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There is widespread concern that elder abuse and neglect (EAN) incidents increased during the onset of the COVID-19 pandemic due in part to increases in risk factors. Initial reports relying on administrative systems such as adult protective services records produced mixed results regarding whether or not there was a change in EAN incidents. Using data from an ongoing longitudinal study on EAN in dementia family caregiving that started before the pandemic, we assessed the hypothesis that the pandemic is related to a change in probability of EAN and EAN protective factors. Family caregivers to persons with dementia completed two waves of 21 daily diaries, 6-months apart, assessing their daily use of EAN behaviors. The first group (n = 32) completed their first wave before the pandemic and their second wave during the pandemic. The second group (n = 32) completed both waves during the pandemic. For this cohort, the generalized linear mixed logistic model results showed inconsistent associations between the onset of COVID-19 and the probability of a caregiver engaging in elder abuse or neglect behaviors. In terms of protective factors, the use of formal services was not significantly impacted by COVID-19; however, the likelihood of receiving informal support from family and friends increased significantly during the pandemic period. Dementia family caregivers were not likely impacted negatively by initial pandemic restrictions, such as shelter-in-place orders, as anticipated. These findings contribute to our understanding of how distal, disruptive processes may influence more proximal caregiver stresses and the likelihood of EAN., Author(s): Carolyn E. Z. Pickering [sup.1] , Christopher D. Maxwell [sup.2] , Maria Yefimova [sup.3] , Danny Wang [sup.1] , Frank Puga [sup.1] , Tami Sullivan [sup.4] Author Affiliations: (1) [...]

I. INTRODUCTION 337 II. ASSISTED REPRODUCTIVE TECHNOLOGIES: A BRIEF OVERVIEW 339 A. PROCEDURES EMPLOYED IN ASSISTED REPRODUCTIVE TECHNOLOGIES 339 B. POTENTIAL RISKS TO OFFSPRING. 340 C. ATTEMPTS TO CREATE A [...]

Background The spread of antibiotic-resistant bacteria may be driven by human-animal-environment interactions, especially in regions with limited restrictions on antibiotic use, widespread food animal production, and free-roaming domestic animals. In this study, we aimed to identify risk factors related to commercial food animal production, small-scale or 'backyard' food animal production, domestic animal ownership, and practices related to animal handling, waste disposal, and antibiotic use in Ecuadorian communities. Methods and findings We conducted a repeated measures study from 2018 to 2021 in 7 semirural parishes of Quito, Ecuador to identify determinants of third-generation cephalosporin-resistant E. coli (3GCR-EC) and extended-spectrum beta-lactamase E. coli (ESBL-EC) in children. We collected 1,699 fecal samples from 600 children and 1,871 domestic animal fecal samples from 376 of the same households at up to 5 time points per household over the 3-year study period. We used multivariable log-binomial regression models to estimate relative risks (RR) of 3GCR-EC and ESBL-EC carriage, adjusting for child sex and age, caregiver education, household wealth, and recent child antibiotic use. Risk factors for 3GCR-EC included living within 5 km of more than 5 commercial food animal operations (RR: 1.26; 95% confidence interval (CI): 1.10, 1.45; p-value: 0.001), household pig ownership (RR: 1.23; 95% CI: 1.02, 1.48; p-value: 0.030) and child pet contact (RR: 1.23; 95% CI: 1.09, 1.39; p-value: 0.001). Risk factors for ESBL-EC were dog ownership (RR: 1.35; 95% CI: 1.00, 1.83; p-value: 0.053), child pet contact (RR: 1.54; 95% CI: 1.10, 2.16; p-value: 0.012), and placing animal feces on household land/crops (RR: 1.63; 95% CI: 1.09, 2.46; p-value: 0.019). The primary limitations of this study are the use of proxy and self-reported exposure measures and the use of a single beta-lactamase drug (ceftazidime with clavulanic acid) in combination disk diffusion tests for ESBL confirmation, potentially underestimating phenotypic ESBL production among cephalosporin-resistant E. coli isolates. To improve ESBL determination, it is recommended to use 2 combination disk diffusion tests (ceftazidime with clavulanic acid and cefotaxime with clavulanic acid) for ESBL confirmatory testing. Future studies should also characterize transmission pathways by assessing antibiotic resistance in commercial food animals and environmental reservoirs. Conclusions In this study, we observed an increase in enteric colonization of antibiotic-resistant bacteria among children with exposures to domestic animals and their waste in the household environment and children living in areas with a higher density of commercial food animal production operations., Author(s): Heather K. Amato 1,*, Fernanda Loayza 2, Liseth Salinas 2, Diana Paredes 2, Daniela Garcia 2, Soledad Sarzosa 2, Carlos Saraiva-Garcia 2, Timothy J. Johnson 3,4, Amy J. Pickering [...]

In our paper we reviewed adoption of point-of-use chlorination in closely monitored interventions in low-income settings. We agree with Lantagne et al. that our results do not represent studies from [...]

Con la voglia di stravolgere il mondo anche solo con un sorriso. (Anna Magnani) To the sorrow of friends and colleagues in diverse academic communities around the globe, Carol Lazzaro-Weis, [...]

American Song and Struggle from Columbus to World War II Will Kaufman. Cambridge and New York: Cambridge University Press, 2022. xviii + 511 pp. Illustrations. Index. ISBN: 978-1-31653-433-7. From time [...]

I. INTRODUCTION 181 II. CHALLENGES FACING LGBTQ YOUTH IN SCHOOLS 181 A. Overview of Federal and State Protections Based on Sexual Orientation and Gender Identity 181 1. Federal Constitutional Law [...]

Background: Centralized chlorination of urban piped water supplies has historically contributed to major reductions in waterborne illness. In locations without effective centralized water treatment, point-of-use (POU) chlorination for households is widely promoted to improve drinking water quality and health. Realizing these health benefits requires correct, consistent, and sustained product use, but real- world evaluations have often observed low levels of use. To our knowledge, no prior reviews exist on adoption of chlorine POU products. Objectives: Our objectives were to identify which indicators of adoption are most often used in chlorine POU studies, summarize levels of adoption observed, understand how adoption changes over time, and determine how adoption is affected by frequency of contact between participants and study staff. Methods: We conducted a systematic review of household POU chlorination interventions or programs from 1990 through 2021 that reported a quantitative measure of adoption, were conducted in low- and middle-income countries, included data collection at households, and reported the intervention start date. Results: We identified 36 studies of household drinking water chlorination products that met prespecified eligibility criteria and extracted data from 46 chlorine intervention groups with a variety of chlorine POU products and locations. There was no consensus definition of adoption of household water treatment; the most common indicator was the proportion of household stored water samples with free chlorine residual >0.1 or 0.2 mg/L. Among studies that reported either free or total chlorine-confirmed adoption of chlorine POU products, use was highly variable (across all chlorine intervention groups at the last time point measured in each study; range: 1.5%-100%; sample size-weighted median = 47%; unweighted median = 58%). The median follow-up duration among intervention groups was 3 months. On average, adoption declined over time and was positively associated with frequency of contact between respondents and study staff. Discussion: Although prior research has shown that POU chlorine products improve health when correctly and consistently used, a reliance on individual adoption for effective treatment is unlikely to lead to the widespread public health benefits historically associated with pressurized, centralized treatment of piped water supplies. https://doi.org/10.1289/EHP10839, Introduction Chlorination of urban piped water supplies contributed to substantial declines in waterborne disease in major cities in the early 1900s. (1) Today the addition of chlorine-based disinfectants is a [...]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19) in humans; symptoms can range from asymptomatic to mild or severe, including severe respiratory distress and sometimes death (1). [...]

Introduction Water, sanitation, and hygiene (WASH) services are described in global action plans as necessary to curb antimicrobial resistance (AMR), despite a lack of supporting data. (1,2) WASH services are [...]

Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient ([fH.sup.-/-]) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged [fH.sup.-/-] males. Examination of [fH.sup.-/-] livers (3-24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8* and F4/80* cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis., Introduction Key functions of the immune system are the ability to discriminate self from nonself, and to rapidly eliminate invasive pathogens while causing minimal injury to the host. Rapid induction [...]

How are resources distributed when administrative units merge? We take advantage of recent, large-scale municipal mergers in Japan to systematically study the impact of municipal mergers within merged municipalities and, in particular, what politicians do when their districts and constituencies suddenly change. We argue that when rural and sparsely populated municipalities merge with more urban and densely populated municipalities, residents of the former are likely to see a reduced share of public spending because they lost political leverage through the merger. Our empirical analyses detect changes in public spending before and after the municipal mergers with remote sensing data, which allows for flexible units of analysis and enables us to proxy for spending within merged municipalities. Overall, our results show that politicians tend to reduce benefits allocated to areas where there are a small number of voters, while increasing the allocation to more populous areas. The micro-foundation of our argument is also corroborated by survey data. The finding suggests that, all things being equal, the quantity rather than quality of electorates matters for politicians immediately after political units change. Keywords municipal merger, size of political unit, urban-rural divide, remote-sensing data, Japan, INTRODUCTION Politics is the art of deciding who gets what, when, and how (Lasswell 1986), and politicians in democracies have to make choices about the allocation of government goods and [...]

We previously demonstrated that genome reorganization, through chromosome territory repositioning, occurs concurrently with significant changes in gene expression in normal primary human fibroblasts treated with the drug rapamycin, or stimulated into quiescence. Although these events occurred concomitantly, it is unclear how specific changes in gene expression relate to reorganization of the genome at higher resolution. We used computational analyses, genome organization assays, and microscopy, to investigate the relationship between chromosome territory positioning and gene expression. We determined that despite relocation of chromosome territories, there was no substantial bias in the proportion of genes changing expressiononany one chromosome, including chromosomes10and 18. Computational analyses identified that clusters of serum deprivation and rapamycin-responsive genes along the linear extent of chromosomes. Chromosome conformation capture (3C) analysis demonstrated the strengthening or loss of specific long-range chromatin interactions in response to rapamycin and quiescence induction, including a cluster of genes containing Interleukin-8 and several chemokine genes on chromosome 4. We further observed that the LIF gene, which is highly induced upon rapamycin treatment, strengthened interactions with up- and down-stream intergenic regions. Our findings indicate that the repositioning of chromosome territories in response to cell stimuli, this does not reflect gene expression changes occurring within physically clustered groups of genes. Key words: rapamycin, quiescence, gene expression, chromosome territory, long-range chromatin interaction. Les auteurs ont précédemment démontré que la réorganisation du génome par l'intermédiaire du repositionnement des territoires chromosomiques, survient parallèlement à des changements de l'expression génique chez des fibroblastes primaires humains normaux traités à la rapamycine ou amenés à la quiescence. Même si ces événements surviennent simultanément, on ignore comment ces changements spécifiques de l'expression génique se rapportent à la réorganisation du génome à une plus haute résolution. À l'aide d'analyses computationnelles, de mesures de l'organisation du génome et de la microscopie, le lien entre le positionnement des territoires chromosomiques et l'expression génique a été examiné. Les auteurs ont déterminé que malgré la relocalisation des territoires chromosomiques, il n'y avait pas de biais substantiel dans la proportion de gènes dont l'expression changeait, sur aucun des chromosomes, y compris les chromosomes 10 et 18. Les analyses computationnelles ont permis d'identifier des grappes de gènes qui répondent à la privation de sérum et à la rapamycine sur l'étendue chromosomique linéaire. L'analyse de capture de conformation des chromosomes (3C) a démontré le renforcement ou la perte d'interactions spécifiques de longue distance sur la chromatine en réponse à la rapamycine et à l'induction de la quiescence y compris dans une grappe de gènes y compris le gène interleukine-8 et plusieurs gènes codant des chimiokines sur le chromosome 4. Les auteurs ont en outre observé que le gène LIF, qui est fortement induit par un traitement à la rapamycine, s'engageait dans des interactions plus fortes avec des régions intergéniques en amont et en aval. Ces données indiquent que le repositionnement des territoires chromosomiques en réponse à des stimuli cellulaires ne reflète pas les changements d'expression génique qui surviennent à l'intérieur de groupes de gènes physiquement organisés en grappe. [Traduit par la Rédaction] Mots-clés : rapamycine, quiescence, expression génique, territoire chromosomique, interaction chromatinienne de longue distance., Introduction Background The genetic material in eukaryotes is organized into long linear polymers of DNA called chromosomes, which provide information for cellular function (e.g., gene expression). It has now become [...]

The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system.sup.1,2. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown.sup.1,3. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy. MicroRNAs from head and neck cancer cells, shuttled to sensory neurons by extracellular vesicles, cause a shift to an adrenergic neuronal phenotype that promotes tumour progression., Author(s): Moran Amit [sup.1] , Hideaki Takahashi [sup.1] [sup.2] , Mihnea Paul Dragomir [sup.3] , Antje Lindemann [sup.1] , Frederico O. Gleber-Netto [sup.1] , Curtis R. Pickering [sup.1] , Simone [...]

Childhood malnutrition is associated with high morbidity and mortality globally.sup.1. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood.sup.2. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0-59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards.sup.3-5. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization's median growth reference standards for a healthy population.sup.6. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces).sup.7; the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes.sup.8. Building from our previous work mapping CGF in Africa.sup.9, here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live.sup.1, aggregated to policy-relevant first and second (for example, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications. High-resolution subnational mapping of child growth failure indicators for 105 low- and middle-income countries between 2000 and 2017 shows that, despite considerable progress, substantial geographical inequalities still exist in some countries., Author(s): Damaris K. Kinyoki [sup.1] [sup.1] [sup.2] , Aaron E. Osgood-Zimmerman [sup.1] , Brandon V. Pickering [sup.1] , Lauren E. Schaeffer [sup.1] , Laurie B. Marczak [sup.1] , Alice Lazzar-Atwood [...]

"The fact that relapse is an almost inevitable feature of [Substance Use Disorder] leads to the straightforward conclusion that relapse is 'not a weakness of character or will.'" (1) I. [...]

ABSTRACT. We report a new Taltheilei site-type found off the west coast of Hudson Bay in southern Nunavut. The Taltheilei is an archaeological culture that existed in the Barrenlands of [...]

Background Diarrhea and acute respiratory infection (ARI) are leading causes of death in children. The WASH Benefits Bangladesh trial implemented a multicomponent sanitation intervention that led to a 39% reduction in the prevalence of diarrhea among children and a 25% reduction for ARI, measured 1 to 2 years after intervention implementation. We measured longer-term intervention effects on these outcomes between 1 to 3.5 years after intervention implementation, including periods with differing intensity of behavioral promotion. Methods and findings WASH Benefits Bangladesh was a cluster-randomized controlled trial of water, sanitation, hygiene, and nutrition interventions (NCT01590095). The sanitation intervention included provision of or upgrades to improved latrines, sani-scoops for feces removal, children's potties, and in-person behavioral promotion. Promotion was intensive up to 2 years after intervention initiation, decreased in intensity between years 2 to 3, and stopped after 3 years. Access to and reported use of latrines was high in both arms, and latrine quality was significantly improved by the intervention, while use of child feces management tools was low. We enrolled a random subset of households from the sanitation and control arms into a longitudinal substudy, which measured child health with quarterly visits between 1 to 3.5 years after intervention implementation. The study period therefore included approximately 1 year of high-intensity promotion, 1 year of low-intensity promotion, and 6 months with no promotion. We assessed intervention effects on diarrhea and ARI prevalence among children Conclusions The observed effect of the WASH Benefits Bangladesh sanitation intervention on diarrhea in children appeared to be sustained for at least 3.5 years after implementation, including 1.5 years after heavy promotion ceased. Existing latrine access was high in the study setting, suggesting that improving on-site latrine quality can deliver health benefits when latrine use practices are in place. Further work is needed to understand how latrine adoption can be achieved and sustained in settings with low existing access and how sanitation programs can adopt transformative approaches of excreta management, including safe disposal of child and animal feces, to generate a hygienic home environment. Trial registration ClinicalTrials.gov; NCT01590095; https://clinicaltrials.gov/ct2/show/NCT01590095., Author(s): Jesse D. Contreras 1, Mahfuza Islam 2, Andrew Mertens 3, Amy J. Pickering 4, Benjamin F. Arnold 5, Jade Benjamin-Chung 6, Alan E. Hubbard 3, Mahbubur Rahman 2, Leanne [...]

From Mummers to Madness: A Social History of Popular Music, c. 1770s to c. 1970s David Taylor. Huddersfield: University of Huddersfield Press, 2021. vi + 442 pp. Illustrations. Index. ISBN: [...]

N.sup.6-methyladenosine (m.sup.6A) is the most prevalent modified nucleotide in mRNA.sup.1,2, with around 25% of mRNAs containing at least one m.sup.6A. Methylation of mRNA to form m.sup.6A is required for diverse cellular and physiological processes.sup.3. Although the presence of m.sup.6A in an mRNA can affect its fate in different ways, it is unclear how m.sup.6A directs this process and why the effects of m.sup.6A can vary in different cellular contexts. Here we show that the cytosolic m.sup.6A-binding proteins--YTHDF1, YTHDF2 and YTHDF3--undergo liquid-liquid phase separation in vitro and in cells. This phase separation is markedly enhanced by mRNAs that contain multiple, but not single, m.sup.6A residues. Polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules or neuronal RNA granules. m.sup.6A-mRNA is subject to compartment-specific regulation, including a reduction in the stability and translation of mRNA. These studies reveal that the number and distribution of m.sup.6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of m.sup.6A-modified mRNAs are governed by liquid-liquid phase separation principles. The cytosolic N.sup.6-methyladenosine (m.sup.6A)-binding proteins YTHDF1, YTHDF2 and YTHDF3 undergo liquid-liquid phase separation in vitro and in cells; this is enhanced by polymethylated mRNAs to form complexes that partition into different cellular phase-separated compartments., Author(s): Ryan J. Ries [sup.1] , Sara Zaccara [sup.1] , Pierre Klein [sup.1] , Anthony Olarerin-George [sup.1] , Sim Namkoong [sup.2] , Brian F. Pickering [sup.1] , Deepak P. Patil [...]

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement- activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complementactivation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases., Introduction Our understanding and treatment of complement-mediated diseases has grown exponentially over the last 20 years. We now understand that complement plays an integral role in many autoimmune-and inflammation-based diseases [...]

The Cradle of Humankind (Cradle) in South Africa preserves a rich collection of fossil hominins representing Australopithecus, Paranthropus and Homo.sup.1. The ages of these fossils are contentious.sup.2-4 and have compromised the degree to which the South African hominin record can be used to test hypotheses of human evolution. However, uranium-lead (U-Pb) analyses of horizontally bedded layers of calcium carbonate (flowstone) provide a potential opportunity to obtain a robust chronology.sup.5. Flowstones are ubiquitous cave features and provide a palaeoclimatic context, because they grow only during phases of increased effective precipitation.sup.6,7, ideally in closed caves. Here we show that flowstones from eight Cradle caves date to six narrow time intervals between 3.2 and 1.3 million years ago. We use a kernel density estimate to combine 29 U-Pb ages into a single record of flowstone growth intervals. We interpret these as major wet phases, when an increased water supply, more extensive vegetation cover and at least partially closed caves allowed for undisturbed, semi-continuous growth of the flowstones. The intervening times represent substantially drier phases, during which fossils of hominins and other fossils accumulated in open caves. Fossil preservation, restricted to drier intervals, thus biases the view of hominin evolutionary history and behaviour, and places the hominins in a community of comparatively dry-adapted fauna. Although the periods of cave closure leave temporal gaps in the South African fossil record, the flowstones themselves provide valuable insights into both local and pan-African climate variability. Climate-driven periodicity of flowstone accretion between 3.2 and 1.3 million years ago in Cradle of Humankind caves reveals that the presence of hominin fossils reflects accumulation in open caves during intermittent, substantially drier phases., Author(s): Robyn Pickering [sup.1] [sup.2] , Andy I. R. Herries [sup.3] [sup.4] , Jon D. Woodhead [sup.5] , John C. Hellstrom [sup.5] , Helen E. Green [sup.5] , Bence Paul [...]

Activation of the type 1 angiotensin II receptor ([AT.sub.1]) triggers proinflammatory signaling through pathways independent of classical Gq signaling that regulate vascular homeostasis. Here, we report that the [AT.sub.1] receptor preformed a heteromeric complex with the receptor for advanced glycation endproducts (RAGE). Activation of the [AT.sub.1] receptor by angiotensin II (Ang II) triggered transactivation of the cytosolic tail of RAGE and NF-[kappa]B-driven proinflammatory gene expression independently of the liberation of RAGE ligands or the ligand-binding ectodomain of RAGE. The importance of this transactivation pathway was demonstrated by our finding that adverse proinflammatory signaling events induced by [AT.sub.1] receptor activation were attenuated when RAGE was deleted or transactivation of its cytosolic tail was inhibited. At the same time, classical homeostatic Gq signaling pathways were unaffected by RAGE deletion or inhibition. These data position RAGE transactivation by the [AT.sub.1] receptor as a target for vasculoprotective interventions. As proof of concept, we showed that treatment with the mutant RAGE peptide S391A-[RAGE.sub.362-404] was able to inhibit transactivation of RAGE and attenuate Ang II-dependent inflammation and atherogenesis. Furthermore, treatment with WT [RAGE.sub.362-404] restored Ang II-dependent atherogenesis in Ager/Apoe-KO mice, without restoring ligand-mediated signaling via RAGE, suggesting that the major effector of RAGE activation was its transactivation., IntroductionBlockade of the renin-angiotensin aldosterone system (RAAS) is one of the most prescribed treatments in all of medicine. The pleiotropic benefits of RAAS blockade on inflammation (1-3), atherogenesis (4, 5), [...]

Background Mass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. Most recently, the MORDOR clinical trial demonstrated that MDA led to an overall reduction in all-cause childhood mortality in targeted communities. There is however concern about the potential of increased antimicrobial resistance in treated communities. This study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study, additionally profiling changes in the gut microbiome after treatment. For faecal metagenomics, 60 children were sampled prior to treatment and 122 children after four rounds of MDA, half receiving azithromycin and half placebo. Results The proportion of bacteria carrying macrolide resistance increased after azithromycin treatment. Diversity and global community structure of the gut was minimally impacted by treatment, however abundance of several species was altered by treatment. Notably, the putative human enteropathogen Escherichia albertii was more abundant after treatment. Conclusions MDA with azithromycin increased carriage of macrolide-resistant bacteria, but had limited impact on clinically relevant bacteria. However, increased abundance of enteropathogenic Escherichia species after treatment requires further, higher resolution investigation. Future studies should focus on the number of treatments and administration schedule to ensure clinical benefits continue to outweigh costs in antimicrobial resistance carriage. Trial registration ClinicalTrial.gov, NCT02047981. Registered January 29th 2014, https://clinicaltrials.gov/ct2/show/NCT02047981 Keywords: Macrolide resistance, Antimicrobial resistance, Gut metagenomics, Microbial, Metagenomics, Mass drug administration, Azithromycin, Gut microbiome, Childhood mortality, Author(s): Harry Pickering[sup.1], John D. Hart[sup.1], Sarah Burr[sup.1,2], Richard Stabler[sup.1], Ken Maleta[sup.2], Khumbo Kalua[sup.2,3], Robin L. Bailey[sup.1] and Martin J. Holland[sup.1] Background Mass drug administration (MDA) with azithromycin has been [...]