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Hajj is associated with an increased risk of the transmission of infectious diseases including upper respiratory tract infections (URTIs). It can be a focal point for the emergence, persistence and dissemination of antimicrobial-resistant (AMR) bacteria. The overuse of antibiotics during Hajj can promote the development of antimicrobial resistance. Little information is known regarding the true appropriateness of prescribing antibiotics for treating URTIs during Hajj. Here we studied the rate, patterns and appropriateness of antibiotic prescription among a cohort of pilgrims who were treated for URTIs during the 2018 Hajj season. Adult pilgrims who sought medical services for URTIs [presenting with coryza, runny nose, nasal irritation, nasal congestion, cough, sore throat, headache or fever (even if subjective)] within the Holy sites were enrolled in this study and consented to provide swabs and medical information. A total of 121 pilgrims were enrolled, with the majority (60.3 %) originating from North African Arab countries. Most were male (89.3 %) with a median age of 45 years. Bacterial infections were detected in 7.3 % (n=9) of the URTI cases. The identified bacteria included Haemophilus influenzae (n=6, all resistant to ampicillin), Streptococcus pneumoniae (n=2), Staphylococcus aureus (n=1, resistant to oxacillin) and Moraxella catarrhalis (n=1, resistant to ampicillin and trimethoprim/sulfamethoxazole). The antibiotic prescription rate was 52.1%, most of which was amoxicillin (81 %). The data demonstrated that the proportion of appropriate practices in treating bacterial URTIs in this cohort was 45.5 %. This study highlights the need for implementing laboratory identification of the aetiological agents and related AMR profiles when treating URTIs in Hajj, rather than relying on clinical assessment alone.

Enterotoxigenic

Antimicrobial resistance (AMR) is a major issue that poses a serious threat to global health. Recent reports from the World Health Organization (WHO) highlighted the increased threat from continuously emerging AMR organisms, accompanied by the paucity of development of new antimicrobial drugs. Low- and middle-income countries are likely to be the most affected, both in terms of the impact on public health and economic burden.

Summary Background In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis. Methods Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing. Findings Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87–94) for rpoB (rifampicin resistance), 86% (74–93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39–68) for pncA (pyrazinamide resistance), 85% (77–91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81–92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing. Interpretation Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation. Funding Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.

Background Respiratory syncytial virus (RSV) is the leading cause of viral pneumonia and bronchiolitis, especially in younger children. The burden of RSV infection in adults, particularly in the older age group, is increasingly recognised. However, RSV disease burden and molecular epidemiology in the World Health Organization (WHO) Western Pacific Region (WPR) has not been reviewed systematically. The aim of this systematic review is to investigate the epidemiological aspects of RSV (incidence, prevalence, seasonality and hospitalisation status) and the associated molecular data in the WPRO countries. Methods A systematic search was conducted in international literature databases (MEDLINE, EMBASE, Scopus and Web of Science) to identify RSV-related publications from January 2000 to October 2017 in the WPR countries. Results A total of 196 studies from 15 WPR countries were included. The positivity rate for RSV among respiratory tract infection patients was 16.73% (95% confidence interval (CI) = 15.12%-18.4%). The RSV-positive cases were mostly found in hospitalised compared with outpatients (18.28% vs 11.54%, P

More human deaths have been attributable to Mycobacterium tuberculosis than any other pathogen, and the epidemic is sustained by ongoing transmission. Various typing schemes have been developed to identify strain-specific differences and track transmission dynamics in affected communities, with recent introduction of whole genome sequencing providing the most accurate assessment. Mycobacterial interspersed repetitive unit (MIRU) typing is a family of variable number tandem repeat schemes that have been widely used to study the molecular epidemiology of M. tuberculosis. MIRU typing was used in most well-resourced settings to perform routine molecular epidemiology. Instances of MIRU homoplasy have been observed in comparison with sequence-based phylogenies, limiting its discriminatory value. A fundamental question is whether the observed homoplasy arises purely through stochastic processes, or whether there is evidence of natural selection. We compared repeat numbers at 24 MIRU loci with a whole genome sequence-based phylogeny of 245 isolates representing three modern M. tuberculosis lineages. This analysis demonstrated extensive homoplasy of repeat numbers, but did not detect any evidence of natural selection of repeat numbers, at least since the ancestral branching of the three modern lineages of M. tuberculosis. In addition, we observed good sensitivity but poor specificity and positive predictive values of MIRU-24 to detect clusters of recent transmission, as defined by whole-genome single nucleotide polymorphism analysis. These findings provide mechanistic insight, and support a transition away from VNTR-based typing toward sequence-based typing schemes for both research and public health purposes.

Salmonella enterica serovar Wangata is an important pathogen in New South Wales (NSW), Australia. The incidence of S. Wangata is increasing and transmission is suspected to be via a non-food source. A recent outbreak investigation of sources of S. Wangata recovered isolates from humans, domestic animals, wildlife and the environment. Here, we extend that investigation by characterising and describing the genomic determinates of these isolates. We found that Australian S. Wangata isolates from different sources exhibited similar virulence and antimicrobial resistance gene profiles. There were no major genomic differences between isolates obtained from different geographical regions within Australia or from different host species. In addition, we found evidence (low number of SNPs and identical virulence gene profiles) suggestive of an international transmission event between Australia and the United Kingdom. This study supports the hypothesis that S. Wangata is shared between different hosts in NSW, Australia and provides strong justification for the continued use of genomic surveillance of Salmonella.

Summary Background Mongolia has high and rising rates of multi-drug resistant tuberculosis (MDR-TB). Spatio-temporal and programmatic evidence suggests a major contribution from MDR-TB transmission, but genotypic evidence has not been assessed. Methods All MDR-TB cases identified during 2012 were examined. Demographic and bacteriological data were obtained from the National Tuberculosis Reference Laboratory. Isolates of Mycobacterium tuberculosis from culture-confirmed category 1 treatment failures were genotyped using 24-loci mycobacterium interspersed repetitive unit (MIRU-24) analysis. Results Of the 210 MDR-TB cases identified, 115 (54.8%) were treatment failures (34.8% category 1; 20.0% category 2). Streptomycin resistance was present in 156 (74.3%) cases; including 55/73 (75.3%) category 1 treatment failures who had never been exposed to streptomycin. Among category 1 treatment failures, Beijing lineage strains predominated (88.0%; 59/67 of genotyped isolates). MIRU-24 clustering was documented in 62.7% (42/67) of strains; 55.2% (37/67) remained clustered when drug susceptibility test results were considered. In total 59.5% (25/42) of clustered strains were Beijing lineage and demonstrated in-vitro resistance to all first-line drugs tested. Conclusion The MDR-TB epidemic in Mongolia appears to be driven by primary transmission of Beijing lineage strains resistant to all first-line drugs. Enhanced infection control strategies together with early MDR-TB case detection and appropriate treatment are necessary to limit escalation of the MDR-TB epidemic.

There is increasing evidence that human movement facilitates the global spread of resistant bacteria and antimicrobial resistance (AMR) genes. We systematically reviewed the literature on the impact of travel on the dissemination of AMR. We searched the databases Medline, EMBASE and SCOPUS from database inception until the end of June 2019. Of the 3052 titles identified, 2253 articles passed the initial screening, of which 238 met the inclusion criteria. The studies covered 30,060 drug-resistant isolates from 26 identified bacterial species. Most were enteric, accounting for 65% of the identified species and 92% of all documented isolates. High-income countries were more likely to be recipient nations for AMR originating from middle- and low-income countries. The most common origin of travellers with resistant bacteria was Asia, covering 36% of the total isolates. Beta-lactams and quinolones were the most documented drug-resistant organisms, accounting for 35% and 31% of the overall drug resistance, respectively. Medical tourism was twice as likely to be associated with multidrug-resistant organisms than general travel. International travel is a vehicle for the transmission of antimicrobial resistance globally. Health systems should identify recent travellers to ensure that adequate precautions are taken.

Background Bougainville, an autonomous region of Papua New Guinea (PNG) is slowly improving services and infrastructure destroyed 20 years ago during the ten year civil war. However, the region still faces significant constraints to economic growth and human development and remains under-developed compared to PNG and close Pacific neighbours. PNG's 2017 Human Development Category (HDC) was one of the lowest at 0.544. The Bougainville Strategic Development Plan 2018–2022 noted significant gaps in health services and infrastructure, had inadequate water and waste disposal and experienced weak markets and cocoa quality. This research examines domestic conditions and the extent to which they impact on livelihoods. Method A cross-sectional livelihood survey was administered to cocoa growing households in 33 Village Assemblies (VAs) with 11 VAs in each of the three regions. Results Data was collected from 5172 individuals. A significant majority of households reported multiple health issues, rudimentary housing, unimproved sanitation and unimproved water. Over two-thirds of cocoa growers did not sell any cocoa bags in 2014–2016 resulting in low incomes and greater food insecurity compared to families selling cocoa. Families that produced no saleable cocoa were more likely to have rudimentary housing, unimproved toilet facilities and unsafe water, factors that increase the likelihood of chronic disease and exacerbate malnutrition and poor labour productivity. Conclusion This study provides key information about the health and livelihood status of cocoa growers in Bougainville. If productivity is to increase, farmer health needs to improve including improving water and sanitation practices and diets. Building a responsive health system for the community is a challenge when a majority of the population live in small villages with difficult access to health centres. Establishing and integrating outreach village health clinics will enable health care to be more accessible to these remote communities., Highlights • Cocoa productivity in Bougainville remains low. • There are major constraints improved livelihoods for cocoa farmers. • Many households are food insecure with unimproved water and sanitation. • An accumulation of conditions may limit capacity to sell cocoa. • A One Health approach can identify and address many factors impacting cocoa farmers livelihoods.

Arbaeen is an annual religious procession in Iraq with an estimated 17-20 million participants. Public health risks associated with such a mass gathering can be serious at both local and global levels. This is the first quantitative examination of risk factors for, and symptoms of, infectious disease among Arbaeen participants.A cross-sectional survey was conducted of a convenience sample of 191 Arbaeen participants in 2017. Interviewers administered a structured questionnaire. Questions included food sources, preventive measures used and symptoms of infectious diseases during the procession.Data were collected for 191 participants (143 males, 58 females). The most prevalent symptoms were respiratory (runny nose: 22.6%, cough: 22.5%). Diarrhoea was reported by 12.6% of participants, with a strong association with high-income country origin and eating (commercial) street food (odds ratios 6.1 and 4.1, respectively, p 0.05). All symptoms investigated, except breathlessness, were more prevalent in high-income country participants (p 0.05).Street food and high-income country origin were independent risk factors for respiratory or gastrointestinal infection symptoms in this sample of Arbaeen participants. However, these results cannot be generalised due to possible selection bias. Further studies are required to inform policy development and health system preparedness to reduce Arbaeen-associated health risks.

Salmonella enterica serovar Wangata (S. Wangata) is an important cause of endemic salmonellosis in Australia, with human infections occurring from undefined sources. This investigation sought to examine possible environmental and zoonotic sources for human infections with S. Wangata in north-eastern New South Wales (NSW), Australia. The investigation adopted a One Health approach and was comprised of three complimentary components: a case–control study examining human risk factors; environmental and animal sampling; and genomic analysis of human, animal and environmental isolates. Forty-eight human S. Wangata cases were interviewed during a 6-month period from November 2016 to April 2017, together with 55 Salmonella Typhimurium (S. Typhimurium) controls and 130 neighbourhood controls. Indirect contact with bats/flying foxes (S. Typhimurium controls (adjusted odds ratio (aOR) 2.63, 95% confidence interval (CI) 1.06–6.48)) (neighbourhood controls (aOR 8.33, 95% CI 2.58–26.83)), wild frogs (aOR 3.65, 95% CI 1.32–10.07) and wild birds (aOR 6.93, 95% CI 2.29–21.00) were statistically associated with illness in multivariable analyses. S. Wangata was detected in dog faeces, wildlife scats and a compost specimen collected from the outdoor environments of cases’ residences. In addition, S. Wangata was detected in the faeces of wild birds and sea turtles in the investigation area. Genomic analysis revealed that S. Wangata isolates were relatively clonal. Our findings suggest that S. Wangata is present in the environment and may have a reservoir in wildlife populations in north-eastern NSW. Further investigation is required to better understand the occurrence of Salmonella in wildlife groups and to identify possible transmission pathways for human infections.

Background Salmonella is an important human pathogen in Australia and annual case rates continue to increase. In addition to foodborne exposures, cases have been associated with animal and contaminated environment contact. However, routine surveillance in Australia has tended to focus on humans and food, with no reported attempts to collate and compare Salmonella data from a wider range of potential sources of exposure. Methods Salmonella data from humans, food, animals and environments were collated from a range of surveillance and diagnostic sources in New South Wales (NSW). Data were categorised to reflect one of 29 sample origins. Serotype diversity was described for each category, and the distribution of serotypes commonly isolated from humans was examined for each sample origin. The distribution of serotypes along the livestock-food-human continuum and at the companion animal-wildlife interface was also examined. Results In total, 49,872 Salmonella isolates were included in this analysis, comprising 325 serotypes. The vast majority of these isolates were from humans (n = 38,106). Overall S. Typhimurium was the most frequently isolated serotype and was isolated from all sample categories except natural environment and game meat. S. Enteriditis was not isolated from any livestock animal, however sporadic cases were documented in food, companion animals and a reptile. Many serotypes that were frequently isolated from livestock animals and associated food products were only rarely isolated from humans. In addition, a number of key human serotypes were only sporadically isolated from livestock and food products, suggesting alternative sources of infection. In particular, S. Paratyphi B Java and S. Wangata were more often isolated from wild animals. Finally, there was some overlap between serotypes in companion animals and wildlife, with cats in particular having a large number of serotypes in common with wild birds. Conclusions This is the most comprehensive description of Salmonella data from humans, food, livestock, wildlife, companion animals and various environments in Australia reported to date. Results confirm that livestock and food are important sources of salmonellosis in humans but that alternative sources - such as contact with wildlife and environments - warrant further investigation. Surveillance in NSW is largely human-focussed: major knowledge gaps exist regarding the diversity and frequency of serotypes in animals. More systematic surveillance of domestic animals and wildlife is needed to inform targeted control strategies and quantitative source attribution modelling in this state. Electronic supplementary material The online version of this article (10.1186/s12879-018-3563-1) contains supplementary material, which is available to authorized users.

With rising population numbers, anthropogenic changes to our environment and unprecedented global connectivity, the World Economic Forum ranks the spread of infectious diseases second only to water crises in terms of potential global impact. Addressing the diverse challenges to human health and well-being in the 21st century requires an overarching focus on ‘Planetary Health’, with input from all sectors of government, non-governmental organisations, academic institutions and industry. To clarify and advance the Planetary Health agenda within Australia, specifically in relation to emerging infectious diseases (EID) and antimicrobial resistance (AMR), national experts and key stakeholders were invited to a facilitated workshop. EID themes identified included animal reservoirs, targeted surveillance, mechanisms of emergence and the role of unrecognised human vectors (the ‘invisible man’) in the spread of infection. Themes related to AMR included antimicrobial use in production and companion animals, antimicrobial stewardship, novel treatment approaches and education of professionals, politicians and the general public. Effective infection control strategies are important in both EID and AMR. We provide an overview of key discussion points, as well as important barriers identified and solutions proposed.

In this review, Ebolavirus Disease (EVD) outbreaks have been comprehensively reviewed from their beginning until now. It chronologically discusses how each outbreak was tackled, national and international actions taken, diagnostic methods applied, the infection control procedures put in place, and the lessons learnt from each epidemic for the control of subsequent epidemics. Data for this review were obtained from literature published between 1967 and 2016 in key medical databases, the official websites of various governmental organisations, international public health agencies, and regulatory bodies. Despite major developments in the field of EVD, there has been little progress in its specific therapy or prevention. Historically, individuals who recovered from EVD acted as a source of fresh frozen plasma (containing IgG) that has been used to treat other acutely ill patients, however this therapeutic modality has limitations due to the risk of transmission of blood-borne infections. With the use of advanced and efficient purification methods the incidence of unwanted side effects following immune serum therapy has currently been greatly reduced. Creation of a safe plasma pool that covers immunoglobulins against all strains of EVD is now a research priority. Recommendations on how future EVD outbreaks can be better managed have been discussed.

This deposit is composed by a publication in which the IGC's authors have had the role of collaboration (it's a collaboration publication). This type of deposit in ARCA is in restrictedAccess (it can't be in open access to the public), and can only be accessed by two ways: either by requesting a legal copy from the author (the email contact present in this deposit) or by visiting the following link: https://www.nature.com/articles/s41588-018-0074-3 This publication hasn't any creative commons license associated. This deposit is composed simultaneously by the original published article and also by the "correction" for the published article (erratum). The link for the original article: https://www.nature.com/articles/s41588-017-0029-0#Ack1 This deposit is composed by the main article plus the supplementary materials of the publication. In the version of this article initially published, the URL listed for TubercuList was incorrect. The correct URL is https://mycobrowser.epfl.ch/. The error has been corrected in the HTML and PDF versions of the article. To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms. The project was supported by the KAUST faculty baseline research fund (BAS/1/1020-01-01) to A.P. The authors wish to thank members of the KAUST Bioscience Core laboratory who sequenced samples. We thank the Wellcome Trust Sanger Institute core and pathogen sequencing and informatics teams who were involved in the Malawi and Uganda studies. The work was funded in part by the Wellcome Trust (grant numbers WT096249/Z/11/B, WT088559MA, WT081814/Z/06/Z and WT098051) and the Wellcome Trust–Burroughs Wellcome Fund Infectious Diseases Initiative grant (number 063410/ABC/00/Z). F.C. was the recipient of a Bloomsbury College PhD Studentship and was supported by the Wellcome Trust (201344/Z/16/Z); J. Perdigão received a Fundação para a Ciência e a Tecnologia (Portugal) postdoctoral fellowship fund (SFRH/BPD/95406/2013). The Calouste Gulbenkian Foundation, the Institute Gulbenkian in Lisbon and the European Society of Clinical Microbiology and Infectious Diseases supported the research of C.P., J. Perdigão, I.P. and M.V. J. Phelan is funded by a BBSRC PhD studentship. T.G.C. is funded by the Medical Research Council UK (grant numbers MR/K000551/1, MR/M01360X/1, MR/N010469/1 and MC_PC_15103). N.F. is funded by the Medical Research Council UK (grant number MR/K020420/1). T.M. is supported by the Ministry of Health, Labor and Welfare of Japan (H21-Shinkou-Ippan-008 and H24-Shinkou-Ippan-010). info:eu-repo/semantics/publishedVersion

ObjectivesTo explore and compare the knowledge, attitudes and experiences of doctors, dentists and veterinarians (as prescribers) in relation to antibiotic use and antibiotic resistance (AbR), and to consider the implications of these for policy-making that support a One Health approach.DesignA cross-sectional survey conducted online.SettingDoctors, dentists and veterinarians practising in primary, secondary or tertiary care in Australia.Participants547 doctors, 380 dentists and 403 veterinarians completed the survey.Main outcome measuresPrescribers’ knowledge, attitudes and perceptions of AbR, the extent to which a range of factors are perceived as barriers to appropriate prescribing practices, and perceived helpfulness of potential strategies to improve antibiotic prescribing in practice.ResultsThere was substantial agreement across prescriber groups that action on AbR is required by multiple sectors and stakeholders. However, prescribers externalised responsibility to some extent by seeing the roles of others as more important than their own in relation to AbR. There were common and context-specific barriers to optimal prescribing across the prescriber groups. Prescriber groups generally perceived restrictive policies as unhelpful to supporting appropriate prescribing in their practice.ConclusionsThe results have implications for implementing a One Health approach that involves doctors, dentists and veterinarians as key players to tackling the crisis of AbR. The findings are that (1) prescribers understand and are likely receptive to a One Health policy approach to AbR, (2) policy development should be sensitive to barriers that are specific to individual prescriber groups and (3) the development and introduction of interventions that might be perceived as reducing prescriber autonomy will need to be carefully designed and implemented.

BACKGROUND Mongolia has the fifth highest incidence of tuberculosis (TB) in the Western Pacific Region, with high rates of multidrug-resistant TB (MDR-TB). OBJECTIVE To examine the recent spatiotemporal dynamics of MDR-TB in Mongolia. METHODS All MDR-TB cases diagnosed from 2004 to 2012, identified from the National Tuberculosis Control Programme database, were included in the study. Cases diagnosed from 2006 to 2012 were further examined using spatial scan statistics. RESULTS Few MDR-TB cases (n = 29) were diagnosed before the programmatic management of MDR-TB was introduced in 2006. During 2006-2012, 1106 MDR-TB cases were detected, at an annualised rate of 5.9 cases per 100 000 population. Most (>80%) cases were identified in the 15-44 year age group; 45% were among those aged 15-29 years. Case notification rates were highest in the capital city, Ulaanbaatar, with an increasing trend over time in all locations. Three MDR-TB hotspots were identified, all in close proximity to the Trans-Siberian Railway line. The majority of the MDR-TB isolates were resistant to all first-line drugs tested. CONCLUSION Spatiotemporal analysis indicates likely cross-border spread of MDR-TB along the Trans-Siberian Railway line, with subsequent spatial expansion across Mongolia. The frequency of MDR-TB among young patients with pan-resistance to all first-line drugs suggests ongoing MDR-TB transmission within the community.

The control of food-borne outbreaks caused by Listeria monocytogenes in humans relies on the timely identification of food or environmental sources and the differentiation of outbreak-related isolates from unrelated ones. This study illustrates the utility of whole-genome sequencing for examining the link between clinical and environmental isolates of L. monocytogenes associated with an outbreak of hospital-acquired listeriosis in Sydney, Australia. Comparative genomic analysis confirmed an epidemiological link between the three clinical and two environmental isolates. Single nucleotide polymorphism (SNP) analysis showed that only two SNPs separated the three human outbreak isolates, which differed by 19 to 20 SNPs from the environmental isolates and 71 to >10,000 SNPs from sporadic L. monocytogenes isolates. The chromosomes of all human outbreak isolates and the two suspected environmental isolates were syntenic. In contrast to the genomes of background sporadic isolates, all epidemiologically linked isolates contained two novel prophages and a previously unreported clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) locus subtype sequence. The mobile genetic element (MGE) profile of these isolates was distinct from that of the other serotype 1/2b reference strains and sporadic isolates. The identification of SNPs and clonally distinctive MGEs strengthened evidence to distinguish outbreak-related isolates of L. monocytogenes from cocirculating endemic strains.

Background Seven drugs are licensed for the treatment of chronic hepatitis B (CHB) in the United Kingdom. Which initial treatment, secondary therapy, and whether antivirals should be given alone or in combination are questions of considerable uncertainty. Objective The aim of this model was to undertake a comprehensive economic evaluation of all antiviral treatments for CHB to recommend the most cost-effective therapeutic sequence. Methods We developed a probabilistic Markov model to compare the cost-effectiveness of all clinically relevant antiviral treatment sequences for nucleos(t)ide-naive adults with hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative CHB. Relative rates of HBeAg seroconversion and viral suppression were obtained from a network meta-analysis. Data on mortality, antiviral drug resistance, durability of response, adverse events, and costs were obtained from published literature. Results are reported in terms of lifetime costs, quality-adjusted life-years (QALYs), and expected net benefit. Results In the base-case analysis, pegylated interferon alpha-2a (peg-IFN α-2a) followed by tenofovir disoproxil fumarate was most effective and cost-effective in HBeAg-positive patients, with a cost of £7488 per QALY gained compared with no treatment. In HBeAg-negative patients, peg-IFN α-2a followed by entecavir was most effective and cost-effective, with a cost of £6981 per QALY gained. The model was robust to a wide range of sensitivity analyses. Conclusions Peg-IFN α-2a followed by tenofovir disoproxil fumarate or entecavir is the most effective antiviral treatment strategy for people with both variants of CHB. At a cost of less than £10,000 per QALY gained, these sequences are considered cost-effective in England and Wales. The results of this analysis were used to inform 2013 National Institute for Health and Care Excellence guideline recommendations.

Infant botulism is a potentially life-threatening paralytic disease that can be associated with prolonged morbidity if not rapidly diagnosed and treated. Four infants were diagnosed and treated for infant botulism in NSW, Australia, between May 2011 and August 2013. Despite the temporal relationship between the cases, there was no close geographical clustering or other epidemiological links. Clostridium botulinum isolates, three of which produced botulism neurotoxin serotype A (BoNT/A) and one BoNT serotype B (BoNT/B), were characterized using whole-genome sequencing (WGS). In silico multilocus sequence typing (MLST) found that two of the BoNT/A-producing isolates shared an identical novel sequence type, ST84. The other two isolates were single-locus variants of this sequence type (ST85 and ST86). All BoNT/A-producing isolates contained the same chromosomally integrated BoNT/A2 neurotoxin gene cluster. The BoNT/B-producing isolate carried a single plasmid-borne bont /B gene cluster, encoding BoNT subtype B6. Single nucleotide polymorphism (SNP)-based typing results corresponded well with MLST; however, the extra resolution provided by the whole-genome SNP comparisons showed that the isolates differed from each other by >3,500 SNPs. WGS analyses indicated that the four infant botulism cases were caused by genomically distinct strains of C. botulinum that were unlikely to have originated from a common environmental source. The isolates did, however, cluster together, compared with international isolates, suggesting that C. botulinum from environmental reservoirs throughout NSW have descended from a common ancestor. Analyses showed that the high resolution of WGS provided important phylogenetic information that would not be captured by standard seven-loci MLST.

OBJECTIVES: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS. METHODS: Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 patients treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes. RESULTS: Over a median 7-year follow-up (range 33-144 months), most patients (52%) required just two cycles of alemtuzumab. In the remaining patients, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of patients had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) patients had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) patients, most commonly involving the thyroid gland. CONCLUSIONS: Alemtuzumab is associated with disease stabilisation in the majority of patients with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

Infectious diseases remain responsible for significant global morbidity and mortality, and diseases emerge and re-emerge in sometimes unpredictable locations and at unpredictable times. Although much is known about how to detect and respond to existing infections, more public health research is needed to predict the likelihood of their emergence and spread, and to improve the precision and timeliness of public health responsiveness. To achieve this, further research is required to develop pathogen genomics from more than just a tool for outbreak investigation to one that will identify and quantify catalysts for emergence within a given population. More research is also needed to develop digital epidemiology techniques to identify syndromic clusters earlier. Beyond human public health, appreciating how animals and the environment affect disease emergence presents us with a new challenge: to develop truly interdisciplinary research that encompasses all aspects of pathogen surveillance and response. This includes understanding why microorganisms cross species to cause diseases (e.g. from animals to humans), factors that drive spread of infections, and systems research that will result in development of joint responses to outbreaks from different professional, government and international groups. Only then will we be better prepared for the next outbreak.

Background There is a large increase in the numbers of refugees and asylum seekers worldwide and a lack of data on the carriage of antimicrobial resistance in refugee/asylum seeking groups. Methods This article aims to identify the impact of refugees and asylum seekers on the acquisition and transmission of antimicrobial resistance (AMR) through a literature search. The databases Embase, Medline, Pubmed, and Web of Science Core Collection were utilised and covered all articles before the 1st of October 2016. In total, 577 articles were identified, and studies were eligible if they met the selection criteria, including observational study design, English language, and AMR strains reported in absolute numbers. In total, 17 articles met the criteria, the majority were from the European region. Results Articles fitting the selection criteria exclusively reported AMR in bacterial species including Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumonia, K. oxytoca, Shigella spp., Staphylococcus aureus , Enterococcus faecium, and Acinetobacter baumannii. The analyses indicated that a high percentage of AMR strains, have been circulating among refugees and asylum seekers. Conclusion The displacement of refugees and asylum seekers seem to play a key role in the transmission of AMR. Therefore, improved AMR control measures are essential. A knowledge gap was identified; further research is strongly recommended.

Background Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing–remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991–1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9 /l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

Urinary tract infections (UTIs) associated with Escherichia coli are a growing threat with an increase in the prevalence of multidrug resistant (MDR) strains, particularly ß-lactamase producers, occurring globally. We investigated the presence of carbapenem-resistant uropathogenic E. coli clones in community-acquired UTIs in Riyadh, Kingdom of Saudi Arabia (KSA) to identify the virulence and resistance structures of the resistant clones and relate the isolates to those circulating globally. A combination of comparative genomics and phenotypic approaches were used to characterize ten MDR-uropathogenic Escherichia coli isolates recovered from UTI patients in Riyadh between November 2014 and January 2015. We report the presence of NDM-1 and 5, and OXA-181 in carbapenem-resistant UPEC strains from Riyadh, KSA. Single nucleotide polymorphism analyses demonstrated that these ten isolates fell into four phylogenetically distinct clades within the UPEC phylogeny. Comparative genomic analyses indicate that these diverse clones could be distinguished according to their multilocus sequencing type (MLST), serology, and virulence and antimicrobial gene architectures. These clones include the blaNDM-1 carrying isolates of the globally predominant MDR ST131 and ST69 types, previously identified as one of the most common UPEC strains in KSA. This is in addition to clones of ST23Cplx (ST410) and ST448Cplx (ST448) that have likely evolved from common intestinal strains, carrying copies of ß-lactamase genes including blaNDM-5, blaCTX-M-15, blaTEM-1, blaCMY-42, blaOXA-1 and blaOXA-181. These data have identified an emerging public health concern and highlight the need to use comprehensive approaches to detect the structure of MDR E. coli populations associated with community-acquired UTIs in KSA.

Human infections with Salmonella enterica subspecies enterica serovar Senftenberg are often associated with exposure to poultry flocks, farm environments, or contaminated food. The recent emergence of multidrug-resistant isolates has raised public health concerns. In this study, comparative genomics and phenotypic analysis were used to characterize 14 Salmonella Senftenberg clinical isolates recovered from multiple outbreaks in Shenzhen and Shanghai, China, between 2002 and 2011. Single-nucleotide polymorphism analyses identified two phylogenetically distinct clades of S . Senftenberg, designated SC1 and SC2, harboring variations in Salmonella pathogenicity island 1 (SPI-1) and SPI-2 and exhibiting distinct biochemical and phenotypic signatures. Although the two variants shared the same serotype, the SC2 isolates of sequence type 14 (ST14) harbored intact SPI-1 and -2 and hence were characterized by possessing efficient invasion capabilities. In contrast, the SC1 isolates had structural deletion patterns in both SPI-1 and -2 that correlated with an impaired capacity to invade cultured human cells and also the year of their isolation. These atypical SC1 isolates also lacked the capacity to produce hydrogen sulfide. These findings highlight the emergence of atypical Salmonella Senftenberg variants in China and provide genetic validation that variants lacking SPI-1 and regions of SPI-2, which leads to impaired invasion capacity, can still cause clinical disease. These data have identified an emerging public health concern and highlight the need to strengthen surveillance to detect the prevalence and transmission of nontyphoidal Salmonella species.

Respiratory syncytial virus (RSV) is a major cause of viral acute respiratory tract infections in young children. The virus is characterised by distinct seasonality that is dependent upon the latitude and its ability to cause reinfection. Respiratory syncytial virus demonstrates a complex molecular epidemiology pattern as multiple strains and/or genotypes cocirculate during a single epidemic. Previous studies have investigated the relationship between RSV genetic diversity, reinfection, and clinical features. Here, we review the evidence behind this relationship together with the impact that the advancement of whole genome sequencing will have upon our understanding and the need for reconsidering the classification of RSV genotypes.

In recent years the State of New South Wales (NSW), Australia, has maintained a low tuberculosis incidence rate with little evidence of local transmission. Nearly 90% of notified tuberculosis cases occurred in people born in tuberculosis-endemic countries. We analyzed geographic, epidemiological and genotypic data of all culture-confirmed tuberculosis cases to identify the bacterial and demographic determinants of tuberculosis hotspot areas in NSW. Standard 24-loci mycobacterium interspersed repetitive unit-variable number tandem repeat (MIRU-24) typing was performed on all isolates recovered between 2009 and 2013. In total 1692/1841 (91.9%) cases with confirmed Mycobacterium tuberculosis infection had complete MIRU-24 and demographic data and were included in the study. Despite some year-to-year variability, spatio-temporal analysis identified four tuberculosis hotspots. The incidence rate and the relative risk of tuberculosis in these hotspots were 2- to 10-fold and 4- to 8-fold higher than the state average, respectively. MIRU-24 profiles of M. tuberculosis isolates associated with these hotspots revealed high levels of heterogeneity. This suggests that these spatio-temporal hotspots, within this low incidence setting, can represent areas of predominantly imported infection rather than clusters of cases due to local transmission. These findings provide important epidemiological insight and demonstrate the value of combining tuberculosis genotyping and spatiotemporal data to guide better-targeted public health interventions.

Clinical laboratories are increasingly using molecular tests for methicillin-resistant Staphylococcus aureus (MRSA) screening. However, primers have to be targeted to a variable chromosomal region, the staphylococcal cassette chromosome mec (SCCmec). We initially screened 726 MRSA isolates from a single UK hospital trust by recombinase polymerase amplification (RPA), a novel, isothermal alternative to PCR. Undetected isolates were further characterised using multilocus sequence, spa typing and whole genome sequencing. 96% of our tested phenotypically MRSA isolates contained one of the six orfX-SCCmec junctions our RPA test and commercially available molecular tests target. However 30 isolates could not be detected. Sequencing of 24 of these isolates demonstrated recombinations within the SCCmec element with novel insertions that interfered with the RPA, preventing identification as MRSA. This result suggests that clinical laboratories cannot rely solely upon molecular assays to reliably detect all methicillin-resistance. The presence of significant recombinations in the SCCmec element, where the majority of assays target their primers, suggests that there will continue to be isolates that escape identification. We caution that dependence on amplification-based molecular assays will continue to result in failure to diagnose a small proportion (∼4%) of MRSA isolates, unless the true level of SCCmec natural diversity is determined by whole genome sequencing of a large collection of MRSA isolates.

Multidrug- (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) present a challenge to disease control and elimination goals. Lisbon, Portugal, has a high TB incidence rate and unusual and successful XDR-TB strains that have been found in circulation for almost two decades. For the last 20 years, a continued circulation of two phylogenetic clades, Lisboa3 and Q1, which are highly associated with MDR and XDR, have been observed. In recent years, these strains have been well characterized regarding the molecular basis of drug resistance and have been inclusively subjected to whole genome sequencing (WGS). Researchers have been studying the genomic diversity of strains circulating in Lisbon and its genomic determinants through cutting-edge next generation sequencing. An enormous amount of whole genome sequence data are now available for the most prevalent and clinically relevant strains circulating in Lisbon. It is the persistence, prevalence and rapid evolution towards drug resistance that has prompted researchers to investigate the properties of these strains at the genomic level and in the future at a global transcriptomic level. Seventy Mycobacterium tuberculosis (MTB) isolates, mostly recovered in Lisbon, were genotyped by 24-loci Mycobacterial Interspersed Repetitive Unit – Variable Number of Tandem Repeats (MIRU-VNTR) and the genomes sequenced using a next generation sequencing platform – Illumina HiSeq 2000. The genotyping data revealed three major clusters associated with MDR-TB (Lisboa3-A, Lisboa3-B and Q1), two of which are associated with XDR-TB (Lisboa3-B and Q1), whilst the genomic data contributed to elucidating the phylogenetic positioning of circulating MDR-TB strains, showing a high predominance of a single SNP cluster group 5. Furthermore, a genome-wide phylogeny analysis from these strains, together with 19 publicly available genomes of MTB clinical isolates, revealed two major clades responsible for MDR/XDR-TB in the region: Lisboa3 and Q1. The data presented by this study contributes to the expanding knowledge of MTB genomic diversity yielding insights on microevolution and identification of novel compensatory mutations. Additionally, the analysis of non-synonymous/synonymous ratios revealed heterogeneities across the chromosome, genotype and Clusters of Orthologous Groups, highlighting possible and different evolution strategies. Overall, the results that are presented support the notion of an increasing genomic diversity that may support both setting and host adaptation.

Objectives The global increase in drug resistance in Mycobacterium tuberculosis (MTB) strains increases the focus on improved molecular diagnostics for MTB. Extensively drug-resistant (XDR) – TB is caused by MTB strains resistant to rifampicin, isoniazid, fluoroquinolone and aminoglycoside antibiotics. Resistance to anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs), in particular MTB genes. However, there is regional variation between MTB lineages and the SNPs associated with resistance. Therefore, there is a need to identify common resistance conferring SNPs so that effective molecular-based diagnostic tests for MTB can be developed. This study investigated used whole genome sequencing (WGS) to characterize 37 XDR MTB isolates from Pakistan and investigated SNPs related to drug resistance. Methods XDR-TB strains were selected. DNA was extracted from MTB strains, and samples underwent WGS with 76-base-paired end fragment sizes using Illumina paired end HiSeq2000 technology. Raw sequence data were mapped uniquely to H37Rv reference genome. The mappings allowed SNPs and small indels to be called using SAMtools/BCFtools. Results This study found that in all XDR strains, rifampicin resistance was attributable to SNPs in the rpo B RDR region. Isoniazid resistance-associated mutations were primarily related to kat G codon 315 followed by inh A S94A. Fluoroquinolone resistance was attributable to gyr A 91–94 codons in most strains, while one did not have SNPs in either gyr A or gyr B. Aminoglycoside resistance was mostly associated with SNPs in rrs , except in 6 strains. Ethambutol resistant strains had emb B codon 306 mutations, but many strains did not have this present. The SNPs were compared with those present in commercial assays such as LiPA Hain MDRTBsl, and the sensitivity of the assays for these strains was evaluated. Conclusions If common drug resistance associated with SNPs evaluated the concordance between phenotypic and genotypic testing, the results would be rifampicin (100%), isoniazid (89%), fluoroquinolones (95%), aminoglycoside (81%) and ethambutol (61%). This work highlights the importance of expanded targets for drug resistance detection in MTB isolates.

The association between lymphopenia and autoimmunity is recognized, but the underlying mechanisms are poorly understood and have not been studied systematically in humans. People with multiple sclerosis treated with the lymphocyte-depleting monoclonal antibody alemtuzumab offer a unique opportunity to study this phenomenon; one in three people develops clinical autoimmunity, and one in three people develops asymptomatic autoantibodies after treatment. Here, we show that T-cell recovery after alemtuzumab is driven by homeostatic proliferation, leading to the generation of chronically activated (CD28(-)CD57(+)), highly proliferative (Ki67(+)), oligoclonal, memory-like CD4 and CD8 T cells (CCR7(-)CD45RA(-) or CCR7(-)CD45RA(+)) capable of producing proinflammatory cytokines. Individuals who develop autoimmunity after treatment are no more lymphopenic than their nonautoimmune counterparts, but they show reduced thymopoiesis and generate a more restricted T-cell repertoire. Taken together, these findings demonstrate that homeostatic proliferation drives lymphopenia-associated autoimmunity in humans.

Background Cholera infection continues to be a threat to global public health. The current cholera pandemic associated with Vibrio cholerae El Tor has now been ongoing for over half a century. Methodology/Principal Findings Thirty-eight V. cholerae El Tor isolates associated with a cholera outbreak in 2009 from the Chandigarh region of India were characterised by a combination of microbiology, molecular typing and whole-genome sequencing. The genomic analysis indicated that two clones of V. cholera circulated in the region and caused disease during this time. These clones fell into two distinct sub-clades that map independently onto wave 3 of the phylogenetic tree of seventh pandemic V. cholerae El Tor. Sequence analyses of the cholera toxin gene, the Vibrio seventh Pandemic Island II (VSPII) and SXT element correlated with this phylogenetic position of the two clades on the El Tor tree. The clade 2 isolates, characterized by a drug-resistant profile and the expression of a distinct cholera toxin, are closely related to the recent V. cholerae isolated elsewhere, including Haiti, but fell on a distinct branch of the tree, showing they were independent outbreaks. Multi-Locus Sequence Typing (MLST) distinguishes two sequence types among the 38 isolates, that did not correspond to the clades defined by whole-genome sequencing. Multi-Locus Variable-length tandem-nucleotide repeat Analysis (MLVA) identified 16 distinct clusters. Conclusions/Significance The use of whole-genome sequencing enabled the identification of two clones of V. cholerae that circulated during the 2009 Chandigarh outbreak. These clones harboured a similar structure of ICEVchHai1 but differed mainly in the structure of CTX phage and VSPII. The limited capacity of MLST and MLVA to discriminate between the clones that circulated in the 2009 Chandigarh outbreak highlights the value of whole-genome sequencing as a route to the identification of further genetic markers to subtype V. cholerae isolates., Author Summary Vibrio cholerae is a diarrheal pathogen that is responsible for substantial morbidity and mortality worldwide. Historically, seven pandemics of cholera have been recognized, with classical biotype strains associated with the sixth and the El Tor biotype with the seventh (current) pandemic. Recently multi-drug resistant El Tor variants expressing classical cholera toxin have replaced the original El Tor strains in many epidemics, and are sometimes associated with more severe diarrhea leading to a higher mortality rate. In regions that experience recurrent cholera outbreaks, such as Northern India, it is important to understand the nature of the circulating strains and establish how they are related to the strains circulating globally. Here, we have demonstrated that whole- genome sequencing is a valuable method to characterize V. cholerae isolates that circulated during the 2009 outbreak in the Northern Indian city of Chandigarh. Through comparative genomic analysis, we identified two clones that circulated during a single outbreak. Importantly, these clones contain significant differences in the structure of the cholera toxin gene and the Vibrio seventh pandemic island II. Our findings demonstrate the limitations of current molecular typing techniques and the importance of surveillance with whole-genome sequencing for identifying V. cholerae clades with distinct genomic signatures.

BACKGROUND: Multidrug- (MDR) and extensively drug resistant (XDR) tuberculosis (TB) presents a challenge to disease control and elimination goals. In Lisbon, Portugal, specific and successful XDR-TB strains have been found in circulation for almost two decades. RESULTS: In the present study we have genotyped and sequenced the genomes of 56 Mycobacterium tuberculosis isolates recovered mostly from Lisbon. The genotyping data revealed three major clusters associated with MDR-TB, two of which are associated with XDR-TB. Whilst the genomic data contributed to elucidate the phylogenetic positioning of circulating MDR-TB strains, showing a high predominance of a single SNP cluster group 5. Furthermore, a genome-wide phylogeny analysis from these strains, together with 19 publicly available genomes of Mycobacterium tuberculosis clinical isolates, revealed two major clades responsible for M/XDR-TB in the region: Lisboa3 and Q1 (LAM).The data presented by this study yielded insights on microevolution and identification of novel compensatory mutations associated with rifampicin resistance in rpoB and rpoC. The screening for other structural variations revealed putative clade-defining variants. One deletion in PPE41, found among Lisboa3 isolates, is proposed to contribute to immune evasion and as a selective advantage. Insertion sequence (IS) mapping has also demonstrated the role of IS6110 as a major driver in mycobacterial evolution by affecting gene integrity and regulation. CONCLUSIONS: Globally, this study contributes with novel genome-wide phylogenetic data and has led to the identification of new genomic variants that support the notion of a growing genomic diversity facing both setting and host adaptation. This work was partially supported by Project Ref. SDH49: “Early Molecular Detection of M/XDRTB in the Great Lisbon Healthcare Region” from Fundação Calouste Gulbenkian (FCG, Portugal) and PTDC/SAU-EPI/122400/ 2010 from Fundação para a Ciência e Tecnologia (FCT). The sequencing was funded by the KAUST Research Fund. J. Perdigão, D. Machado and C. Silva were supported by FCT grants SFRH/BPD/95406/2013, SFRH/BD/65060/2009 and SFRH/BD/73579/2010, respectively. TGC is funded by the Medical Research Council (UK) and Wellcome Trust.

AIM To estimate the pharyngeal carriage rate of Neisseria meningitidis (N. meningitidis), Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) among Australian Hajj pilgrims. METHODS In 2014, surveillance was conducted in two phases among Australian Hajj pilgrims: The first phase during Hajj in Mina, and the second phase soon after returning home to Australia. Nasopharyngeal or oropharyngeal swabs were taken from participants then tested, firstly by nucleic acid testing, and also by standard culture. RESULTS Of 183 participants recruited in the first phase, 26 (14.2%) tested positive for S. pneumoniae; 4 had received pneumococcal conjugate vaccine (PCV13). Only one tested positive for N. meningitidis (W). Of 93 2nd phase samples cultured, 17 (18.3%) grew S. aureus, all methicillin sensitive, 2 (2.2%) grew N. meningitidis (on subculture; one serotype B, one negative), and 1 (1%), from an unvaccinated pilgrim, grew S. pneumoniae. CONCLUSION Relatively high carriage of S. pneumoniae and little meningococcal carriage was found. This indicates the importance of a larger study for improved infection surveillance and possible vaccine evaluation.

The junior doctors’ contract dispute has shown the need for major and sustained changes in education, training, and policy, say Steven Alderson and colleagues

Background Improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. Whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways. Methods We sequenced 22 isolates from a Mycobacterium tuberculosis cluster in New South Wales, Australia, identified during routine 24-locus mycobacterial interspersed repetitive unit typing. Following high-depth paired-end sequencing using the Illumina HiSeq 2000 platform, two independent pipelines were employed for analysis, both employing read mapping onto reference genomes as well as de novo assembly, to control biases in variant detection. In addition to single-nucleotide polymorphisms, the analyses also sought to identify insertions, deletions and structural variants. Results Isolates were highly similar, with a distance of 13 variants between the most distant members of the cluster. The most sensitive analysis classified the 22 isolates into 18 groups. Four of the isolates did not appear to share a recent common ancestor with the largest clade; another four isolates had an uncertain ancestral relationship with the largest clade. Conclusion Whole genome sequencing, with analysis of single-nucleotide polymorphisms, insertions, deletions, structural variants and subpopulations, enabled the highest possible level of discrimination between cluster members, clarifying likely transmission pathways and exposing the complexity of strain origin. The analysis provides a basis for targeted public health intervention and enhanced classification of future isolates linked to the cluster.

Genetic studies of autism spectrum conditions (ASC) have mostly focused on the "low functioning" severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a "high-functioning" subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P