Opportunities and challenges for improving antimicrobial stewardship in low and middle income countries ; lessons learnt from the maternal sepsis intervention in Western Uganda

This paper presents findings from an action-research intervention designed to identify ways of improving antimicrobial stewardship in a Ugandan Regional Referral Hospital. Building on an existing health partnership and extensive action-research on maternal health, it focused on maternal sepsis. Sepsis is one of the main causes of maternal mortality in Uganda and Surgical Site Infection, a major contributing factor. Post-natal wards also consume the largest volume of antibiotics. The findings from the Maternal Sepsis Intervention demonstrate the potential for remarkable changes in health worker behaviour through multi-disciplinary engagement. Nurses and midwives create the connective tissue linking pharmacy, laboratory scientists and junior doctors to support an evidence-based response to prescribing. These multi-disciplinary ‘huddles’ form a necessary, but insufficient, grounding for active clinical pharmacy. The impact on antimicrobial stewardship and maternal mortality and morbidity is ultimately limited by very poor and inconsistent access to antibiotics and supplies. Insufficient and predictable stock-outs undermine behaviour change frustrating health workers’ ability to exercise their knowledge and skill for the benefit of their patients. This escalates healthcare costs and contributes to Anti-Microbial Resistance

Antibiotic Resistance Profiles and Population Structure of Healthcare-associated and Community-associated Staphylococcus aureus isolated in Fort Portal, Western Uganda

Antimicrobials currently hold infectious pathogens at bay, but with cases of resistance ever increasing, those same pathogens have the potential to reverse decades of medical progress, creating one of the biggest threats to global health, food security and development in the world today. The impact of antimicrobial resistance (AMR) is of particular concern for low-income countries which already suffer from a high burden of infectious bacterial diseases in both humans and animals, with cost constraints preventing the widespread application of newer, more expensive agents. Tackling AMR is particularly challenging in settings such as Fort Portal Regional Referral Hospital (FPRRH), Western Uganda, where specific knowledge of local AMR epidemiology is required to inform evidence-based improvement of antibiotic stewardship measures in the local area.This study focused on the evaluation of Staphylococcus aureus, a commensal bacterium carried by roughly 30% of the human population commonly in the nasopharynx and/or on skin. S. aureus also acts as a major human pathogen frequently associated with nosocomial infections where the skin has been broken, for example from a wound or surgical procedure. The three core aims of this study involved the evaluation of clinical and community associated S. aureus resistance profiles; evaluation of the population diversity of clinically associated S. aureus; and the elucidation of key resistance associated genes through the whole genome sequencing (WGS) of 41 clinical isolates.A population structure for the 41 sequenced isolates was inferred by comparing their core genomes. Twenty isolates formed a tight cluster corresponding to multilocus sequence typing (MLST) clonal complex (CC) 152, a CC found to be particularly prevalent in northern Africa. In agreement with other studies, the occurrence of Panton-Valentine leukocidin toxin-encoding genes was significantly higher among CC152 strains than non-CC152 strains. However, it was also observed that the coagulase gene was over-represented in this CC, further defining the virulence strategy of this important pathogen.Initial analysis of antimicrobial susceptibility testing (AST) data of S. aureus isolated from both clinical infections at FPRRH and the hand swabs of people in the local community revealed 64% (45/70) and 83% (104/125) of isolates were resistant to one or more antibiotic and 26% (18/70) and 49% (61/125) were multidrug resistant (MDR) respectively. Methicillin-resistant S. aureus (MRSA) was isolated at rates of 38% (8/21) and 22% (27/125) for the clinical and community associated isolates respectively.WGS of the 41 clinical S. aureus isolates revealed resistance phenotypes were largely explained by the presence of antibiotic resistance genes. Although all isolates were susceptible to clindamycin, a 24% carriage of erm genes suggests potential for rapid development of resistance. The frequency of genes associated with methicillin, chloramphenicol and ciprofloxacin resistance were significantly lower amongst CC152 strains than non-CC152 strains; thus, in keeping with previous work, it was found that CC152 was almost exclusively methicillin-sensitive S. aureus (MSSA). By generating detailed information about the epidemiology of circulating S. aureus and their antibiotic susceptibility, this study has provided, for the first time, data on which evidence-based infection and AMR interventions at FPRRH can be based, including the procurement and prescription of antibiotics. Furthermore, this study was able to build and promote international collaborations between Salford University, FPRRH, Ugandan Infectious Diseases Institute and Makerere University for the effective transfer of knowledge and completion of advanced research

Anti-microbial resistance in global perspective

This open access book provides an accessible introduction to the mechanics of international development and global health text for policy-makers and students across a wide range of disciplines. Antimicrobial resistance is a major threat to the well-being of patients and health systems the world over. In fragile health systems so challenged, on a day-today basis, by the overwhelming burden of both infectious and non-communicable disease, it is easy to overlook the impacts of AMR. The Maternal Sepsis Intervention, focusing on a primary cause of maternal death in Uganda, demonstrates the systemic nature of AMR and the gains that can be made through improved Infection Prevention Control and direct engagement of laboratory testing in antibiotic prescribing

Antibiotic resistance profiles and population structure of disease-associated Staphylococcus aureus infecting patients in Fort Portal Regional Referral Hospital, Western Uganda

Tackling antimicrobial resistance (AMR) is particularly challenging in low-resource settings such as Fort Portal Regional Referral Hospital (FPRRH) in Western Uganda. Specific knowledge of local AMR epidemiology is required to inform evidence-based improvement of antibiotic stewardship measures in the hospital. To address this, we combined existing antimicrobial susceptibility testing (AST) from FPRRH, with whole genome sequencing (WGS) of 41 Staphylococcus aureus isolates (2017–2019). AST revealed 73 % (30 of 41) of isolates were resistant to one or more antibiotics and 29 % (12 of 41) were multi-drug resistant (MDR). Resistance phenotypes were largely explained by the presence of antibiotic resistance genes in WGS data. Five isolates were methicillin-resistant S. aureus (MRSA) and MDR. Although all isolates were susceptible to clindamycin, a 24 % carriage of erm genes suggests potential for rapid development of resistance. We inferred a population structure for the S. aureus isolates by comparing their core genomes. Twenty isolates formed a tight cluster corresponding to multilocus sequence typing clonal complex (CC) 152, a CC found to be particularly prevalent in northern Africa. The frequency of genes associated with methicillin, chloramphenicol and ciprofloxacin resistance were significantly lower among CC152 strains than non-CC152 strains; thus, in keeping with previous work, we find that CC152 is almost exclusively methicillin-sensitive S. aureus (MSSA). Also, in agreement with other studies, we observed that the occurrence of Panton–Valentine leukocidin toxin-encoding genes was significantly higher among CC152 strains than non-CC152 strains. However, we also observed that the coagulase gene was over-represented in this CC, further defining the virulence strategy of this important pathogen. By generating detailed information about the epidemiology of circulating S. aureus and their antibiotic susceptibility, our study has provided, for the first time, data on which evidence-based infection and AMR interventions at FPRRH can be based

Limits to scale invariance in alluvial rivers

Assumptions about fluvial processes and process–form relations are made in general models and in many site‐specific applications. Many standard assumptions about reach‐scale flow resistance, bed‐material entrainment thresholds and transport rates, and downstream hydraulic geometry involve one or other of two types of scale invariance: a parameter (e.g. critical Shields number) has the same value in all rivers, or doubling one variable causes a fixed proportional change in another variable in all circumstances (e.g. power‐law hydraulic geometry). However, rivers vary greatly in size, gradient, and bed material, and many geomorphologists regard particular types of river as distinctive. This review examines the tension between universal scaling assumptions and perceived distinctions between different types of river. It identifies limits to scale invariance and departures from simple scaling, and illustrates them using large data sets spanning a wide range of conditions. Scaling considerations and data analysis support the commonly made distinction between coarse‐bed and fine‐bed reaches, whose different transport regimes can be traced to the different settling‐velocity scalings for coarse and fine grains. They also help identify two end‐member sub‐types: steep shallow coarse‐bed ‘torrents’ with distinctive flow‐resistance scaling and increased entrainment threshold, and very large, low‐gradient ‘mega rivers’ with predominantly suspended load, subdued secondary circulation, and extensive backwater conditions

MARK4 controls ischaemic heart failure through microtubule detyrosination.

Myocardial infarction is a major cause of premature death in adults. Compromised cardiac function after myocardial infarction leads to chronic heart failure with systemic health complications and a high mortality rate1. Effective therapeutic strategies are needed to improve the recovery of cardiac function after myocardial infarction. More specifically, there is a major unmet need for a new class of drugs that can improve cardiomyocyte contractility, because inotropic therapies that are currently available have been associated with high morbidity and mortality in patients with systolic heart failure2,3 or have shown a very modest reduction of risk of heart failure4. Microtubule detyrosination is emerging as an important mechanism for the regulation of cardiomyocyte contractility5. Here we show that deficiency of microtubule-affinity regulating kinase 4 (MARK4) substantially limits the reduction in the left ventricular ejection fraction after acute myocardial infarction in mice, without affecting infarct size or cardiac remodelling. Mechanistically, we provide evidence that MARK4 regulates cardiomyocyte contractility by promoting phosphorylation of microtubule-associated protein 4 (MAP4), which facilitates the access of vasohibin 2 (VASH2)-a tubulin carboxypeptidase-to microtubules for the detyrosination of α-tubulin. Our results show how the detyrosination of microtubules in cardiomyocytes is finely tuned by MARK4 to regulate cardiac inotropy, and identify MARK4 as a promising therapeutic target for improving cardiac function after myocardial infarction.BHF fellowship grant (FS/14/28/30713), Issac Newton Trust Grant (18.40u), and Cambridge BHF Centre of Research Excellence grants (RE/13/6/30180 and RE/18/1/34212)

The present and future of serum diagnostic tests for testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371-373 and miR-302-367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

Quantitative Models of the Mechanisms That Control Genome-Wide Patterns of Transcription Factor Binding during Early Drosophila Development

Transcription factors that drive complex patterns of gene expression during animal development bind to thousands of genomic regions, with quantitative differences in binding across bound regions mediating their activity. While we now have tools to characterize the DNA affinities of these proteins and to precisely measure their genome-wide distribution in vivo, our understanding of the forces that determine where, when, and to what extent they bind remains primitive. Here we use a thermodynamic model of transcription factor binding to evaluate the contribution of different biophysical forces to the binding of five regulators of early embryonic anterior-posterior patterning in Drosophila melanogaster. Predictions based on DNA sequence and in vitro protein-DNA affinities alone achieve a correlation of ∼0.4 with experimental measurements of in vivo binding. Incorporating cooperativity and competition among the five factors, and accounting for spatial patterning by modeling binding in every nucleus independently, had little effect on prediction accuracy. A major source of error was the prediction of binding events that do not occur in vivo, which we hypothesized reflected reduced accessibility of chromatin. To test this, we incorporated experimental measurements of genome-wide DNA accessibility into our model, effectively restricting predicted binding to regions of open chromatin. This dramatically improved our predictions to a correlation of 0.6–0.9 for various factors across known target genes. Finally, we used our model to quantify the roles of DNA sequence, accessibility, and binding competition and cooperativity. Our results show that, in regions of open chromatin, binding can be predicted almost exclusively by the sequence specificity of individual factors, with a minimal role for protein interactions. We suggest that a combination of experimentally determined chromatin accessibility data and simple computational models of transcription factor binding may be used to predict the binding landscape of any animal transcription factor with significant precision

ATLAS pixel detector electronics and sensors

The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd