Host adaptation drives genetic diversity in a vector-borne disease system.

The range of hosts a pathogen can infect is a key trait, influencing human disease risk and reservoir host infection dynamics. Borrelia burgdorferi sensu stricto (Bb), an emerging zoonotic pathogen, causes Lyme disease and is widely considered a host generalist, commonly infecting mammals and birds. Yet the extent of intraspecific variation in Bb host breadth, its role in determining host competence, and potential implications for human infection remain unclear. We conducted a long-term study of Bb diversity, defined by the polymorphic ospC locus, across white-footed mice, passerine birds, and tick vectors, leveraging long-read amplicon sequencing. Our results reveal strong variation in host breadth across Bb genotypes, exposing a spectrum of genotype-specific host-adapted phenotypes. We found support for multiple niche polymorphism, maintaining Bb diversity in nature and little evidence of temporal shifts in genotype dominance, as would be expected under negative frequency-dependent selection. Passerine birds support the circulation of several human-invasive strains (HISs) in the local tick population and harbor greater Bb genotypic diversity compared with white-footed mice. Mouse-adapted Bb genotypes exhibited longer persistence in individual mice compared with nonadapted genotypes. Genotype communities infecting individual mice preferentially became dominated by mouse-adapted genotypes over time. We posit that intraspecific variation in Bb host breadth and adaptation helps maintain overall species fitness in response to transmission by a generalist vector.

Ecological interactions driving population dynamics of two tick-borne pathogens, Borrelia burgdorferi and Babesia microti.

Borrelia burgdorferi (Bb) and Babesia microti (Bm) are vector-borne zoonotic pathogens commonly found co-circulating in Ixodes scapularis and Peromyscus leucopus populations. The restricted distribution and lower prevalence of Bm has been historically attributed to lower host-to-tick transmission efficiency and limited host ranges. We hypothesized that prevalence patterns are driven by coinfection dynamics and vertical transmission. We use a multi-year, multiple location, longitudinal dataset with mathematical modelling to elucidate coinfection dynamics between Bb and Bm in natural populations of P. leucopus, the most competent reservoir host for both pathogens in the eastern USA. Our analyses indicate that, in the absence of vertical transmission, Bb is viable at lower tick numbers than Bm. However, with vertical transmission, Bm is viable at lower tick numbers than Bb. Vertical transmission has a particularly strong effect on Bm prevalence early in the active season while coinfection has an increasing role during the nymphal peak. Our analyses indicate that coinfection processes, such as facilitation of Bm infection by Bb, have relatively little influence on the persistence of either parasite. We suggest future work examines the sensitivity of Bm vertical transmission and other key processes to local environmental conditions to inform surveillance and control of tick-borne pathogens.

Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation.

BACKGROUNDEpicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT's immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODSWe recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients' clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTSFlow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSIONAdaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDINGBarts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.

High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.

Host Specialisation, Immune Cross-Reaction and the Composition of Communities of Co-circulating Borrelia Strains.

We use mathematical modelling to examine how microbial strain communities are structured by the host specialisation traits and antigenic relationships of their members. The model is quite general and broadly applicable, but we focus on Borrelia burgdorferi, the Lyme disease bacterium, transmitted by ticks to mice and birds. In this system, host specialisation driven by the evasion of innate immunity has been linked to multiple niche polymorphism, while antigenic differentiation driven by the evasion of adaptive immunity has been linked to negative frequency dependence. Our model is composed of two host species, one vector, and multiple co-circulating pathogen strains that vary in their host specificity and their antigenic distances from one another. We explore the conditions required to maintain pathogen diversity. We show that the combination of host specificity and antigenic differentiation creates an intricate niche structure. Unequivocal rules that relate the stability of a strain community directly to the trait composition of its members are elusive. However, broad patterns are evident. When antigenic differentiation is weak, stable communities are typically composed entirely of generalists that can exploit either host species equally well. As antigenic differentiation increases, more diverse stable communities emerge, typically around trait compositions of generalists, generalists and very similar specialists, and specialists roughly balanced between the two host species.

Stakeholder perspectives of Community Mental Health Forums: a qualitative study in Sierra Leone.

BACKGROUND: Mental health is the leading cause of disability worldwide. In the wake of both a civil war and an Ebola outbreak, Sierra Leone ranks as one of the lowest ranked countries on the Human Development Index (UNDP. Human Development Report 2015, Work for Human Development. The United Nations Development Programme; 2015). The WHO identified Sierra Leone among its priority countries for the piloting of its Mental Health Gap Action Programme (mhGAP). Aligned to these efforts, CBM and their affiliated partners employed the use of Community Mental Health Forums (CMHFs), facilitated by Mental Health Nurses (MHNs), as a sensitive and practical way of engaging key community stakeholders to discuss and address issues of mental health. This study sought firstly, to identify factors that affect the successful implementation of CMHFs, as identified by programme participants. Second, the study sought to identify what changes participants perceived as having taken place as a result of their participation in CMHFs. METHODS: 10 MHNs and 52 forum participants were purposely selected to take part in key informant interviews and focus group discussions, conducted across eight districts in Sierra Leone. Interview transcripts were analysed across four rounds of coding, using a mixture of deductive and inductive approaches. RESULTS: Results identified three themes, Traditional Beliefs and Culture; Health System; and Inclusive Approaches as affecting the implementation of CMHFs in their districts. Participants further perceived that their participation in the Community Mental Health Forums resulted in changes taking place across the themes of Awareness and beliefs, Behaviours towards people experiencing psychological distress, and as leading to greater Collaboration and cooperation between formal and informal mental health practitioners. CONCLUSIONS: Results are discussed in the context of the extant literature and a novel framework, that incorporates multiple best practice recommendations and factors which influence the successful implementation of CMHFs is put forward.

Analysis of spatial mobility in subjects from a Dengue endemic urban locality in Morelos State, Mexico.

INTRODUCTION: Mathematical models and field data suggest that human mobility is an important driver for Dengue virus transmission. Nonetheless little is known on this matter due the lack of instruments for precise mobility quantification and study design difficulties. MATERIALS AND METHODS: We carried out a cohort-nested, case-control study with 126 individuals (42 cases, 42 intradomestic controls and 42 population controls) with the goal of describing human mobility patterns of recently Dengue virus-infected subjects, and comparing them with those of non-infected subjects living in an urban endemic locality. Mobility was quantified using a GPS-data logger registering waypoints at 60-second intervals for a minimum of 15 natural days. RESULTS: Although absolute displacement was highly biased towards the intradomestic and peridomestic areas, occasional displacements exceeding a 100-Km radius from the center of the studied locality were recorded for all three study groups and individual displacements were recorded traveling across six states from central Mexico. Additionally, cases had a larger number of visits out of the municipality´s administrative limits when compared to intradomestic controls (cases: 10.4 versus intradomestic controls: 2.9, p = 0.0282). We were able to identify extradomestic places within and out of the locality that were independently visited by apparently non-related infected subjects, consistent with houses, working and leisure places. CONCLUSIONS: Results of this study show that human mobility in a small urban setting exceeded that considered by local health authority's administrative limits, and was different between recently infected and non-infected subjects living in the same household. These observations provide important insights about the role that human mobility may have in Dengue virus transmission and persistence across endemic geographic areas that need to be taken into account when planning preventive and control measures. Finally, these results are a valuable reference when setting the parameters for future mathematical modeling studies.

Day-to-Day Population Movement and the Management of Dengue Epidemics.

Dengue is a growing public health problem in tropical and subtropical cities. It is transmitted by mosquitoes, and the main strategy for epidemic prevention and control is insecticide fumigation. Effective management is, however, proving elusive. People's day-to-day movement about the city is believed to be an important factor in the epidemiological dynamics. We use a simple model to examine the fundamental roles of broad demographic and spatial structures in epidemic initiation, growth and control. We show that the key factors are local dilution, characterised by the vector-host ratio, and spatial connectivity, characterised by the extent of habitually variable movement patterns. Epidemic risk in the population is driven by the demographic groups that frequent the areas with the highest vector-host ratio, even if they only spend some of their time there. Synchronisation of epidemic trajectories in different demographic groups is governed by the vector-host ratios to which they are exposed and the strength of connectivity. Strategies for epidemic prevention and management may be made more effective if they take into account the fluctuating landscape of transmission intensity associated with spatial heterogeneity in the vector-host ratio and people's day-to-day movement patterns.

Improving the performance of community health workers in humanitarian emergencies: a realist evaluation protocol for the PIECES programme.

INTRODUCTION: Understanding what enhances the motivation and performance of community health workers (CHWs) in humanitarian emergencies represents a key research gap within the field of human resources for health. This paper presents the research protocol for the Performance ImprovEment of CHWs in Emergency Settings (PIECES) research programme. Enhancing Learning and Research in Humanitarian Action (ELRHA) funded the development of this protocol as part of their Health in Humanitarian Crises (R2HC) call (No.19839). PIECES aims to understand what factors improve the performance of CHWs in level III humanitarian emergencies. METHODS AND ANALYSIS: The suggested protocol uses a realist evaluation with multiple cases across the 3 country sites: Turkey, Iraq and Lebanon. Working with International Medical Corps (IMC), an initial programme theory was elicited through literature and document reviews, semistructured interviews and focus groups with IMC programme managers and CHWs. Based on this initial theory, this protocol proposes a combination of semistructured interviews, life histories and critical incident narratives, surveys and latent variable modelling of key constructs to explain how contextual factors work to trigger mechanisms for specific outcomes relating to IMC's 300+ CHWs' performance. Participants will also include programme staff, CHWs and programme beneficiaries. Realist approaches will be used to better understand 'what works, for whom and under what conditions' for improving CHW performance within humanitarian contexts. ETHICS AND DISSEMINATION: Trinity College Dublin's Health Policy and Management/Centre for Global Health Research Ethics Committee gave ethical approval for the protocol development phase. For the full research project, additional ethical approval will be sought from: Université St. Joseph (Lebanon), the Ethics Committee of the Ministry of Health in Baghdad (Iraq) and the Middle East Technical University (Turkey). Dissemination activities will involve a mixture of research feedback, policy briefs, guidelines and recommendations, as well as open source academic articles.

Disease and disaster: Optimal deployment of epidemic control facilities in a spatially heterogeneous population with changing behaviour.

Epidemics of water-borne infections often follow natural disasters and extreme weather events that disrupt water management processes. The impact of such epidemics may be reduced by deployment of transmission control facilities such as clinics or decontamination plants. Here we use a relatively simple mathematical model to examine how demographic and environmental heterogeneities, population behaviour, and behavioural change in response to the provision of facilities, combine to determine the optimal configurations of limited numbers of facilities to reduce epidemic size, and endemic prevalence. We show that, if the presence of control facilities does not affect behaviour, a good general rule for responsive deployment to minimise epidemic size is to place them in exactly the locations where they will directly benefit the most people. However, if infected people change their behaviour to seek out treatment then the deployment of facilities offering treatment can lead to complex effects that are difficult to foresee. So careful mathematical analysis is the only way to get a handle on the optimal deployment. Behavioural changes in response to control facilities can also lead to critical facility numbers at which there is a radical change in the optimal configuration. So sequential improvement of a control strategy by adding facilities to an existing optimal configuration does not always produce another optimal configuration. We also show that the pre-emptive deployment of control facilities has conflicting effects. The configurations that minimise endemic prevalence are very different to those that minimise epidemic size. So cost-benefit analysis of strategies to manage endemic prevalence must factor in the frequency of extreme weather events and natural disasters.

Household demographic determinants of Ebola epidemic risk.

A salient characteristic of Ebola, and some other infectious diseases such as Tuberculosis, is intense transmission among small groups of cohabitants and relatively limited indiscriminate transmission in the wider population. Here we consider a mathematical model for an Ebola epidemic in a population structured into households of equal size. We show that household size, a fundamental demographic unit, is a critical factor that determines the vulnerability of a community to epidemics, and the effort required to control them. Our analysis is based on the household reproduction number, but we also consider the basic reproduction number, intrinsic growth rate and final epidemic size. We show that, when other epidemiological parameters are kept the same, all of these quantifications of epidemic growth and size are increased by larger households and more intense within-household transmission. We go on to model epidemic control by case detection and isolation followed by household quarantine. We show that, if household quarantine is ineffective, the critical probability with which cases must be detected to halt an epidemic increases significantly with each increment in household size and may be a very challenging target for communities composed of large households. Effective quarantine may, however, mitigate the detrimental impact of large household sizes. We conclude that communities composed of large households are fundamentally more vulnerable to epidemics of infectious diseases primarily transmitted by close contact, and any assessment of control strategies for these epidemics should take into account the demographic structure of the population.

Weighing the evidence for harm from long-term treatment with antipsychotic medications: A systematic review.

Research findings supporting the use of antipsychotic medication for acute treatment of schizophrenia are relatively consistent and undisputed. However, the rationale for recommending long-term antipsychotic medication treatment-the current standard of care treatment strategy-is unclear. A controversial hypothesis proposed recently suggests people with schizophrenia who are exposed to long-term treatment with antipsychotic medications have worse outcomes than people with schizophrenia who are not exposed to these medications. We tested whether a systematic appraisal of published literature would produce data consistent with this hypothesis. We reviewed the published literature to identify studies of patients with psychotic disorders who were followed for at least 2 years that compared outcomes in patients who received antipsychotic medication during the follow-up with patients who did not receive antipsychotic medication during the follow-up. We included all English language articles published through 2013 in this review. Our process for selecting studies and documenting study findings included a consensus decision of 2 members of the research team. We found the published data to be inadequate to test this hypothesis. By extension, these data were also inadequate to conclusively evaluate whether long-term antipsychotic medication treatment results in better outcomes on average. We conclude that careful reappraisal of existing data is useful to ensure standard of care treatment strategies are indeed evidence-based. In the case of long-term use of antipsychotic medications, new data may be needed to establish a sufficient evidence base to understand its benefit/risk balance for patients with schizophrenia. (PsycINFO Database Record

Determining optimal fluid and air leak cut off values for chest drain management in general thoracic surgery.

BACKGROUND: Chest drain duration is one of the most important influencing aspects of hospital stay but the management is perhaps one of the most variable aspects of thoracic surgical care. The aim of our study is to report outcomes associated with increasing fluid and air leak criteria of protocol based management. METHODS: A 6-year retrospective analysis of protocolised chest drain management starting in 2007 with a fluid criteria of 3 mL/kg increasing to 7 mL/kg in 2011 to no fluid criteria in 2012, and an air leak criteria of 24 hours without leak till 2012 when digital air leak monitoring was introduced with a criteria of <20 mL/min of air leak for more than 6 hours. Patient data were obtained from electronic hospital records and digital chest films were reviewed to determine the duration of chest tube drainage and post-drain removal complications. RESULTS: From 2009 to 2012, 626 consecutive patients underwent thoracic surgery procedures under a single consultant. A total of 160 did not require a chest drain and data was missing in 22, leaving 444 for analysis. The mean age [standard deviation (SD)] was 57±19 years and 272 (61%) were men. There were no differences in the incidence of pneumothoraces (P=0.191), effusion (P=0.344) or re-interventions (P=0.431) for drain re-insertions as progressively permissive criteria were applied. The median drain duration dropped from 1-3 days (P<0.001) and accordingly hospital stay reduced from 4-6 days (P<0.001). CONCLUSIONS: Our results show that chest drains can be safely removed without fluid criteria and air leak of less than 20 mL/min with median drain duration of 1 day, associated with a reduced length of hospital stay.

Partial cross-enhancement in models for dengue epidemiology.

Four distinct serotypes of dengue virus co-circulate in many parts of the world. Antibodies to one serotype prevent infection with the homologous serotype, but may enhance infections with heterologous serotypes. Enhanced secondary infections have been implicated in the majority of severe cases, termed dengue hemorrhagic fever. Conventionally, mathematical models assume that all heterologous secondary infections are subject to enhanced susceptibility or transmissibility. However, empirical data show that only a minority of secondary infections lead to severe disease, which suggests that only a minority of secondary infections are subject to enhancement. We present a new modelling framework in which the population susceptible to secondary infection is split into a group prone to enhanced infection and a group with some degree of cross-protection. We use this framework to re-evaluate the role of enhanced infections in several well known dengue models that exhibit multi-annual epidemiological oscillations. We show that enhancement is unlikely to be driving such oscillations but may be modifying the effects of other drivers.

THE ROLES OF COMBAT EXPOSURE, PERSONAL VULNERABILITY, AND INVOLVEMENT IN HARM TO CIVILIANS OR PRISONERS IN VIETNAM WAR-RELATED POSTTRAUMATIC STRESS DISORDER.

The diagnosis, Posttraumatic Stress Disorder, was introduced in 1980 amidst debate about the psychiatric toll of the Vietnam War. There is controversy, however, about its central assumption that potentially traumatic stressors are more important than personal vulnerability in causing the disorder. We tested this assumption with data from a rigorously diagnosed male subsample (n = 260) from the National Vietnam Veterans Readjustment Study. Combat exposure, pre-war vulnerability, and involvement in harming civilians or prisoners were examined, with only combat exposure proving necessary for disorder onset. While none of the three factors proved sufficient, estimated onset reached 97% for veterans high on all three, with harm to civilians or prisoners showing the largest independent contribution. Severity of combat exposure proved more important than pre-war vulnerability in onset; pre-war vulnerability at least as important in long-term persistence. Implications for the primacy of the stressor assumption, further research, and policy are discussed.

Medico-legal and ethical aspects of nasal fractures secondary to assault: do we owe a duty of care to advise patients to have a facial x-ray?

Guidelines advise that x-rays do not contribute to the clinical management of simple nasal fractures. However, in cases of simple nasal fracture secondary to assault, a facial x-ray may provide additional legal evidence should the victim wish to press charges, though there is no published guidance. We examine the ethical and medico-legal issues surrounding this controversial area.