typically exhibits high levels of pollinator dependence and pollen limitation. This is unusual among Drosera species worldwide and suggests that pollinators are likely to mediate strong selection on attractive traits such as floral colour and size in D. cistiflora s.l. These results also suggest that the floral colour forms of D. cistiflora s.l. which are rare and threatened are likely to be vulnerable to local extinction if mutualisms were to collapse indefinitely.PostprintPeer reviewe

Home-based voluntary HIV counselling and testing found highly acceptable and to reduce inequalities

<p>Abstract</p> <p>Background</p> <p>Low uptake of voluntary HIV counselling and testing (VCT) in sub-Saharan Africa is raising acceptability concerns which might be associated with ways by which it is offered. We investigated the acceptability of home-based delivery of counselling and HIV testing in urban and rural populations in Zambia where VCT has been offered mostly from local clinics.</p> <p>Methods</p> <p>A population-based HIV survey was conducted in selected communities in 2003 (n = 5035). All participants stating willingness to be HIV tested were offered VCT at home and all counselling was conducted in the participants' homes. In the urban area post-test counselling and giving of results were done the following day whereas in rural areas this could take 1-3 weeks.</p> <p>Results</p> <p>Of those who indicated willingness to be HIV tested, 76.1% (95%CI 74.9-77.2) were counselled and received the test result. Overall, there was an increase in the proportion ever HIV tested from 18% before provision of home-based VCT to 38% after. The highest increase was in rural areas; among young rural men aged 15-24 years up from 14% to 42% vs. for urban men from 17% to 37%. Test rates by educational attainment changed from being positively associated to be evenly distributed after home-based VCT.</p> <p>Conclusions</p> <p>A high uptake was achieved by delivering HIV counselling and testing at home. The highest uptakes were seen in rural areas, in young people and groups with low educational attainment, resulting in substantial reductions in existing inequalities in accessing VCT services.</p

The impact of provider-initiated (opt-out) HIV testing and counseling of patients with sexually transmitted infection in Cape Town, South Africa: a controlled trial

<p>Abstract</p> <p>Background</p> <p>The effectiveness of provider-initiated HIV testing and counseling (PITC) for patients with sexually transmitted infection (STI) in resource-constrained settings are of particular concern for high HIV prevalence countries like South Africa. This study evaluated whether the PITC approach increased HIV testing amongst patients with a new episode of sexually transmitted infection, as compared to standard voluntary counseling and testing (VCT) at the primary care level in South Africa, a high prevalence and low resource setting.</p> <p>Methods</p> <p>The design was a pragmatic cluster-controlled trial with seven intervention and 14 control clinics in Cape Town. Nurses in intervention clinics integrated PITC into standard HIV care with few additional resources, whilst lay counselors continued with the VCT approach in control clinics. Routine data were collected for a six-month period following the intervention in 2007, on new STI patients who were offered and who accepted HIV testing. The main outcome measure was the proportion of new STI patients tested for HIV, with secondary outcomes being the proportions who were offered and who declined the HIV test.</p> <p>Results</p> <p>A significantly higher proportion of new STI patients in the intervention group tested for HIV as compared to the control group with (56.4% intervention versus 42.6% control, p = 0.037). This increase was achieved despite a significantly higher proportion intervention group declining testing when offered (26.7% intervention versus 13.5% control, p = 0.0086). Patients were more likely to be offered HIV testing in intervention clinics, where providers offered the HIV test to 76.8% of new STI patients versus 50.9% in the control group (p = 0.0029). There was significantly less variation in the main outcomes across the intervention clinics, suggesting that the intervention also facilitated more consistent performance.</p> <p>Conclusions</p> <p>PITC was successful in three ways: it increased the proportion of new STI patients tested for HIV; it increased the proportion of new STI patients offered HIV testing; and it delivered more consistent performance across clinics. Recommendations are made for increasing the impact and feasibility of PITC in high HIV prevalence and resource-constrained settings. These include more flexible use of clinical and lay staff, and combining PITC with VCT and other community-based approaches to HIV testing.</p> <p>Trial registration</p> <p>Controlled trial ISRCTN93692532</p