RESUMEN
It is little appreciated not only how closely linked are the disciplines of neurology, psychiatry, and anthropology but even more so the degree to which they share a "common ancestry". This paper briefly reviews the definition and historical origins of each area of study to then begin to illustrate how their "genealogies" overlap. This illustration is by way of a sampling of the many key figures who contributed to the rise of not just neuropsychiatry or anthropology but both disciplines. That is, a selective review is undertaken of paragons whose careers bridged medicine, neuropsychiatry, and anthropology. A sampling from among the dozens who have made major contributions to spanning these disciplines illuminates the significant extent of their co-mingled intellectual ancestry. This series is akin to a data table of necessarily concise biographical vignettes - past scholars with some or full medical training who also advanced both anthropology and neuropsychiatry as these disciplines grew into intellectual maturity. Each is, in a sense, a data point that bolsters the overarching thesis that the intellectual history of both disciplines has shared ancestry. Thus, even this preliminary and topical survey of a few past "exemplars" underscores the importance of this unique intellectual siblingship. Moreover, there is now a profusion of living scholars who add fulsomely to what might be deemed this 'trilateral marriage' of anthropology, psychiatry, and neurology. A compilation of more contemporary contributors is well worthy of a future review that expands from this first consideration. This initial work is meant to engender more robust scholarship that better elucidates and, thereby, enriches and enlivens further work while also uncovering new avenues of deeper insight, notably as to the "conceptual and heuristic progression" of evolutionary neurosciences with respect to the normative and pathologic.
RESUMEN
Acetyl coenzyme A synthase (ACS) catalyzes the formation and deconstruction of the key biological metabolite, acetyl coenzyme A (acetyl-CoA). The active site of ACS features a {NiNi} cluster bridged to a [Fe4S4]n+ cubane known as the A-cluster. The mechanism by which the A-cluster functions is debated, with few model complexes able to replicate the oxidation states, coordination features, or reactivity proposed in the catalytic cycle. In this work, we isolate the first bimetallic models of two hypothesized intermediates on the paramagnetic pathway of the ACS function. The heteroligated {Ni2+Ni1+} cluster, [K(12-crown-4)2][1], effectively replicates the coordination number and oxidation state of the proposed "Ared" state of the A-cluster. Addition of carbon monoxide to [1]- allows for isolation of a dinuclear {Ni2+Ni1+(CO)} complex, [K(12-crown-2)n][2] (n = 1-2), which bears similarity to the "ANiFeC" enzyme intermediate. Structural and electronic properties of each cluster are elucidated by X-ray diffraction, nuclear magnetic resonance, cyclic voltammetry, and UV/vis and electron paramagnetic resonance spectroscopies, which are supplemented by density functional theory (DFT) calculations. Calculations indicate that the pseudo-T-shaped geometry of the three-coordinate nickel in [1]- is more stable than the Y-conformation by 22 kcal mol-1, and that binding of CO to Ni1+ is barrierless and exergonic by 6 kcal mol-1. UV/vis absorption spectroscopy on [2]- in conjunction with time-dependent DFT calculations indicates that the square-planar nickel site is involved in electron transfer to the CO π*-orbital. Further, we demonstrate that [2]- promotes thioester synthesis in a reaction analogous to the production of acetyl coenzyme A by ACS.
Asunto(s)
Níquel , Níquel/química , Níquel/metabolismo , Acetato CoA Ligasa/química , Acetato CoA Ligasa/metabolismo , Modelos Moleculares , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Oxidación-Reducción , Acetilcoenzima A/metabolismo , Acetilcoenzima A/químicaRESUMEN
The efficiency of translation termination is determined by the nature of the stop codon as well as its context. In eukaryotes, recognition of the A-site stop codon and release of the polypeptide are mediated by release factors eRF1 and eRF3, respectively. Translation termination is modulated by other factors which either directly interact with release factors or bind to the E-site and modulate the activity of the peptidyl transferase center. Previous studies suggested that the Saccharomyces cerevisiae ABCF ATPase New1 is involved in translation termination and/or ribosome recycling, however, the exact function remained unclear. Here, we have applied 5PSeq, single-particle cryo-EM and readthrough reporter assays to provide insight into the biological function of New1. We show that the lack of New1 results in ribosomal stalling at stop codons preceded by a lysine or arginine codon and that the stalling is not defined by the nature of the C-terminal amino acid but rather by the identity of the tRNA isoacceptor in the P-site. Collectively, our results suggest that translation termination is inefficient when ribosomes have specific tRNA isoacceptors in the P-site and that the recruitment of New1 rescues ribosomes at these problematic termination contexts.
RESUMEN
Severe tooth wear is related to substantial loss of tooth structure, with dentin exposure and significant loss (≥1/3) of the clinical crown. The objective of this systematic review was to summarize and analyze the scientific evidence regarding the mechanical performance of computer-aided design/computer-aided manufacturing (CAD/CAM) composite resin and CAD/CAM lithium disilicate ceramic occlusal veneers, in terms of fatigue and fracture resistance, on severely worn posterior teeth. Currently, occlusal veneers are an alternative for treating worn posterior teeth. Although scientific evidence demonstrates the good performance of lithium disilicate occlusal veneers, there are less brittle materials with a modulus of elasticity more similar to dentin than ceramics, such as resin CAD/CAM blocks. Therefore, it is important to identify which type of material is best for restoring teeth with occlusal wear defects and which material can provide better clinical performance. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of the PubMed, Embase, Web of Science, Scopus, Cochrane, OpenGrey, Redalyc, DSpace, and Grey Literature Report databases was conducted and supplemented by a manual search, with no time or language limitations, until January 2022. We aimed to identify studies evaluating the fatigue and fracture resistance of CAD/CAM composite resin and ceramic occlusal veneers. The quality of the full-text articles was evaluated according to the modified Consolidated Standards of Reporting Trials (CONSORT) criteria for in vitro studies, and 400 articles were initially identified. After removing duplicates and applying the selection criteria, 6 studies were included in the review. The results demonstrated that the mechanical performance of CAD/CAM composite resin occlusal veneers is comparable to that of CAD/CAM lithium disilicate occlusal veneers in terms of fatigue and fracture resistance.
Asunto(s)
Cerámica , Resinas Compuestas , Diseño Asistido por Computadora , Coronas con Frente Estético , Humanos , Porcelana Dental , Fracaso de la Restauración Dental , Desgaste de los Dientes/etiología , Desgaste de los Dientes/terapiaRESUMEN
The current work focuses on developing nanocomposite films using taro starch and cellulose nanofibers extracted from the root's peel. Films were prepared using mixtures of starch, cellulose nanofibers (0 %, 5 %, 10 %, and 15 % w/w), glycerol, and water. Results showed that the addition of cellulose nanofibers increased film thickness, opacity, UV-light barrier capacity, and water swelling percentage. All films showed a typical B-type X-ray diffraction pattern characteristic of semicrystalline materials. FTIR analysis confirmed chemical interactions between the starch chains and the nanofibers, which probably interact through hydrogen bonds. Nanocomposite films exhibited increased tensile strength and reduced strain at break compared to control materials. Films with cellulose nanofibers showed an increase in Young's modulus compared to control ones, with no differences observed between films with cellulose nanofibers at 10 % and 15 %. Furthermore, films with cellulose nanofibers at 5 % and 10 % exhibited lower water vapor permeability than control samples, while those with cellulose nanofibers at 15 % showed an increase in this parameter compared to other materials. These results suggest that incorporating taro cellulose nanofibers is a promising alternative for obtaining taro starch nanocomposites films with improved properties.
Asunto(s)
Celulosa , Nanocompuestos , Nanofibras , Permeabilidad , Almidón , Nanofibras/química , Nanocompuestos/química , Celulosa/química , Almidón/química , Resistencia a la Tracción , Vapor , Agua/química , Difracción de Rayos XRESUMEN
The paenilamicins are a group of hybrid non-ribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here, we have determined structures of the paenilamicin PamB2 stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site tRNAs. In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms utilized by P. larvae. We could further demonstrate that PamB2 interferes with the translocation of mRNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a new class of context-specific translocation inhibitors.
RESUMEN
PURPOSE: This study assessed the reliability and load-velocity profiles of 3 different landmine-punch-throw variations (seated without trunk rotation, seated with trunk rotation, and standing whole body) with different loads (20, 22.5, and 25.0 kg), all with the dominant hand and nondominant hand. METHODS: In a quasi-randomized order, 14 boxers (24.1 [4.3] y, 72.6 [10.1] kg) performed 3 repetitions of each variation with their dominant hand and their nondominant hand, with maximal effort and 3 minutes of interset rest. Peak velocity was measured via the GymAware Power Tool (Kinetic Performance Technologies). The interclass correlation coefficients and their 95% CIs were used to determine the intrasession reliability of each variation × load × hand combination. Additionally, a 2 (hand) × 3 (variation) repeated-measures analysis of variance assessed the load-velocity profile slope, and a 3 (variation) × 2 (hand) × 3 (load) repeated-measures analysis of variance assessed the peak velocity of each variation. RESULTS: Most variations were highly reliable (intraclass correlation coefficient > .91), with the nondominant hand being as reliable or more reliable than the dominant hand. Very strong linear relationships were observed for the group average for each variation (R2 ≥ .96). However, there was no variation × hand interaction for the slope, and there was no main effect for variation or hand. Additionally, there was no interaction for the peak velocity, but there were main effects for variation, hand, and load (P < .01). CONCLUSION: Each variation was reliable and can be used to create upper-body ballistic unilateral load-velocity profiles. However, as with other research on load-velocity profile, individual data allowed for more accurate profiling than group average data.
Asunto(s)
Mano , Humanos , Reproducibilidad de los Resultados , Adulto Joven , Mano/fisiología , Masculino , Fenómenos Biomecánicos , Adulto , Lateralidad Funcional/fisiología , Rotación , SedestaciónRESUMEN
Purpose: The primary aim of this study was to explore whether intravoxel incoherent motion (IVIM) can offer a contrast-agent-free alternative to dynamic contrast-enhanced (DCE)-MRI for measuring breast tumor perfusion. The secondary aim was to investigate the relationship between tissue diffusion measures from DWI and DCE-MRI measures of the tissue interstitial and extracellular volume fractions. Materials and methods: A total of 108 paired DWI and DCE-MRI scans were acquired at 1.5 T from 40 patients with primary breast cancer (median age: 44.5 years) before and during neoadjuvant chemotherapy (NACT). DWI parameters included apparent diffusion coefficient (ADC), tissue diffusion (Dt), pseudo-diffusion coefficient (Dp), perfused fraction (f), and the product f×Dp (microvascular blood flow). DCE-MRI parameters included blood flow (Fb), blood volume fraction (vb), interstitial volume fraction (ve) and extracellular volume fraction (vd). All were extracted from three tumor regions of interest (whole-tumor, ADC cold-spot, and DCE-MRI hot-spot) at three MRI visits: pre-treatment, after one, and three cycles of NACT. Spearman's rank correlation was used for assessing between-subject correlations (r), while repeated measures correlation was employed to assess within-subject correlations (rrm) across visits between DWI and DCE-MRI parameters in each region. Results: No statistically significant between-subject or within-subject correlation was found between the perfusion parameters estimated by IVIM and DCE-MRI (f versus vb and f×Dp versus Fb; P=0.07-0.81). Significant moderate positive between-subject and within-subject correlations were observed between ADC and ve (r=0.461, rrm=0.597) and between Dt and ve (r=0.405, rrm=0.514) as well as moderate positive within-subject correlations between ADC and vd and between Dt and vd (rrm=0.619 and 0.564, respectively) in the whole-tumor region. Conclusion: No correlations were observed between the perfusion parameters estimated by IVIM and DCE-MRI. This may be attributed to imprecise estimates of fxDp and vb, or an underlying difference in what IVIM and DCE-MRI measure. Care should be taken when interpreting the IVIM parameters (f and f×Dp) as surrogates for those measured using DCE-MRI. However, the moderate positive correlations found between ADC and Dt and the DCE-MRI parameters ve and vd confirms the expectation that as the interstitial and extracellular volume fractions increase, water diffusion increases.
RESUMEN
During the COVID-19 pandemic, forecasting COVID-19 trends to support planning and response was a priority for scientists and decision makers alike. In the United States, COVID-19 forecasting was coordinated by a large group of universities, companies, and government entities led by the Centers for Disease Control and Prevention and the US COVID-19 Forecast Hub (https://covid19forecasthub.org). We evaluated approximately 9.7 million forecasts of weekly state-level COVID-19 cases for predictions 1-4 weeks into the future submitted by 24 teams from August 2020 to December 2021. We assessed coverage of central prediction intervals and weighted interval scores (WIS), adjusting for missing forecasts relative to a baseline forecast, and used a Gaussian generalized estimating equation (GEE) model to evaluate differences in skill across epidemic phases that were defined by the effective reproduction number. Overall, we found high variation in skill across individual models, with ensemble-based forecasts outperforming other approaches. Forecast skill relative to the baseline was generally higher for larger jurisdictions (e.g., states compared to counties). Over time, forecasts generally performed worst in periods of rapid changes in reported cases (either in increasing or decreasing epidemic phases) with 95% prediction interval coverage dropping below 50% during the growth phases of the winter 2020, Delta, and Omicron waves. Ideally, case forecasts could serve as a leading indicator of changes in transmission dynamics. However, while most COVID-19 case forecasts outperformed a naïve baseline model, even the most accurate case forecasts were unreliable in key phases. Further research could improve forecasts of leading indicators, like COVID-19 cases, by leveraging additional real-time data, addressing performance across phases, improving the characterization of forecast confidence, and ensuring that forecasts were coherent across spatial scales. In the meantime, it is critical for forecast users to appreciate current limitations and use a broad set of indicators to inform pandemic-related decision making.
Asunto(s)
COVID-19 , Predicción , Pandemias , SARS-CoV-2 , COVID-19/epidemiología , COVID-19/transmisión , Humanos , Predicción/métodos , Estados Unidos/epidemiología , Pandemias/estadística & datos numéricos , Biología Computacional , Modelos EstadísticosRESUMEN
Ribosomes trapped on mRNAs during protein synthesis need to be rescued for the cell to survive. The most ubiquitous bacterial ribosome rescue pathway is trans-translation mediated by tmRNA and SmpB. Genetic inactivation of trans-translation can be lethal, unless ribosomes are rescued by ArfA or ArfB alternative rescue factors or the ribosome-associated quality control (RQC) system, which in Bacillus subtilis involves MutS2, RqcH, RqcP and Pth. Using transposon sequencing in a trans-translation-incompetent B. subtilis strain we identify a poorly characterized S4-domain-containing protein YlmH as a novel potential RQC factor. Cryo-EM structures reveal that YlmH binds peptidyl-tRNA-50S complexes in a position analogous to that of S4-domain-containing protein RqcP, and that, similarly to RqcP, YlmH can co-habit with RqcH. Consistently, we show that YlmH can assume the role of RqcP in RQC by facilitating the addition of poly-alanine tails to truncated nascent polypeptides. While in B. subtilis the function of YlmH is redundant with RqcP, our taxonomic analysis reveals that in multiple bacterial phyla RqcP is absent, while YlmH and RqcH are present, suggesting that in these species YlmH plays a central role in the RQC.
Asunto(s)
Bacillus subtilis , Proteínas Bacterianas , Biosíntesis de Proteínas , Ribosomas , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Ribosomas/metabolismo , Dominios Proteicos , Microscopía por Crioelectrón , Unión Proteica , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Modelos Moleculares , Aminoacil-ARN de TransferenciaRESUMEN
Complexes featuring multiple metal centres are of growing interest regarding metal-metal cooperation and its tuneability. Here the synthesis and characterisation of heterobimetallic complexes of a 3d metal (4: Mn, 5: Co) and lanthanum supported by a (1,1,1-tris[(3-methoxysalicylideneamino)methyl]ethane) ligand is reported, as well as discussion of their electronic structure via electron paramagnetic resonance (EPR) spectroscopy, electrochemical experiments and computational studies. Competitive binding experiments of the ligand and various metal salts unequivocally demonstrate that in these heterobimetallic complexes the 3d metal (Mn, Co) selectively occupies the κ6-N3O3 binding site of the ligand, whilst La occupies the κ6-O6 metal binding site in line with their relative oxophilicities. EPR spectroscopy supported by density functional theory analysis indicates that the 3d metal is high spin in both cases (S = 5/2 (Mn), 3/2 (Co)). Cyclic voltammetry studies on the Mn/La and Co/La bimetallic complexes revealed a quasi-reversible Mn2+/3+ redox process and poorly-defined irreversible oxidation events respectively.
RESUMEN
This study investigates the humoral and cellular immune responses and health-related quality of life measures in individuals with mild to moderate long COVID (LC) compared to age and gender matched recovered COVID-19 controls (MC) over 24 months. LC participants show elevated nucleocapsid IgG levels at 3 months, and higher neutralizing capacity up to 8 months post-infection. Increased spike-specific and nucleocapsid-specific CD4+ T cells, PD-1, and TIM-3 expression on CD4+ and CD8+ T cells were observed at 3 and 8 months, but these differences do not persist at 24 months. Some LC participants had detectable IFN-γ and IFN-ß, that was attributed to reinfection and antigen re-exposure. Single-cell RNA sequencing at the 24 month timepoint shows similar immune cell proportions and reconstitution of naïve T and B cell subsets in LC and MC. No significant differences in exhaustion scores or antigen-specific T cell clones are observed. These findings suggest resolution of immune activation in LC and return to comparable immune responses between LC and MC over time. Improvement in self-reported health-related quality of life at 24 months was also evident in the majority of LC (62%). PTX3, CRP levels and platelet count are associated with improvements in health-related quality of life.
Asunto(s)
COVID-19 , Síndrome Post Agudo de COVID-19 , Humanos , Linfocitos T CD8-positivos , Calidad de Vida , SARS-CoV-2 , Anticuerpos AntiviralesRESUMEN
Anthocyanins (ACNs) are natural compounds with potential applications due to their colorimetric response to pH. Due to their sensitivity to various environmental factors, nanoencapsulation with biopolymers is a successful strategy for stabilizing ACNs. In this work ACNs were extracted from grape skins and encapsulated into chitosan (CS) nanoparticles by ionic gelation using sodium tripolyphosphate (TPP) as a cross-linking agent. CS nanoparticles loaded with ACNs had particle sizes between 291 and 324 nm and polydispersity index around 0.3. The encapsulation efficiency of ACNs was approximately 60 %; and encapsulated anthocyanins (ACN-NPs) exhibited color change properties under different pH conditions. pH-sensitive labels based on polyvinyl alcohol (PVA) were prepared by the casting method. The effect of incorporating ACN-NPs on the physical, structural, and pH-sensitive properties of PVA labels was evaluated, and its application as shrimp freshness indicator was studied. The nanoencapsulation protected ACNs against heat and light treatments, preserving the original purple color. When applying the label, visible changes from red to blue until reaching yellow were observed with the change in the quality of the shrimp at the refrigeration temperature. The results suggest that PVA labels containing ACNs encapsulated in C-NPs can be used as smart packaging labels in the food industry.
Asunto(s)
Quitosano , Nanopartículas , Vitis , Quitosano/química , Alcohol Polivinílico/química , Antocianinas/química , Nanopartículas/química , Extractos Vegetales/química , Embalaje de Alimentos/métodos , Concentración de Iones de HidrógenoRESUMEN
Nascent polypeptide chains can induce translational stalling to regulate gene expression. This is exemplified by the E. coli secretion monitor (SecM) arrest peptide that induces translational stalling to regulate expression of the downstream encoded SecA, an ATPase that co-operates with the SecYEG translocon to facilitate insertion of proteins into or through the cytoplasmic membrane. Here we present the structure of a ribosome stalled during translation of the full-length E. coli SecM arrest peptide at 2.0 Å resolution. The structure reveals that SecM arrests translation by stabilizing the Pro-tRNA in the A-site, but in a manner that prevents peptide bond formation with the SecM-peptidyl-tRNA in the P-site. By employing molecular dynamic simulations, we also provide insight into how a pulling force on the SecM nascent chain can relieve the SecM-mediated translation arrest. Collectively, the mechanisms determined here for SecM arrest and relief are also likely to be applicable for a variety of other arrest peptides that regulate components of the protein localization machinery identified across a wide range of bacteria lineages.
Asunto(s)
Proteínas de Escherichia coli , Escherichia coli , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Extensión de la Cadena Peptídica de Translación , Ribosomas/metabolismo , Péptidos/metabolismo , Biosíntesis de Proteínas , Factores de Transcripción/metabolismoRESUMEN
Arrest peptides containing RAPP (ArgAlaProPro) motifs have been discovered in both Gram-positive and Gram-negative bacteria, where they are thought to regulate expression of important protein localization machinery components. Here we determine cryo-EM structures of ribosomes stalled on RAPP arrest motifs in both Bacillus subtilis and Escherichia coli. Together with molecular dynamics simulations, our structures reveal that the RAPP motifs allow full accommodation of the A-site tRNA, but prevent the subsequent peptide bond from forming. Our data support a model where the RAP in the P-site interacts and stabilizes a single hydrogen atom on the Pro-tRNA in the A-site, thereby preventing an optimal geometry for the nucleophilic attack required for peptide bond formation to occur. This mechanism to short circuit the ribosomal peptidyltransferase activity is likely to operate for the majority of other RAPP-like arrest peptides found across diverse bacterial phylogenies.
Asunto(s)
Peptidil Transferasas , Peptidil Transferasas/metabolismo , Antibacterianos/metabolismo , Bacterias Gramnegativas/metabolismo , Bacterias Grampositivas/genética , Biosíntesis de Proteínas , Ribosomas/metabolismo , Péptidos/metabolismo , ARN de Transferencia/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismoRESUMEN
[This corrects the article DOI: 10.4102/sajid.v37i1.363.].
RESUMEN
BACKGROUND: Relatively clean cooking fuels such as liquefied petroleum gas (LPG) emit less fine particulate matter (PM2·5) and carbon monoxide (CO) than polluting fuels (eg, wood, charcoal). Yet, some clean cooking interventions have not achieved substantial exposure reductions. This study evaluates determinants of between-community variability in exposures to household air pollution (HAP) across sub-Saharan Africa. METHODS: In this measurement study, we recruited households cooking primarily with LPG or exclusively with wood or charcoal in peri-urban Cameroon, Ghana, and Kenya from previously surveyed households. In 2019-20, we conducted monitoring of 24 h PM2·5 and CO kitchen concentrations (n=256) and female cook (n=248) and child (n=124) exposures. PM2·5 measurements used gravimetric and light scattering methods. Stove use monitoring and surveys on cooking characteristics and ambient air pollution exposure (eg, walking time to main road) were also administered. FINDINGS: The mean PM2·5 kitchen concentration was five times higher among households cooking with charcoal than those using LPG in the Kenyan community (297 µg/m3, 95%âCIâ216-406, vs 61 µg/m3, 49-76), but only 4 µg/m3 higher in the Ghanaian community (56 µg/m3, 45-70, vs 52 µg/m3, 40-68). The mean CO kitchen concentration in charcoal-using households was double the WHO guideline (6·11 parts per million [ppm]) in the Kenyan community (15·81 ppm, 95%âCIâ8·71-28·72), but below the guideline in the Ghanaian setting (1·77 ppm, 1·04-2·99). In all communities, mean PM2·5 cook exposures only met the WHO interim-1 target (35 µg/m3) among LPG users staying indoors and living more than 10 min walk from a road. INTERPRETATION: Community-level variation in the relative difference in HAP exposures between LPG and polluting cooking fuel users in peri-urban sub-Saharan Africa might be attributed to differences in ambient air pollution levels. Thus, mitigation of indoor and outdoor PM2·5 sources will probably be critical for obtaining significant exposure reductions in rapidly urbanising settings of sub-Saharan Africa. FUNDING: UK National Institute for Health and Care Research.