Dynamical epidemic suppression using stochastic prediction and control

We consider the effects of noise on a model of epidemic outbreaks, where the outbreaks appear. randomly. Using a constructive transition approach that predicts large outbreaks, prior to their occurrence, we derive an adaptive control. scheme that prevents large outbreaks from occurring. The theory inapplicable to a wide range of stochastic processes with underlying deterministic structure.Comment: 14 pages, 6 figure

Effect of dietary treatment with dimethylarsinous acid (DMA\u3csup\u3eIII\u3c/sup\u3e) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAV, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMAIII was shown to be the likely urinary metabolite of DMAV inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMAIII-induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMAIII, 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1–5, with higher rating indicating greater extent of cytotoxicity visualized. DMAIII significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMAIII induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMAIII induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMAV does not induce hyperplasia in mice, suggesting that urinary concentrations of DMAIII do not reach cytotoxic levels in DMAV-treated mice

Effect of dietary treatment with dimethylarsinous acid (DMA\u3csup\u3eIII\u3c/sup\u3e) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice

Chronic exposure to inorganic arsenic (iAs) is carcinogenic to the human urinary bladder. It produces urothelial cytotoxicity and proliferation in rats and mice. DMAV, a major methylated urinary metabolite of iAs, is a rat bladder carcinogen, but without effects on the mouse urothelium. DMAIII was shown to be the likely urinary metabolite of DMAV inducing urothelial changes and is also postulated to be one of the active metabolites of iAs. To evaluate potential DMAIII-induced urothelial effects, it was administered to As3mt knockout mice which cannot methylate arsenicals. Female C57BL/6 wild type and As3mt knockout mice (10/group) were administered DMAIII, 77.3 ppm in water for four weeks. Urothelial effects were evaluated by light and scanning electron microscopy (EM) and immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation. EM findings were rated 1–5, with higher rating indicating greater extent of cytotoxicity visualized. DMAIII significantly increased the BrdU labeling index, a ratio of BrdU labeled cells to non-labeled cells, in the treated knockout group compared to control and wild type treated groups. DMAIII induced simple hyperplasia in more knockout mice (4/10) compared to wild type mice (2/10). All treated knockout mice had more and larger intracytoplasmic granules compared to the treated wild type mice. Changes in EM classification were not significant. In conclusion, DMAIII induces urothelial toxicity and regenerative hyperplasia in mice and most likely plays a role in inorganic arsenic-induced urothelial changes. However, DMAV does not induce hyperplasia in mice, suggesting that urinary concentrations of DMAIII do not reach cytotoxic levels in DMAV-treated mice

Effect of trivalent arsenicals on cell proliferation in mouse and human microvascular endothelial cells

AbstractChronic exposure to high levels of inorganic arsenic (iAs) has been associated with cancerous and non-cancerous health effects, including cardiovascular effects. However, the mechanism for a presumed toxic effect of arsenic on vascular tissue is not clear. Our working hypothesis is that inorganic trivalent arsenic and its methylated metabolites react with cysteine-containing cellular proteins and alter their function leading to adverse events such as cytotoxicity or proliferation. In this study, human microvascular endothelial cells (HMEC1) and mouse microvascular endothelial cells (MFP-MVEC) were exposed to arsenite (iAsIII), monomethylarsonous acid (MMAIII), or dimethylarsinous acid (DMAIII) for 72h to evaluate cytotoxicity, and for 24, 48 or 72h to evaluate cell proliferation. Both cell lines showed similar LC50 values, from 0.1 to 2.4μM, for all three trivalent arsenicals. The endothelial cells treated with1nM to 1μM concentrations of the three trivalent arsenicals did not show increased cell proliferation at 24, 48 or 72h or increased rate of proliferation at 72h of exposure. Overall, cytotoxicity of trivalent arsenicals to microvascular endothelial cells is similar to their cytotoxicity to epithelial cells, and that these compounds are not mitogenic

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery

Why small-quantity lipid-based nutrient supplements should be integrated into comprehensive strategies to prevent child undernutrition in nutritionally vulnerable populations : response to Gupta et al.’s commentary

We write in response to the commentary by Gupta et al. (2023) on small-quantity lipid-based nutrient supplements (SQ-LNS) for infants and young children 6 to 24 months of age, which was prompted by the recent brief guidance note from UNICEF (2023) explaining when, why and how SQ-LNS are being prioritized as part of their package of preventive actions to combat early childhood malnutrition. The UNICEF document was disseminated shortly after publication of a correspondence in Nature Food (Aguayo et al. 2023), authored by nutrition leaders from several organizations, that summarized the evidence on the benefits of SQ-LNS and called for this intervention to be scaled up and integrated into programs for populations in which child undernutrition is prevalent and dietary quality is very poor. We agree with Gupta et al. that child malnutrition is the result of many factors and there is no single “quick fix” or “magic bullet”. In fact, the above-cited documents state clearly and frequently that provision of SQ-LNS is not a stand-alone intervention and must be integrated into comprehensive strategies to improve infant and young child feeding (IYCF), including the promotion of dietary diversity, as well as other actions needed to prevent malnutrition. SQ-LNS are intended for vulnerable populations who lack access to an affordable, nutritionally adequate complementary feeding diet and have high rates of stunting, wasting and mortality. In such populations, we agree with Gupta et al. that IYCF messages alone are not enough. This is precisely why SQ-LNS were originally developed

Adapting evidence-informed complex population health interventions for new contexts : a systematic review of guidance

Background Adapting interventions that have worked elsewhere can save resources associated with developing new interventions for each specific context. While a developing body of evidence shows benefits of adapted interventions compared with interventions transported without adaptation, there are also examples of interventions which have been extensively adapted, yet have not worked in the new context. Decisions on when, to what extent, and how to adapt interventions therefore are not straightforward, particularly when conceptualising intervention effects as contingent upon contextual interactions in complex systems. No guidance currently addresses these questions comprehensively. To inform development of an overarching guidance on adaptation of complex population health interventions, this systematic review synthesises the content of the existing guidance papers. Methods We searched for papers published between January 2000 and October 2018 in 7 bibliographic databases. We used citation tracking and contacted authors and experts to locate further papers. We double screened all the identified records. We extracted data into the following categories: descriptive information, key concepts and definitions, rationale for adaptation, aspects of adaptation, process of adaptation, evaluating and reporting adapted interventions. Data extraction was conducted independently by two reviewers, and retrieved data were synthesised thematically within pre-specified and emergent categories. Results We retrieved 6694 unique records. Thirty-eight papers were included in the review representing 35 sources of guidance. Most papers were developed in the USA in the context of implementing evidence-informed interventions among different population groups within the country, such as minority populations. We found much agreement on how the papers defined key concepts, aims, and procedures of adaptation, including involvement of key stakeholders, but also identified gaps in scope, conceptualisation, and operationalisation in several categories. Conclusions Our review found limitations that should be addressed in future guidance on adaptation. Specifically, future guidance needs to be reflective of adaptations in the context of transferring interventions across countries, including macro- (e.g. national-) level interventions, better theorise the role of intervention mechanisms and contextual interactions in the replicability of effects and accordingly conceptualise key concepts, such as fidelity to intervention functions, and finally, suggest evidence-informed strategies for adaptation re-evaluation and reporting

Small-quantity lipid-based nutrient supplements for children age 6-24 months: a systematic review and individual participant data meta-analysis of effects on developmental outcomes and effect modifiers

BACKGROUND: Small-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development. OBJECTIVES: We aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024). RESULTS: In 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11). CONCLUSIONS: Child SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million personyears of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eG FR values 105 mL.min(-1).1.73 m(-2), compared with those with eG FR between 60 and 105 mL.min(-1).1.73 m(-2). Mendelian randomization analyses for CHD showed an association among participants with eGFR 105 mL.min(-1).1.73 m(-2). Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin Alc, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead