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Antimicrobial resistance burden estimates from the bottom-up:research priorities for estimating the impact of antimicrobial resistance in Brazil
No full textRecent estimates of deaths attributable to bacterial antimicrobial resistance (AMR) highlight the immense public health threat of AMR to healthcare systems, economies, and communities in Latin America. Although global modelling studies generate important statistics to motivate and guide global and national agendas, their complex methodology and aggregation mean that they have a more limited impact at the local scales where AMR is experienced and tackled. At the same time, it is increasingly recognised that we need to study and design AMR policies ‘from the bottom-up’, drawing on data and perspectives that ensure local ownership of the research and policy agenda. But how do we integrate ‘bottom-up’ perspectives into AMR burden estimation? Brazil is used as a case study to illustrate the importance of this approach. Brazil's vast and decentralised healthcare system would benefit from robust regional estimates of AMR's clinical, economic, and social burdens to move political decision-making and design appropriate interventions. We report on recommendations gathered from interdisciplinary stakeholder exercises and propose strategic priorities for estimating the AMR burden in Brazil at subnational scales of governance. These include focusing on individual-level data linkages at various scales; capturing public and private healthcare systems; understanding AMR inequalities; and capturing linked clinical, economic, and social burdens
The Spiritual Ecology of Ordinary Life: Shaker Sister Helena Sarle’s Botanical Drawings
No full textBlog post for the "Thinking with Plants and Fungi" Initiative at the Harvard's Center for the Study of World Religion
Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043–02):an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial
No full textBackground The broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models.Methods This open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa. Adults aged 18–64 years with newly diagnosed pulmonary tuberculosis sensitive to rifampicin and isoniazid, who weighed at least 40 kg, had a positive sputum smear graded at least 1+, were HIV negative, and had no history of hypertension or other substantial comorbidities were admitted to hospital. In stage 1 (multiple-ascending dose phase 1b with an adaptive continual reassessment method), the starting dose of BTZ-043 was 250 mg, with planned dose increments of 250 mg up to 2000 mg, and cohorts of three participants were enrolled sequentially. In stage 2 (phase 2a dose-expansion stage), participants were randomly assigned (3:3:3:2) to receive one of three doses of oral BTZ-043 (decided after stage 1) or standard of care (isoniazid, rifampicin, pyrazinamide, and ethambutol) using sealed opaque envelopes. The BTZ-043 groups also received oral dolutegravir (a third of participants) or a probe drug cocktail (caffeine [probe for CYP1A2], tolbutamide [CYP2C9], dextromethorphan [CYP2D6], midazolam [CYP3A4], and digoxin [P-glycoprotein]; two-thirds of participants). Study staff and participants were not masked, but laboratory staff were masked to treatment assignment. The primary outcome was to assess the safety and tolerability of BTZ-43 over 14 days of dosing by evaluation of adverse events in the safety analysis population. Secondary outcomes were bactericidal activity, measured by time to positivity (TTP) and colony-forming unit (CFU) count; pharmacokinetics (stage 2; including the food effect on BTZ-043); and drug–drug interactions with CYP450 enzymes, P-glycoprotein, and dolutegravir. This study is registered with ClinicalTrials.gov, NCT04044001 (completed).Findings In stage 1, 61 patients were assessed for eligibility and 24 were enrolled into seven dose cohorts between Nov 13, 2019, and Aug 13, 2020. Dose escalations were performed safely up to 1750 mg of BTZ-043 with three participants per dose cohort (and two dose cohorts for the highest dose). In stage 2, 151 patients were assessed for eligibility and 54 were enrolled and randomly assigned between Feb 2, 2021, and Feb 9, 2022, to receive 250, 500, and 1000 mg of BTZ-043 or standard of care. 66 (85%) of 78 participants were male and 12 (15%) were female. The most frequently observed adverse events were nausea (12 [8%] of 154), headache (11 [7%]), dizziness (11 [7%]), and vomiting (eight [5%]). Most participants had adverse events of mild (46 [60%] of 77 participants) or moderate (22 [29%]) severity. Transient increases in alanine aminotransferase were observed in both stages, which declined again despite continued dosing and were classified as signs of adaptation of hepatic metabolism rather than hepatotoxicity. The worsening of pre-existing anaemia and QTcF interval prolongation in one individual each were rated as possibly related to the study drug. One patient died before the first scheduled dose of BTZ-043 500 mg due to a pulmonary embolism. In stage 1, bactericidal activity measured as CFU counts on solid media was highest at doses 750–1500 mg; in stage 2, all doses of BTZ-043 showed 14-day bactericidal activity, highest at 1000 mg on solid media (log10 CFU/mL per day –0·115 [95% CI –0·162 to –0·069]) and TTP estimates were highest at 500 mg in liquid media (log10 h per day 0·015 [0·010 to 0·019]). BTZ-043 pharmacokinetics showed increased exposure with high-fat food versus fasting (area under the curve [AUC]0–last geometric mean ratio 4·13 [90% CI 1·65 to 10·30] for BTZ-043; 2·99 [1·39 to 6·41] for BTZ-043total [BTZ-043 plus metabolite 2]; and 1·25 [0·66 to 2·39] for metabolite 1). When taken with a standard breakfast, BTZ-043total AUC showed a dose-proportional increase up to 33 200 ng/mL × h (range 12 500 to 48 200) at 1000 mg. The maximum concentration (Cmax) increased to 5060 ng/mL (2450 to 8020); and median half-life was 3·72 h (2·45 to 6·60). Probe drug evaluations showed bioequivalence (ie, 90% CI of the AUC0–infinity geometric mean ratio from administration to day 14 entirely within the range of 80 to 125%) for caffeine (100·0% [90% CI 86·3 to 115·9]), digoxin (113·4% [105·9 to 121·5]), and dolutegravir (106·1% [91·5 to 122·9]). Dextromethorphan (116·2% [104·6 to 129·1]), tolbutamide (252·7% [230·7 to 276·9]), and midazolam (77·0% [69·2 to 85·6]) did not meet the bioequivalence criterion.Interpretation Based on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug–drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs
Education towards a reasonable humanism
No full textEducation is twice over concerned with human nature, most extensively as it is presupposed in the pursuit of diverse aims, and more specifically, as understanding it and applying such understanding are themselves made objects of study and teaching. The latter was a principal concern of ancient, renaissance and enlightenment humanists. These and others who focussed on the human condition have tended to arrive at one of the three attitudes: the celebratory, the gloomy and the condemnatory. Recent decades have seen tyrannies, global wars, campaigns of genocide, economic crises, seemingly irreconcilable political polarisation, man-made environmental degradation and other evils. Besides posing practical challenges, these put in question ideas of historical progress, of social harmony and of personal flourishing, and thereby have implications for an understanding of the human condition and for what to teach concerning it, and what qualities of character to seek to inculcate
Bank business model identification, evolution and outcomes:evidence for South Africa
No full textThis paper presents the findings of an investigation of the type, evolution and impacts on performance of bank business models in South Africa. We identify the various business models used by South African banks using data on the monthly balance sheets of commercial banks made available by the South African Reserve Bank between 1993 and 2022. We cluster banks into different business models based on the composition of their balance sheets. Based on these clusters, we identify business models oriented to wholesale and retail funding, as well as to universal, investment and interbank activities. Overall, our clustering exercise returns six distinct business models. We observe large differences in terms of business size, performance and risk profiles across the business models. We also analyse the evolution of business models over time. The results suggest that banks exhibit relatively stable business models, but where transition exists it tends to be between certain business models. Increased risk is associated with a higher probability of banks shifting business models
Navigating the nexus of elections, technology and democracy amid escalating disinformation and misinformation challenges in Kenya
No full textDespite Kenya’s transformative and progressive 2010 Constitution, it is still grappling with a hybrid democracy, displaying both authoritarian and democratic traits. Scholars attribute this status to several factors, with a prominent one being the domination of the political order and wielding of political power by a few individuals and families with historical ties to patronage networks and informal power structures. The persisting issues of electoral fraud, widespread corruption, media harassment, weak rule of law and governance challenges further contribute to the hybrid democracy status. While the 2010 Constitution aims to restructure the state and enhance democratic institutions, the transition process is considered incomplete, especially since the judiciary’s role of judicial review is mostly faced with the difficult task of countering democratic regression. Moreover, critical institutions such as the Independent Electoral and Boundaries Commission (IEBC) have faced criticism due to corruption scandals and perceptions of partisanship, eroding public trust in their ability to oversee fair elections effectively
Investigation of the effect of solvation on <sup>1</sup>J(Metal–P) spin–spin coupling
No full textThe solvent effect on the indirect 1J(M–P) spin–spin coupling constant in phosphine selenoether peri-substituted acenaphthene complexes LMCl2 is studied at the PP86 level of nonrelativistic and four-component relativistic density functional theory. Depending on the metal, the solvent effect can amount to as much as 50% or more of the total J-value. This explains the previously found disagreement between the 1J(Hg–P) coupling in LHgCl2, observed experimentally and calculated without considering solvent effects. To address the solvent effect, we have used polarizable continuum and microsolvated models. The solvent effect can be separated into indirect (structural changes) and direct (changes in the electronic structure). These effects are additive, each brings roughly about 50% of the total effect. For the in-depth analysis, we use a model with a lighter metal, Zn, instead of Hg. A much smaller solvent effect on 1J(Hg–P) for a dimer form of LHgCl2 is explained. Pilot calculations of 1J(M–P) couplings in analogous systems with other metals indicate that for metals preferring square planar structures the solvent effect is insignificant because these structures are fairly rigid. Tetrahedral structures are less constrained and can respond more easily to external effects such as solvation
Is the Modified Dental Anxiety Scale (MDAS) a single or two construct measure?:A theoretical and pragmatic perspective
No full textBackground: The MDAS questionnaire is one of a number of scales available to assess dental anxiety. It is widely used and translated into many world languages, however it lacks an explicit theoretical backdrop to the content and structure of the measure. This paper draws upon original expositions of dental anxiety: how it develops, is maintained and how this draws attention to a re-evaluation of the measure. To assist this inspection it was proposed to investigate a two latent construct formulation through a stepwise analysis using data from a representative survey of English respondents on their oral health (the Adult Dental Health Survey). Aim: To present a brief theoretical framework to underpin the measure and, as part of this study’s objectives, to provide some evidence to support the measure’s potential two-construct structure. Method: Narrative re- view, structural equation modelling and testing of specific associations to indicate a two latent con- struct formulation. Data included the MDAS items (where items 1 and 2 comprise the Anticipatory subscale, and items 3 to 5 describe the Treatment-related subscale). These items were completed by the representative sample of respondents from the most recent Adult Dental Health Survey conducted in 2009. Results: The two latent construct solution for describing dental anxiety was sup- ported. The Anticipated and Treatment-related subscales could be discriminated although were strongly correlated demonstrating overlap. Comparison of how each construct varied across the three age groups suggests an interesting heterogeneity. In addition, the two constructs behaved differently when acknowledging previous experience of respondents’ last dental visit. Anticipatory Dental Anxiety was more strongly related to Oral Health Related Quality of Life (OHRQoL) than Treatment-related Dental Anxiety as predicted. This partial evidence from empirical data and previous reports in other studies suggests that the separation of the MDAS measure into the two subscales may be warranted. Discussion: Researchers are recommended to report not only the total score of the MDAS in their studies but consider also presenting the two subscale scores, namely: Anticipatory and Treatment-related Dental Anxiety. Further work is indicated to determine if clinicians may find the subscales of use when assessing their patients
Memories of Musical Lives:Music and dance in personal music collections from Australia and New Zealand ed. Rosemary Richards and Julja Szuster
No full textReview of a collection of essays about the emigration of Scottish music to Australia, and uses of that music to build new colonial identities
Fractal percolation on statistically self-affine carpets
No full textWe consider a random self-affine carpet F based on an n x m subdivision of rectangles and a probability 0<p<1. Starting by dividing [0,1]2 into an n x m grid of rectangles and selecting these independently with probability p, we then divide the selected rectangles into n x m subrectangles which are again selected with probability p; we continue in this way to obtain a statistically self-affine set F. We are particularly interested in topological properties of F. We show that the critical value of p above which there is a positive probability that F connects the left and right edges of [0,1]2 is the same as the critical value for F to connect the top and bottom edges of [0,1]2.Once this is established we derive various topological properties of F analogous to those known for self-similar carpets.</div