Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques.

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history-in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

Value of parental concern and clinician's gut feeling in recognition of serious bacterial infections: a prospective observational study.

BACKGROUND: Serious bacterial infections (SBI) are a significant cause of mortality worldwide. Parental concern and clinician's gut feeling that there is something wrong has been associated with increased likelihood of developing SBI in primary care studies. The aim of this study is to assess the diagnostic value of parental concern and gut feeling at the emergency department of a tertiary hospital. METHODS: This prospective observational study included children with fever attending the emergency department of Children's Clinical University hospital in Riga between October 2017 and July 2018. Data were collected via parental and clinician questionnaires. "Gut feeling" was defined as intuitive feeling that the child may have a serious illness, and "Sense of reassurance" as a feeling that the child has a self-limiting illness. "Parental concern" was defined as impression that this illness is different from previous illnesses. SBI included bacterial meningitis, sepsis, bacteraemia, pneumonia, urinary tract infection, appendicitis, bacterial gastroenteritis, and osteomyelitis. Pearson's Chi-Squared test or Fisher's exact test were used to compare the variables between children with and without SBI. Positive likelihood ratio was calculated for "gut feeling", "sense of reassurance", and parental concern. RESULTS: The study included 162 patients aged 2 months to 17.8 years. Forty-six patients were diagnosed with SBI. "Sense of reassurance" expressed by all clinicians was associated with lower likelihood of SBI (positive likelihood ratio 8.8, 95% confidence interval 2.2-34.8). "Gut feeling" was not significantly predictive of the patient being diagnosed with SBI (positive likelihood ratio 3.1, 95% confidence interval 1.9-5.1), The prognostic rule-in value of parental concern was insignificant (positive likelihood ratio 1.4, 95% confidence interval 1.1-1.7). CONCLUSION: Sense of reassurance was useful in ruling out SBI. Parental concern was not significantly predictive of SBI.

Resilience to stress and risk of gastrointestinal infections.

Background: Exposure to psychological stress can elicit a physiological response that may influence characteristics of the gastrointestinal mucosa, including increased intestinal permeability, in turn possibly increasing susceptibility to gastrointestinal infections. We investigated whether low stress resilience in adolescence is associated with an 'increased' risk of gastrointestinal infections in subsequent adulthood. Methods: Data were provided by Swedish registers for a cohort of 237 577 men who underwent military conscription assessment in late adolescence (1969-76). As part of the assessment procedure, certified psychologists evaluated stress resilience through semi-structured interviews. The cohort was followed from conscription assessment until 31 December 2009 (up to age 57 years). Cox regression assessed the association of stress resilience with gastrointestinal infections (n = 5532), with adjustment for family background measures in childhood and characteristics in adolescence. Peptic ulcer disease (PUD) in adulthood was modelled as a time-dependent covariate. Results: Compared with high stress resilience, lower stress resilience was associated with a 'reduced' risk of gastrointestinal infections after adjustment for family background in childhood, characteristics in adolescence and PUD in adulthood, with hazard ratios (and 95% confidence intervals) of 0.88 (0.81-0.97) and 0.83 (0.77-0.88) for low and moderate stress resilience, respectively. Conclusion: Lower stress resilience in adolescence is associated with reduced risk of gastrointestinal infections in adulthood, rather than the hypothesized increased risk.

Campaign Preparation for Complex Initiatives: A Person-Centered Approach to Audience Segmentation of Parents' Antibiotic Stewardship.

The evolution of antibiotic resistance is outpacing the speed at which new antibiotics will reach the marketplace. To slow the rate of resistance, people need to engage in antibiotic stewardship, which includes acts to prevent the spread of bacteria and judicious use of antibiotics to treat infections. This study identified the patterns and predictors of antibiotic stewardship behaviors of parents (N = 516) related to their children. The latent class analysis revealed three profiles of parental stewardship, labeled Stewards, Requesters, and Non-Stewards. The findings implied different campaign goals: to encourage Stewards to follow through on their intentions, to encourage Requesters to stop asking providers for antibiotics when their children have ear infections, and to influence Non-Stewards to accept medical advice when an antibiotic is not indicated and to dispose of leftover antibiotics. The covariate analysis provided theoretical insight into the strategies to pursue in campaigns targeting these three groups. For example, parents who perceived antibiotic-resistant infections as less serious health conditions, felt less worry when thinking about their child getting an antibiotic-resistant infection, and had stronger misattributions of antibiotics' efficacy to treat multiple symptoms were more likely to be Requesters and Non-Stewards, instead of Stewards.

Synergistic Effects of Psychosocial Stress and Mild Peripheral Infection on Inducing Microglial Activation in the Hippocampal Dentate Gyrus and Long-Lasting Deficits in Hippocampus-Related Memory.

Lipopolysaccharide (LPS) treatment and stress may cause immune activation in the brain, an event which has been thought to play a role in mediating stress-induced cognitive dysfunction. However, the enduring impact of psychosocial stress on brain immune activation or cognitive deficits has not been well investigated. Likewise, it remains unexplored whether there exist synergistic effects of psychosocial stress and a weak systemic LPS treatment on brain immune activation and/or cognitive function. In this work, a 10-day social defeat regimen was used to model psychosocial stress and the number and density of ionized calcium-binding adaptor molecule 1 (Iba1)-stained microglia was used to reveal brain immune activation in male Balb/C mice. The social defeat regimen did not cause observable microglial activation in dentate gyrus (DG) 24 h after the conclusion of the regimen. Microglial activation peaked in DG 24 h following a single 1 mg/kg intra-peritoneal LPS injection. At this time point, DG microglial activation was not evident providing 0.125 mg/kg or lower of LPS was used, this dose of LPS was, thus, regarded as the "sub-threshold" in this study. Twenty-four h after the conclusion of the defeat regimen, mice received a social interaction test to determine their defeat stress susceptibility and a "sub-threshold" LPS injection. DG microglial activation was observed in the defeat-stress susceptible, but not in the resilient, mice. Furthermore, the stress-susceptible mice showed impairment in object location and Y maze tasks 24 and 72 h after the "sub-threshold" LPS injection. These results suggest that psychosocial stress, when combined with a negligible peripheral infection, may induce long-lasting hippocampus-related memory deficits exclusively in subjects susceptible to psychosocial stresses.

Adapting to environmental stresses: the role of the microbiota in controlling innate immunity and behavioral responses.

Mammals are subject to colonization by an astronomical number of mutualistic and commensal microorganisms on their environmental exposed surfaces. These mutualistic species build up a complex community, called the indigenous microbiota, which aid their hosts in several physiological activities. In this review, we show that the transition between a non-colonized and a colonized state is associated with modification on the pattern of host inflammatory and behavioral responsiveness. There is a shift from innate anti-inflammatory cytokine production to efficient release of proinflammatory mediators and rapid mobilization of leukocytes upon infection or other stimuli. In addition, host responses to hypernociceptive and stressful stimuli are modulated by indigenous microbiota, partly due to the altered pattern of innate and acquired immune responsiveness of the non-colonized host. These altered responses ultimately lead to significant alteration in host behavior to environmental threats. Therefore, host colonization by indigenous microbiota modifies the way the host perceives and reacts to environmental stimuli, improving resilience of the entire host-microorganism consortium to environmental stresses.

[Topical preparations for therapy of tonsillar pathology].

This paper highlights clinical and diagnostic aspects of tonsillar pathology with special reference to modern methods for the treatment of pharyngeal diseases of different etiology. A detailed characteristic of local symptomatic therapy is presented including the use of NSAIDs (non-steroidal anti-inflammatory drugs). These agents have advantages over other medications for local therapy due to high anti-inflammatory and analgesic activities. Also, they significantly improve the patients' quality of life. The use of a local anti-inflammatory drug is a major component of the treatment of inflammatory pharyngeal pathology. Regardless of the nature of the disease, either bacterial or viral.

Sexual dimorphism in oxytocin responses to health perception and disgust, with implications for theories on pathogen detection.

In response to a recent hypothesis that the neuropeptide oxytocin might be involved in human pathogen avoidance mechanisms, we report the results of a study in which we investigate the effect of intranasal oxytocin on two behaviors serving as proxies for pathogen detection. Participants received either oxytocin or a placebo and were asked to evaluate (1) the health of Caucasian male computer-generated pictures that varied in facial redness (an indicator of hemoglobin perfusion) and (2) a series of pictures depicting disgusting scenarios. Men, but not women, evaluated all faces, regardless of color, as less healthy when given oxytocin compared to a placebo. Women, on the other hand, expressed decreased disgust when given oxytocin compared to a placebo. These results suggest that intranasal oxytocin administration does not facilitate pathogen detection based on visual cues, but instead reveal clear sex differences in the perception of health and sickness cues.

Exploring communication preferences and risk thresholds of clinicians and parents of febrile infants under 90 days presenting to the emergency department: a qualitative study.

BACKGROUND: Febrile infants under 3 months of age are at higher risk of invasive bacterial illness (IBI) when compared with older children. Increasingly sequential assessment based on age, clinical appearance and biomarkers is used to determine the risk of IBI, and appropriateness of invasive procedures such as lumbar puncture. The purpose of this qualitative study is to report parents and clinicians' opinions on communication of risks and benefits of sequential assessment and tailored treatment. METHODS: 18 parents enrolled in the Febrile Infant Diagnostic Assessment and Outcomes study and seven clinicians from England, Wales and Northern Ireland were purposively selected to participate in virtual qualitative interviews. Data were analysed thematically. RESULTS: Tailored treatment plans were widely supported. Confidence in the clinician was central to parents' attitude towards management recommendations. Parents' decision-making preferences change throughout their child's clinical journey, with an initial preference for clinician-led decisions evolving towards collaborative decision-making as their stress and anxiety reduce. There were widespread differences in preferences for how risk was discussed. Parents self-reported poor retention of information and felt communication adjuncts helped their understanding. Clinicians were generally positive about the use of clinical decision aids as a communication tool, rather than relying on them for decision-making. DISCUSSION: Parents want to feel informed, but their desire to be involved in shared decision-making evolves over time.Clinicians appear to use their clinical judgement to provide individualised information, evolving their communication in response to perceived parental needs.Poor information retention highlights the need for repetition of information and use of communication adjuncts. TRIAL REGISTRATION NUMBER: NCT05259683.

Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.

BACKGROUND & AIMS: A causal relationship between infection, systemic inflammation, and hepatic encephalopathy (HE) has been suggested in cirrhosis. No study, however, has specifically examined, in cirrhotic patients with infection, the complete pattern of clinical and subclinical cognitive alterations and its reversibility after resolution. Our investigation was aimed at describing the characteristics of cognitive impairment in hospitalized cirrhotic patients, in comparison with patients without liver disease, with and without infection. METHODS: One hundred and fifty cirrhotic patients were prospectively enrolled. Eighty-one patients without liver disease constituted the control group. Bacterial infections and sepsis were actively searched in all patients independently of their clinical evidence at entry. Neurological and psychometric assessment was performed at admission and in case of nosocomial infection. The patients were re-evaluated after the resolution of the infection and 3months later. RESULTS: Cognitive impairment (overt or subclinical) was recorded in 42% of cirrhotics without infection, in 79% with infection without SIRS and in 90% with sepsis. The impairment was only subclinical in controls and occurred only in patients with sepsis (42%). Multivariate analysis selected infection as the only independent predictor of cognitive impairment (OR 9.5; 95% CI 3.5-26.2; p=0.00001) in cirrhosis. The subclinical alterations detected by psychometric tests were also strongly related to the infectious episode and reversible after its resolution. CONCLUSIONS: Infections are associated with a worse cognitive impairment in cirrhotics compared to patients without liver disease. The search and treatment of infections are crucial to ameliorate both clinical and subclinical cognitive impairment of cirrhotic patients.

Increased resistance of immobilized-stressed mice to infection: correlation with behavioral alterations.

Immobilization is an easy and convenient method to induce both psychological and physical stress resulting in restricted motility and aggression and is believed to be the most severe type of stress in rodent models. Although it has been generally accepted that chronic stress often results in immunosuppression while acute stress has been shown to enhance immune responses, the effects of IS on the host resistance to Escherichia coli (E. coli) infection and associated behavioral changes are still not clear. In a series of experiments aimed at determining the level of hypothalamic COX-2, HSP-90, HSP-70, SOD-1 and plasma level of corticosterone, cytokine, antibody titer and their association with behavioral activities, mice were infected with viable E. coli during acute and chronic IS by taping their paws. In this study we show that acute and chronic IS enhances the resistance of mice to E. coli infection via inhibiting the production of pro-inflammatory cytokines, free radicals, and by improving the exploratory behavior. Altogether, our findings support the notion that cytokines released during immune activation and under the influence of corticosterone can modulate the open field behavior both in terms of locomotor activity as well as exploration. One of the features observed with chronic stressor was a lower ability to resist bacterial infection, although in case of acute stress, a better clearance of bacterial infection was observed in vivo with improvement of exploratory behavior and cognitive functions.

Cysticlean® a highly pac standardized content in the prevention of recurrent urinary tract infections: an observational, prospective cohort study.

BACKGROUND: The present study was aimed at determining the prophylactic efficacy of American cranberry (AC) extract (Cysticlean®) in women with recurrent symptomatic postcoital urinary tract infections (PCUTI), non-consumer of AC extract in the past 3 months before inclusion, and to determine changes in their quality of life (QoL). METHODS: This was a single center, observational, prospective study in a total of 20 women (mean age 35.2 years; 50.0% were married). Patients were followed up for 3 and 6 months during treatment. RESULTS: The number of PCUTIs in the previous 3 months prior to start the treatment with Cysticlean® was 2.8±1.3 and it was reduced to 0.2±0.5 at Month 6 (P<0.0001), which represent a 93% improvement. At baseline, the mean score on the VAS scale (range from 0 to 100) for assessing the QoL was 62.4±19.1, increasing to 78.2±12.4 at Month 6 (P=0.0002), which represents a 20% improvement. All patients had an infection with positive urine culture at baseline, after 6 months there were only 3 symptomatic infections (P<0.001). The most common bacterium was Escherichia coli. CONCLUSIONS: Prophylaxis with American cranberry extract (Cysticlean®) could be an alternative to classical therapies with antibiotics. Further studies are needed to confirm results obtained in this pilot study.

Association between infection early in life and mental disorders among youth in the community: a cross-sectional study.

BACKGROUND: The objective of this study was to examine the association between infection early in life and mental disorders among youth in the community. METHODS: Data were drawn from the MECA (Methods in Epidemiology of Child and Adolescent psychopathology), a community-based study of 1,285 youth in the United States conducted in 1992. Multiple logistic regression analyses were used to investigate the association between parent/caregiver-reported infection early in life and DSM/DISC diagnoses of mental disorders at ages 9-17. RESULTS: Infection early in life was associated with a significantly increased odds of major depression (OR = 3.9), social phobia (OR = 5.8), overanxious disorder (OR = 6.1), panic disorder (OR = 12.1), and oppositional defiant disorder (OR = 3.7). CONCLUSIONS: These findings are consistent with and extend previous results by providing new evidence suggesting a link between infection early in life and increased risk of depression and anxiety disorders among youth. These results should be considered preliminary. Replication of these findings with longitudinal epidemiologic data is needed. Possible mechanisms are discussed.

Sex-specific social regulation of inflammatory responses and sickness behaviors.

In many mammals, the availability of familiar conspecifics in the home environment can affect immune function and morbidity. Numerous sex differences exist in immune responses, but whether the social environment impacts the immune system differently in males and females is not fully understood. This study examined behavioral and physiological responses to simulated bacterial infection in adult male and female Wistar rats housed either with three same-sex non-siblings (Group) or alone (Isolate). Rats were injected with bacterial lipopolysaccharide (Escherichia coli LPS; 150 microg/kg, i.p.), and behavioral (orectic, locomotor, and social) and physiological (thermoregulatory, cytokine, and corticosterone) inflammatory responses were measured. Among males, LPS-induced fever, suppressed locomotor activity, and inhibited feeding behavior and the magnitude of these responses were greater in Isolate relative to Group housed individuals. In contrast, among females group housing exacerbated behavioral and physiological symptoms of simulated infection. LPS treatments elicited IL-1beta production in all groups, but plasma IL-1beta concentrations were higher and peaked earlier in Isolate relative to Group males, and in Group relative to Isolate females. Furthermore, plasma concentrations of TNFalpha and IL-2 were higher in Group relative to Isolate males. Plasma corticosterone concentrations did not vary as a function of social housing conditions. Together, the data indicate that the social environment markedly influences innate immune responses. Group housing exacerbates inflammatory responses and sickness behaviors in females, but attenuates these responses in males. These sex differences are mediated in part by differential effects of the social environment on pro- and anti-inflammatory cytokine production.

The conditioned stimulus elicits taste aversion but not sickness behavior in conditioned mice.

OBJECTIVES: This article extends previous reports on (i) elicitation of taste aversion after pairing a flavored beverage (saccharin solution) with a disease-provoking microbial product (lipopolysaccharide, LPS, or polyinosinic:polycytidylic acid, poly I:C); (ii) elicitation of sickness behavior (assessed as diminished ingestion of water and food) by the conditioned stimulus, and (iii) development of tolerance to those microbial products. METHODS: Mice of the CD1 strain were conditioned by pairing ingestion of 0.15% saccharin solution with injection of LPS (100 mug/mouse) or poly I:C (6 mg/kg). A few days later, some mice were offered saccharin solution and were injected with saline, whereas other mice were offered saccharin solution and were injected with the microbial product. RESULTS: Regardless of the nature of the unconditioned stimulus (LPS or poly I:C), (i) taste aversion to saccharin ensued, (ii) tolerance ensued to sickness elicitation by a second administration of the microbial component, and (iii) saccharin taste did not evoke sickness. CONCLUSIONS: Symptoms of infectious sickness in the absence of infection are hardly explained by exposure to the conditioned stimulus.

Common bacterial infections and risk of incident cognitive decline or dementia: a systematic review protocol.

INTRODUCTION: The global burden of dementia is rising, emphasising the urgent need to develop effective approaches to risk reduction. Recent evidence suggests that common bacterial infections may increase the risk of dementia, however the magnitude and timing of the association as well as the patient groups affected remains unclear. We will review existing evidence of the association between common bacterial infections and incident cognitive decline or dementia. METHODS AND ANALYSIS: We will conduct a comprehensive search of published and grey literature from inception to 18 March 2019. The following electronic databases will be searched; MEDLINE, EMBASE, Global health, PsycINFO, Web of Science, Scopus, Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, Open Grey and the British Library of Electronic Theses databases. There will be no restrictions on the date, language or geographical location of the studies. We will include longitudinal studies with a common clinically symptomatic bacterial infection as an exposure and incident cognitive decline or dementia as an outcome. Study selection, data extraction and risk of bias will be performed independently by two researchers. We will assess the risk of bias using the Cochrane collaboration approach. The overall quality of the studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. We will explore the heterogeneity of relevant studies and, if feasible, a meta-analysis will be performed, otherwise we will present a narrative synthesis. We will group the results by exposure and outcome definitions and differences will be described by subgroups and outcomes. ETHICS AND DISSEMINATION: Ethical approval will not be required as this is a systematic review of existing research in the public domain. Results will be disseminated in a peer-reviewed journal and presented at national and international meetings and conferences. PROSPERO REGISTRATION NUMBER: CRD42018119294.

The socio-economic impact of multidrug-resistant nosocomial infections: a qualitative study.

The burden of healthcare-associated infections (HCAIs) has traditionally been measured using clinical and economic outcomes. We conducted semi-structured interviews with 18 patients or their caregivers affected by HCAI caused by multidrug-resistant organisms to better understand the human impact of HCAI. Most patients had misconceptions about HCAI and antimicrobial resistance, leading to strong negative feelings towards HCAIs despite positive views of their healthcare providers. Communication issues across power imbalances need to be addressed to help deal with trauma of HCAIs. A holistic approach to HCAIs incorporating patient perspectives will likely help guide policymakers developing solutions to improve patient outcomes.

Evaluation in general practice of the patient's feelings about a recent hospitalization and isolation for a multidrug-resistant infection.

BACKGROUND: Isolation precautions used against multidrug-resistant (MDR) organisms are responsible for many emotional side effects. We evaluated patient's feeling after a hospitalization for an MDR infection. METHODS: We conducted a qualitative study that included 11 interviews from August 2017 to June 2018. We used phenomenology and verbatim transcription analysis was performed using NVivo software. Patients reported mainly negative feelings. Among them, 4 main themes were expressed: a desire to "be free from carriage," self-questioning regarding its nosocomial origin, the reduction of the therapeutic arsenal, and the expression of many fears especially relapse. RESULTS: For most of the participants (n = 6/11), the type of bacteria that colonized their digestive tract was precisely known including the MDR characteristics of the infection. Participants were convinced that the infection was strongly linked to the hospital and considered it as nosocomial that led to anxiety, especially regarding the origin of the infection and the absence of formal source of infection. CONCLUSIONS: MDR infections are negatively impacting patient's lived experience even after hospital discharge, partly owing to prior implementation of isolation precautions. We need to improve communication between specialists and general practitioners to reassure the patient and his surroundings regarding the anxiety resulting from such hospitalization.

Incomplete childhood vaccination and associated factors among children aged 12-23 months in Gondar city administration, Northwest, Ethiopia 2018.

OBJECTIVE: Despite the fact that immunization services are offered free of charge in Ethiopia but the coverage of complete vaccination is still low. The aim of the study is to determine incomplete vaccination and associated factors among children aged 12-23 months in Gondar city administration, Northwest Ethiopia, 2018. RESULT: The proportion of incomplete vaccination among children aged 12-23 months in Gondar city adminstration was 24.3% (95% CI 19.3, 29.2). Knowledge about the benefits of vaccination (AOR = 6.1 (95% CI 1.3, 28.9), the age at which the child begins vaccination (AOR = 2.4 (95% CI 1.09, 8.4) time taken to reach nearby health facility and means of transportation to nearby health facility (AOR = 0.22 95% CI 0.06, 0.9) have statistically significant association with incomplete vaccination. In the current study the proportion of incomplete vaccination was found to be high. Increasing the awareness about vaccination for child care givers and further improve caregiver's knowledge towards the benefit of vaccination is important.