Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

Whole Genome Sequence Analysis of Brucella abortus Isolates from Various Regions of South Africa.

The availability of whole genome sequences in public databases permits genome-wide comparative studies of various bacterial species. Whole genome sequence-single nucleotide polymorphisms (WGS-SNP) analysis has been used in recent studies and allows the discrimination of various Brucella species and strains. In the present study, 13 Brucella spp. strains from cattle of various locations in provinces of South Africa were typed and discriminated. WGS-SNP analysis indicated a maximum pairwise distance ranging from 4 to 77 single nucleotide polymorphisms (SNPs) between the South African Brucella abortus virulent field strains. Moreover, it was shown that the South African B. abortus strains grouped closely to B. abortus strains from Mozambique and Zimbabwe, as well as other Eurasian countries, such as Portugal and India. WGS-SNP analysis of South African B. abortus strains demonstrated that the same genotype circulated in one farm (Farm 1), whereas another farm (Farm 2) in the same province had two different genotypes. This indicated that brucellosis in South Africa spreads within the herd on some farms, whereas the introduction of infected animals is the mode of transmission on other farms. Three B. abortus vaccine S19 strains isolated from tissue and aborted material were identical, even though they originated from different herds and regions of South Africa. This might be due to the incorrect vaccination of animals older than the recommended age of 4-8 months or might be a problem associated with vaccine production.

Investigation of Brucella melitensis in Sable Antelope (Hippotragus niger) in South Africa.

In this study, Brucella melitensis infection in sable antelope (Hippotragus niger) was investigated on two wildlife ranches in South Africa over a 12-year period in order to determine the origin of the outbreaks and the role of livestock in maintaining the disease. Retrospective data were obtained from farm records and interviews as well as samples tested from different disease scenarios and clinical settings. On one ranch, 10 of 74 sable tested seropositive for B. melitensis in 2004 but were certified clear of infection after no further brucellosis cases were detected following repeated serological tests and culling over a five-year period. Recrudescence occurred in 2013 (7 of 187 brucellosis positives) and in 2014 (one positive), with persistent, latent infection being the most reasonable explanation. In a second case study, linked to the first one through a common vendor, 15 of 80 sable tested positive in 2016, some five years after the acquisition of the animals from a putative source. Brucella melitensis biovar 1 and/or 3 were isolated from each outbreak on both ranches. Both outbreaks resulted in substantial losses for the owners, arising from testing and culling and significant resource expenditure by the state. The study identified the diagnostic challenges for identifying and resolving disease outbreaks in wildlife, the persistence of B. melitensis in sable, the risks associated with animal movements, and the need for a wildlife-sensitive disease control scheme. Although the actual source of infection could not be identified, the investigation points away from local livestock as a source of ongoing infection while the persistent infection is consistent with the disease circulating within small, ranched populations and being spread through the keeping and trading of high-value animals. The implications of the study findings to disease control in wildlife are discussed.

Problem formulation for gene drive mosquitoes designed to reduce malaria transmission in Africa: results from four regional consultations 2016-2018.

BACKGROUND: Gene drive mosquitoes have been proposed as a possible means to reduce the transmission of malaria in Africa. Because this technology has no prior use-history at this time, environmental risk assessments for gene drive mosquitoes will benefit from problem formulation-an organized and ordered process to identify protection goals and potential pathways to harm to the environment, or animal or human health. Recognizing this need, the New Partnership for Africa's Development (NEPAD), with support from African and international partners, organized four regional consultative workshops in Africa to initiate this process. METHODS: The workshops were attended by a diverse set of participants and stakeholders, including scientists, ethicists, health professionals, government regulators in the fields of environment health and biosafety as well government policymakers, who met for 4 days to deliberate on protection goals and pathways relevant to the use of gene drive mosquitoes for malaria control. The goal of the workshops was not to produce a comprehensive and detailed environmental risk assessment of gene drive mosquitoes, but rather to introduce problem formulation as a tool to the stakeholder community, and to serve as a starting point for conducting systematic environmental risk assessments in the future, identifying protection goals related to gene drive mosquitoes that are particular to African stakeholders. RESULTS: Participants in the workshops frequently identified human health and biodiversity as being relevant broad protection goals. Results of the deliberations provide insight into the concerns of African participants at an early stage in the development of gene drive organism/products that should be instructive to developers using this technology. CONCLUSIONS: In general, the African participants of the consultations had a precautionary perspective with regard to environmental risk assessment of gene drive technology. As gene drive technology develops, protection goals will become further refined and candidate products will be further defined. These workshops represent only the beginning of a continuing process that will ultimately inform environmental risk assessment for gene drive mosquitoes to control malaria in Africa.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Strengthening regulatory capacity for gene drives in Africa: leveraging NEPAD's experience in establishing regulatory systems for medicines and GM crops in Africa.

The New Partnership for Africa's Development (NEPAD) Agency recognizes that Africa is in a period of transition and that this demands exploring and harnessing safe advances made in science-based innovations including modern biotechnology. To advance the science of biotechnology in Africa effectively, while at the same time safeguarding human health and the environment, the African Union (AU) adopted a High-Level Panel report on modern biotechnology entitled, Freedom to Innovate, which advocated for a coevolutionary approach where technology development goes hand in hand with regulation. Furthermore, most AU member states are Parties to the Cartagena Protocol on Biosafety (CPB), a legally binding international agreement negotiated, concluded and adopted within the framework of the Convention on Biological Diversity. This seeks to guide Parties in developing systems for the environmentally sound management of modern biotechnology applications. Currently, 49 AU Member States have signed and ratified the CPB, of which 12 have passed biosafety laws. African Union (AU) member states are at different stages in the development of regulatory frameworks for applications of modern biotechnology, which include genetically modified (GM) products and other emerging technologies. Biosafety regulatory frameworks comprise: biotechnology and/or biosafety policy; laws, regulations and guidelines; administrative systems; decision-making systems; and mechanisms for public engagement. To assist Member States to implement functional regulatory frameworks for both agriculture and health applications, the NEPAD Agency established the African Biosafety Network of Expertise (ABNE) and the African Medicines Regulatory Harmonization (AMRH). Currently, transgenic insects and GM crops are regulated by Competent National Authorities whose mandate derives from national biosafety laws. For GM crops, a lot of research has been conducted up to the confined field trial (CFT) and multi-location trials stages in a number of African countries. Burkina Faso has fully functional containment facilities for transgenic mosquitoes while Mali and Uganda are developing theirs. The Burkina Faso regulatory agency has granted permits and has already received sets of sterile mosquito eggs for trials in the contained facility. It is instructive to note that both ABNE and AMRH have worked with national and regional regulatory bodies in Africa to enhance their technical capacities for informed decision making, adoption of best practices, and compliance with international standards. It is against the backdrop of a rich blend of on-the-ground knowledge, experience, expertise, and insight into the context and political sensitivities of member states that the NEPAD Agency seeks to expand existing support. This would include capacity strengthening in the regulation of emerging technologies, such as the application of gene drives in the development of transgenic mosquito for the control of malaria transmission.

The first report of Escherichia fergusonii isolated from non-human primates, in Africa.

The aim of this study was to determine the resistance phenotypes of selected enteric bacteria isolated from non-human primates at a wildlife-human interface. Bacterial isolates from faecal samples of non-human primates at two wildlife rehabilitation centres in South Africa were screened for the presence of Escherichia coli. The biochemical characterisation of E. coli and E. coli-like bacteria revealed both adonitol positive and sorbitol negative strains - a unique characteristic of Escherichia fergusonii and Escherichia coli K99. Further tests were carried out to identify the isolates, namely growth on Simmons citrate agar supplemented with 2% adonitol and biochemical tests based on their ability to ferment cellobiose and d-arabitol. Antimicrobial sensitivity was determined with microbroth dilution tests employing microtitre plates with 21 different antimicrobial drugs. Molecular characterisation was done with a duplex polymerase chain reaction (PCR) assay that targeted the yliE and EFER_1569 genes. E. fergusonii strains were confirmed by the presence of a 233 bp segment of the yliE gene and a 432 bp segment of the EFER_1569 gene. Twenty-three E. coli-like bacteria were confirmed as E. fergusonii based on the confirmatory tests and they were in 100% agreement. Approximately 87% of them were resistant to polymyxins B and E (colistin) as well as the carbapenem group with occasional resistance to amikacin. This is the first reported isolation and identification of E. fergusonii strains in non-human primates. The findings point to E. fergusonii as a possible emerging pathogen of zoonotic importance.