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Introduction: Sudden non-cardiac death (SNCD) is a clinical entity comprising deaths lacking previous clinically significant symptoms, and in which the mechanisms of death do not involve the heart. Infection is a major cause of SNCD, particularly in children, and viruses are frequently involved in the disease process. Nevertheless, SNCD of viral infectious causes remains poorly characterized. Thus, a systematic review of the literature describing the association between viral infection and the development of SNCD was performed., Methods: PRISMA statement guidelines were followed in this systematic review. A literature search was conducted across MEDLINE, Scopus and Web of Science databases. Studies considered eligible were autopsy series or cohort studies of sudden death cases, in which evidence of viral disease as a cause of death was demonstrated, along with identification of causative agents., Results: Twelve studies published between 1996 and 2020 were included in this review. Selected studies were categorized into three groups according to the study population: infants and young children (up to four years of age); presumed sudden infant death syndrome patients; and older individuals (five years of age and older). SNCD with viral implication represents a minority of sudden death cases in all age groups, with infants and young children having a higher prevalence across studies. Respiratory infection was the main cause of viral SNCD, with influenza virus and respiratory syncytial virus being the most commonly identified agents in older individuals, and infants and young children respectively. Disseminated infection, gastrointestinal infection, and meningitis were other identified causes of SNCD in children., Conclusions: No studies have directly assessed the frequency and causes of viral SNCD. Infants and young children show a considerable, but variable, prevalence of this clinical entity. Wider implementation of post-mortem virological molecular testing may help uncover previously unknown cases. More research into viral SNCD is needed, especially in the adult population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: Viral infection outcomes vary widely between individuals, ranging from mild symptoms to severe organ failure and death, and it is clear that host genetic factors play a role in this variability. Type I interferon (IFN) is a critical anti-viral cytokine, and we have previously noted differences in type I IFN levels between world populations., Methods: In this study, we investigate the interrelationship between regional European genetic ancestry, type I IFN levels and severe viral infection outcomes., Results: In cohorts of European ancestry lupus patients living in Europe, we noted higher IFN in the Northwestern populations as compared to Southeastern populations. In an independent cohort of European ancestry lupus patients from the USA with varying proportional regional European genetic admixture, we observed the same Northwest vs. Southeast European ancestry IFN gradient. We developed a model to predict type I IFN level based on regional European ancestry (Area under the curve (AUC) = 0.73, P = 6.1e-6). Examining large databases containing serious viral outcomes data, we found that lower predicted IFN in the corresponding European country was significantly correlated with increased viral infection fatality rate, including Coronavirus Disease 2019 (COVID-19), viral hepatitis and HIV [correlation coefficients: -0.79 (P = 4e-2), -0.94 (P = 6e-3) and -0.96 (P = 8e-2), respectively]., Conclusions: This association between predicted type I IFN level and viral outcome severity suggests a potential causal relationship, as greater intrinsic type I IFN is beneficial in host defense against viruses. Genetic testing could provide insight into individual and population level risk of fatality due to viruses prior to infection, across a wide range of viral pathogens., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1 ), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics., (© 2023. The Author(s).)

Objective: To assess the impact of the covid-19 pandemic on hospital admission rates and mortality outcomes for childhood respiratory infections, severe invasive infections, and vaccine preventable disease in England., Design: Population based observational study of 19 common childhood respiratory, severe invasive, and vaccine preventable infections, comparing hospital admission rates and mortality outcomes before and after the onset of the pandemic in England., Setting: Hospital admission data from every NHS hospital in England from 1 March 2017 to 30 June 2021 with record linkage to national mortality data., Population: Children aged 0-14 years admitted to an NHS hospital with a selected childhood infection from 1 March 2017 to 30 June 2021., Main Outcome Measures: For each infection, numbers of hospital admissions every month from 1 March 2017 to 30 June 2021, percentage changes in the number of hospital admissions before and after 1 March 2020, and adjusted odds ratios to compare 60 day case fatality outcomes before and after 1 March 2020., Results: After 1 March 2020, substantial and sustained reductions in hospital admissions were found for all but one of the 19 infective conditions studied. Among the respiratory infections, the greatest percentage reductions were for influenza (mean annual number admitted between 1 March 2017 and 29 February 2020 was 5379 and number of children admitted from 1 March 2020 to 28 February 2021 was 304, 94% reduction, 95% confidence interval 89% to 97%), and bronchiolitis (from 51 655 to 9423, 82% reduction, 95% confidence interval 79% to 84%). Among the severe invasive infections, the greatest reduction was for meningitis (50% reduction, 47% to 52%). For the vaccine preventable infections, reductions ranged from 53% (32% to 68%) for mumps to 90% (80% to 95%) for measles. Reductions were seen across all demographic subgroups and in children with underlying comorbidities. Corresponding decreases were also found for the absolute numbers of 60 day case fatalities, although the proportion of children admitted for pneumonia who died within 60 days increased (age-sex adjusted odds ratio 1.71, 95% confidence interval 1.43 to 2.05). More recent data indicate that some respiratory infections increased to higher levels than usual after May 2021., Conclusions: During the covid-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions) and societal strategies (school closures, lockdowns, and restricted travel) were used to reduce transmission of SARS-CoV-2, which also reduced admissions for common and severe childhood infections. Continued monitoring of these infections is required as social restrictions evolve., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Office for Health Improvement and Disparities, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre for the submitted work; grants from the National Institute for Health Research, Bill and Melinda Gates Foundation, Wellcome Trust, and Astra Zeneca in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Macrobrachium rosenbergii Taihu virus (MrTV) is a fierce pathogen that causes high mortality in M. rosenbergii larvae. Little is known about the pathogenesis of MrTV and host-virus interactions. In this study, a virus overlay protein binding assay (VOPBA), followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, was carried out to search for novel host molecules that bind with VP3, one of the main capsid proteins of MrTV. Macrobrachium rosenbergii 14-3-3 protein (Mr14-3-3) was identified as the binding protein of VP3, which was further confirmed by co-immunoprecipitation (Co-IP) and co-localization assay. A preincubation assay was developed, which indicated that preincubation with recombinant Mr14-3-3 (rMr14-3-3) could significantly decrease the expression level of VP3 in MrTV-infected M. rosenbergii larvae, suggesting that preincubation with rMr14-3-3 could partially block MrTV infection. This study revealed that Mr14-3-3 acts as a binding protein for MrTV-VP3 and plays an important role in MrTV infection, offering a potential target for the development of anti-MrTV therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Six foals with interstitial pneumonia of undetermined etiology from Southern California were analyzed by viral metagenomics. Spleen, lung, and colon content samples obtained during necropsy from each animal were pooled, and nucleic acids from virus-like particles enriched for deep sequencing. The recently described equine copiparvovirus named eqcopivirus, as well as three previously uncharacterized viruses, were identified. The complete ORFs genomes of two closely related protoparvoviruses, and of a bocaparvovirus, plus the partial genome of a picornavirus were assembled. The parvoviruses were classified as members of new ungulate protoparvovirus and bocaparvovirus species in the Parvoviridae family. The picornavirus was classified as a new species in the Salivirus genus of the Picornaviridae family. Spleen, lung, and colon content samples from each foal were then tested for these viral genomes by nested PCR and RT-PCR. When present, parvoviruses were detected in both feces and spleen. The picornavirus, protoparvovirus, and eqcopivirus genomes were detected in the lungs of one animal each. Three foals were co-infected with the picornavirus and either a protoparvovirus, bocaparvovirus, or eqcopivirus. Two other foals were infected with a protoparvovirus only. No viral infection was detected in one animal. The complete ORFs of the first equine protoparvoviruses and bocaparvovirus, the partial ORF of the third equine picornavirus, and their detection in tissues of foals with interstitial pneumonia are described here. Testing the involvement of these viruses in fatal interstitial pneumonia or other equine diseases will require larger epidemiological and/or inoculation studies.

Different emerging viral infections may emerge in different regions of the world and pose a global pandemic threat with high fatality. Clarification of the immunopathogenesis of different emerging viral infections can provide a plan for the crisis management and prevention of emerging infections. This perspective article describes how an emerging viral infection evolves from microbial mutation, zoonotic and/or vector-borne transmission that progresses to a fatal infection due to overt viremia, tissue-specific cytotropic damage or/and immunopathology. We classified immunopathogenesis of common emerging viral infections into 4 categories: 1) deficient immunity with disseminated viremia (e.g., Ebola); 2) pneumocytotropism with/without later hyperinflammation (e.g., COVID-19); 3) augmented immunopathology (e.g., Hanta); and 4) antibody-dependent enhancement of infection with altered immunity (e.g., Dengue). A practical guide to early blocking of viral evasion, limiting viral load and identifying the fatal mechanism of an emerging viral infection is provided to prevent and reduce the transmission, and to do rapid diagnoses followed by the early treatment of virus neutralization for reduction of morbidity and mortality of an emerging viral infection such as COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang and Yang.)

Background: Acute myocarditis is an inflammatory disease of the heart mostly diagnosed in young people, which can present as sudden death. The etiology includes infectious agents (mostly viruses), systemic diseases and toxins. We aim to characterize infants and children with myocarditis at post-mortem presenting as sudden deaths., Methods: Retrospective evaluation of 813 post-mortems in infants and children dying suddenly and unexpectedly between 2009-2019. Data retrieved included histological features, microbiology and clinical history., Results: 23 of 813 post-mortems reviewed corresponded to acute myocarditis and 1 to dilated cardiomyopathy related to remote Parvovirus infection. PCR identified enterovirus (7), parvovirus (7 cases, 2 also with HHV6 and 1 case with EVB), Influenza A (1), Parainfluenza type 3 (1). Two cases corresponded to hypersensitivity myocarditis, 1 was Group A Streptococcus and 5 idiopathic myocarditis. Enterovirus was frequent in infants (7/10), and in newborns was associated with meningoencephalitis or congenital myocarditis. More than 50% were less than 2 years of age and all remained clinically unsuspected., Conclusion: Myocarditis represents almost 3% of all sudden pediatric deaths. Enterovirus and parvovirus were the most common viruses. This retrospective analysis showed that patients experienced viral symptoms but remained unsuspected, highlighting the need for more clinical awareness of myocarditis.

The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Illouz, Biragyn, Iulita, Flores-Aguilar, Dierssen, De Toma, Antonarakis, Yu, Herault, Potier, Botté, Roper, Sredni, London, Mobley, Strydom and Okun.)

Introduction: The recovery of other pathogens in patients with SARS-CoV-2 infection has been reported, either at the time of a SARS-CoV-2 infection diagnosis (co-infection) or subsequently (superinfection). However, data on the prevalence, microbiology, and outcomes of co-infection and superinfection are limited. The purpose of this study was to examine the occurrence of co-infections and superinfections and their outcomes among patients with SARS-CoV-2 infection., Patients and Methods: We searched literature databases for studies published from October 1, 2019, through February 8, 2021. We included studies that reported clinical features and outcomes of co-infection or superinfection of SARS-CoV-2 and other pathogens in hospitalized and non-hospitalized patients. We followed PRISMA guidelines, and we registered the protocol with PROSPERO as: CRD42020189763., Results: Of 6639 articles screened, 118 were included in the random effects meta-analysis. The pooled prevalence of co-infection was 19% (95% confidence interval [CI]: 14%-25%, I2 = 98%) and that of superinfection was 24% (95% CI: 19%-30%). Pooled prevalence of pathogen type stratified by co- or superinfection were: viral co-infections, 10% (95% CI: 6%-14%); viral superinfections, 4% (95% CI: 0%-10%); bacterial co-infections, 8% (95% CI: 5%-11%); bacterial superinfections, 20% (95% CI: 13%-28%); fungal co-infections, 4% (95% CI: 2%-7%); and fungal superinfections, 8% (95% CI: 4%-13%). Patients with a co-infection or superinfection had higher odds of dying than those who only had SARS-CoV-2 infection (odds ratio = 3.31, 95% CI: 1.82-5.99). Compared to those with co-infections, patients with superinfections had a higher prevalence of mechanical ventilation (45% [95% CI: 33%-58%] vs. 10% [95% CI: 5%-16%]), but patients with co-infections had a greater average length of hospital stay than those with superinfections (mean = 29.0 days, standard deviation [SD] = 6.7 vs. mean = 16 days, SD = 6.2, respectively)., Conclusions: Our study showed that as many as 19% of patients with COVID-19 have co-infections and 24% have superinfections. The presence of either co-infection or superinfection was associated with poor outcomes, including increased mortality. Our findings support the need for diagnostic testing to identify and treat co-occurring respiratory infections among patients with SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist.

Background: Genetic predispositions in cases suffering sudden unexpected infant death have been a research focus worldwide during the past decade. Despite large efforts, there is still uncertainty concerning the molecular pathogenesis of these deaths. With genetic technology in constant development, the possibility of an alternative approach into this research field has become available, like mRNA expression studies., Methods: In this study, we investigated mRNA gene expression in 14 cases who died suddenly and unexpectedly from infection without a history of severe illness prior to death. The control group included eight accidents, two cases of natural death, one undetermined, one case of medical malpractice, and two homicides. The study included tissue from liver, heart, and brain using Illumina whole-genome gene expression assay., Results: From the array, 19 genes showed altered expression in the infectious deaths compared to controls. Tissue from the heart showed 15 genes with altered mRNA expression compared to the control group., Conclusions: Downregulation of KCNE5 in heart tissue from cases of infectious death was of particular interest. Variants of KCNE5 are associated with Brugada syndrome and sudden death and could be responsible for the fatal outcome in the group of infectious death., Impact: KCNE5 is downregulated in tissue from the heart in cases of infectious death in infancy. This study provides knowledge about the gene expression profile in cases of infectious death. Variants of a gene known to give increased risk of cardiac arrhythmia is downregulated in cases of infectious death in infancy. The results could give us better knowledge as to why some infants do not survive an infection. This study provides a candidate gene for future studies.

Background: Viral infections after burns are less common than bacterial infections but usually occur in the more severely burned patients and have been associated with poor outcomes. Methods: Retrospective reviews and case series were examined to provide an overview of the management of viral infections in the burn patient. Results: The most common viral pathogens in these patients are the herpesviruses, which include herpes simplex, varicella zoster, cytomegalovirus, and human herpesvirus 6. Established viral infections that may complicate patient management include human immunodeficiency virus, hepatitis B and C, and, more recently, the novel coronavirus SARS-CoV-2. Herpesvirus infections can occur as primary or nosocomial pathogens but clinical manifestations most commonly are re-activation of latent viral infection. Because of the paucity of data in the burn population, much of the evidence for specific treatments is extrapolated from patients with severe immunosuppression or critical illness. Antiviral therapy is employed for the burn patient with herpesvirus infections. This is an area of active study, and further research is needed to better understand the risks, clinical manifestations, and attributable morbidity and mortality of viral infections. Conclusions: Major burn injury results in immunosuppression and viral infection in a small number of patients. Recognition and antiviral therapy are employed, but additional studies are necessary to improve outcomes in these patients.

Objectives: To describe the burden, epidemiology and outcomes of co-infections and superinfections occurring in hospitalized patients with coronavirus disease 2019 (COVID-19)., Methods: We performed an observational cohort study of all consecutive patients admitted for ≥48 hours to the Hospital Clinic of Barcelona for COVID-19 (28 February to 22 April 2020) who were discharged or dead. We describe demographic, epidemiologic, laboratory and microbiologic results, as well as outcome data retrieved from electronic health records., Results: Of a total of 989 consecutive patients with COVID-19, 72 (7.2%) had 88 other microbiologically confirmed infections: 74 were bacterial, seven fungal and seven viral. Community-acquired co-infection at COVID-19 diagnosis was uncommon (31/989, 3.1%) and mainly caused by Streptococcus pneumoniae and Staphylococcus aureus. A total of 51 hospital-acquired bacterial superinfections, mostly caused by Pseudomonas aeruginosa and Escherichia coli, were diagnosed in 43 patients (4.7%), with a mean (SD) time from hospital admission to superinfection diagnosis of 10.6 (6.6) days. Overall mortality was 9.8% (97/989). Patients with community-acquired co-infections and hospital-acquired superinfections had worse outcomes., Conclusions: Co-infection at COVID-19 diagnosis is uncommon. Few patients developed superinfections during hospitalization. These findings are different compared to those of other viral pandemics. As it relates to hospitalized patients with COVID-19, such findings could prove essential in defining the role of empiric antimicrobial therapy or stewardship strategies., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

Background: Community-acquired respiratory viruses (CARV) cause upper and lower respiratory tract infections (URTI/LRTI) and may be life-threatening for recipients of an allogeneic stem cell transplantation (allo-SCT)., Methods: In a prospective study encompassing 4 winter-seasons, we collected throat gargles (TG) at random time points from allo-SCT recipients (patients) and controls and followed them up for at least 3 weeks including repetitive sampling and documentation of symptoms. A Multiplex-PCR system to identify 20 CARV and Mycoplasma pneumoniae was used to detect CARV., Results: One hundred ninety-four patients with 426 TG and 273 controls with 549 TG were included. There were more patients with a positive test result (25% vs 11% in the controls), and the patients had a higher number of positive TG (70 = 16%) compared to controls (32 = 6%) (P < .001). Altogether, 115 viruses were detected. Multiple viruses in one TG (11/48, 34%) and prolonged shedding were only observed in patients (13/48, 27%). Patients had more RSV (18/83, 26%) and adenovirus (15/83, 21%) than controls (both viruses 2/32, 6%). Independent risk factors for the detection of CARV included age >40 years (OR 3.38, 95% CI 1.8-6.4, P < .001) and presence of URTI-symptoms (OR 3.22, 95% CI 1.9-5.5, P < .001). No controls developed a LRTI or died whereas 4/48 (8%) patients developed a LRTI (coronavirus in 2, RSV in 1 and influenza A H1N1 in 1 patient). One patient died of CARV (influenza A H1N1)., Conclusion: Allo-SCT-recipients have more CARV-infections, exhibit a different epidemiology, have more cases of co-infection or prolonged shedding and have a higher rate of LRTI and mortality., (© 2020 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Background: We are communicating the results of investigating statistics on SARS-CoV-2-related pneumonias in Russia: percentage, mortality, cases with other viral agents, cases accompanied by secondary bacterial pneumonias, age breakdown, clinical course and outcome., Methods: We studied two sampling sets (Set 1 and Set 2). Set 1 consisted of results of testing 3382 assays of out-patients and hospital patients (5-88 years old) with community-acquired and hospital-acquired pneumonia of yet undetermined aetiology. Set 2 contained results of 1204 assays of hospital patients (12-94 years old) with pneumonia and COVID-19 already diagnosed by molecular biological techniques in test laboratories. The results were collected in twelve Russian cities/provinces in time range 2 March - 5 May 2020. Assays were analysed for 10 bacterial, 15 viral, 2 fungal and 2 parasitic aetiological agents., Results: In Set 1, 4.35% of total pneumonia cases were related to SARS-CoV-2, with substantially larger proportion (18.75%) of deaths of pneumonia with COVID-19 diagnosed. However, studying Set 2, we revealed that 52.82% patients in it were also positive for different typical and atypical aetiological agents usually causing pneumonia. 433 COVID-19 patients (35.96%) were tested positive for various bacterial aetiological agents, with Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae infections accounting for the majority of secondary pneumonia cases., Conclusions: SARS-CoV-2, a low-pathogenic virus itself, becomes exceptionally dangerous if secondary bacterial pneumonia attacks a COVID-19 patient as a complication. An essential part of the severest complications and mortality associated with COVID-19 in Russia in March-May 2020, may be attributed to secondary bacterial pneumonia and to a much less extent viral co-infections. The problem of hospital-acquired bacterial infection is exceptionally urgent in treating SARS-CoV-2 patients. The risk of secondary bacterial pneumonia and its further complications, should be given very serious attention in combating SARS-CoV-2., Competing Interests: Competing interests: The author completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author) and declares no conflicts of interest., (Copyright © 2020 by the Journal of Global Health. All rights reserved.)

Systemic lupus erythematosus (SLE) is an inflammatory and multi-systemic autoimmune disorder, characterized by an uncontrolled auto-reactivity of B and T lymphocytes, leading to the production of autoantibodies against self-directed antigens and tissue damage. The life expectancy in patients with SLE has improved tremendously in the last two decades, but the mortality rates still remain three times greater compared to those of the general population. Despite increased awareness and improved management, infections remain a major source of morbidity, mortality, hospitalization, and death in patients with SLE. The infections in SLE patients widely range from opportunistic to common bacterial and viral infections with typical or atypical presentations. Moreover, SLE patients exhibit an increased susceptibility to hospital-acquired infections. Factors associated with increased risk of infections include high disease activity, specific immune dysregulation, drug-induced immune deficiency, and organ failure with irreversible damage. Furthermore, immunosuppressive agents may make patients more susceptible to opportunistic infections. A big challenge faced by physicians in these patients is to distinguish between infections and flares of SLE, as infections may mimic them, leading to predicament in diagnosis and appropriate management. Immunosuppression used to treat severe flares of lupus can have catastrophic complications in patients with active infections. There is an urgent need for biomarkers to make an accurate differential diagnosis in this situation. In spite of increased understanding of SLE, many questions remain unanswered. Further research is needed to determine specific immune dysregulation underlying the increased susceptibility to specific infections, predictors of infection in SLE such as genetic markers, and biomarkers that discriminate between disease activity and active infections. Also, measures must be evaluated appropriately to prevent infections, and their complications in SLE.

Human evidence for the role of continuous antigenic stimulation from persistent latent infections in frailty is limited. We conducted a nested case-control study (99 deceased and 43 survivors) of participants aged 55 and above in a longitudinal ageing cohort followed up from 2003 to 2017. Using blood samples and baseline data collected in 2003-2004, we examined the association of pathogenic load (PL) count of seropositivity to 10 microbes (viruses, bacteria and mycoplasma) with cumulated deficit-frailty index (CD-FI) and the physical frailty (PF) phenotype, and mortality. Controlling for age, sex, education, smoking and alcohol histories, high PL (7-9) versus low PL (3-6) was associated with an estimated increase of 0.035 points in the CD-FI (Cohen's D=0.035 / 0.086, or 0.41). High PL was associated with 8.5 times odds of being physically frail (p=0.001), 2.8 times odds of being weak (p=0.010), 3.4 times odds of being slow (p=0.024), and mortality hazard ratio of 1.53 (p=0.046). There were no significant associations for specific pathogens, except marginal associations for Epstein-Barr virus and Chikungunya. Conclusion: A high pathogenic load of latent infections was associated with increased risks of frailty and mortality.

Background: Heart transplantation is a life-saving procedure that has seen improvements in transplant and patient outcomes due to advances in immunosuppression and prevention of posttransplantation infectious episodes (IEps). This study systematically evaluates IEps in the modern era of heart transplantation at Stanford University Medical Center., Methods: This is a single-center retrospective review that includes 279 consecutive adult heart transplantation recipients from January 2008 to September 2017. Baseline demographic, clinical, serological, and outcomes information were collected. Kaplan-Meier estimator was used to assess survival stratified by IEp occurrence within the first year., Results: A total of 600 IEps occurred in 279 patients (2.15 IEps per patient) during a median follow-up period of 3 years. Overall survival was 83.3% (95% confidence interval [CI], 76.2-88.4) at 1 year posttransplantation for those with any IEp compared with 93.0% (95% CI, 87.2-96.4) in those without IEp (P = 0.07). Bacterial IEps were the most common (n = 375; 62.5%), followed by viral (n = 180; 30.0%), fungal (n = 40; 6.7%), and parasitic (n = 5; 0.8%). IEps by Gram-negative bacteria (n = 210) outnumbered those by Gram-positive bacteria (n = 142). Compared with prior studies from our center, there was a decreased proportion of viral (including cytomegalovirus), fungal (including Aspergillus spp. and non-Aspergillus spp. molds), and Nocardia infections. There were no IEps due to Mycobacterium tuberculosis, Pneumocystis jirovecii, or Toxoplasma gondii., Conclusions: A significant reduction in viral, fungal, and Nocardia IEps after heart transplantation was observed, most likely due to advancements in immunosuppression and preventive strategies, including pretransplant infectious diseases screening and antimicrobial prophylaxis.

Objective: To estimate the contribution of infections to childhood deaths in England and Wales over a 3-year period., Design: Retrospective analysis of national electronic death registration data., Setting: England and Wales., Patients: Children aged 28 days to 15 years who died during 2013-15., Main Outcome Measures: The proportion of children who died of infection compared with total deaths over 3 years; the main pathogens responsible for infection-related deaths in different age groups; comparison with similar data from 2003 to 2005., Results: There were 5088 death registrations recorded in children aged 28 days to <15 years in England and Wales during the three calendar years, 2013-2015 (17.6 deaths/100 000 children annually) compared with 6897 (23.9/100 000) during 2003-05 (incidence rate ratios (IRR) 0.74, 95% CI 0.71 to 0.77). During 2013-15, there were 951 (18.7%, 951/5088) infection-related deaths compared with 1368 (19.8%, 1368/6897) during 2003-05, equivalent to an infection-related mortality rate of 3.3/100 000 compared with 4.8/100 000 during the two periods (IRR 0.69, 95% CI 0.64 to 0.75), respectively. An underlying comorbidity was recorded in 55.0% (523/951) of death registrations during 2013-15 and increased with age. Where recorded, respiratory tract infection was the most commonly reported presentation (374/876, 42.7%) during 2013-15. Central nervous system infections accounted for only 4.8% (42/876). Overall, 63.1% (378/599) of infection-related deaths were associated with a bacterial, 34.2% (205/599) with a viral and 2.5% (15/599) with a fungal infection., Conclusions: Beyond the neonatal period, all-cause and infection-related childhood mortality rates have declined by 26% and 31%, respectively, over the past decade. However, infection continues to contribute to one in five childhood deaths., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This is an update of a previous review. Case reports and case series have described dramatic responses to intravenous immunoglobulin (IVIG) in people with presumed viral myocarditis, and its administration has become commonplace., Objectives: The primary objective of this review was to compare event-free (death, requirement for a cardiac transplant, or placement of a left ventricular assist device) or overall (death) survival of adults and children with presumed viral myocarditis treated with IVIG versus those who did not receive IVIG. A secondary objective was to determine if a group of patients with presumed viral myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from IVIG., Search Methods: We searched CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection, and LILACS in July 2019, and two trial registries in November 2019. We contacted authors of trials and checked reference lists of relevant papers. We applied no language restrictions., Selection Criteria: We included studies if (1) participants had a clinical diagnosis of acute myocarditis with a left ventricular ejection fraction (LVEF) ≤ 0.45, left ventricular end-diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm, or a left ventricular shortening fraction (LVSF) > 2 SDs below the mean, with duration of cardiac symptoms < 6 months; (2) participants had no evidence of non-infectious or bacterial cardiac disease; and (3) participants were randomly assigned to receive at least 1 g/kg of IVIG versus no IVIG or placebo. We excluded studies if (1) participants had received immunosuppression before outcome assessment; or (2) onset of myocarditis was reported to have occurred < 6 months postpartum., Data Collection and Analysis: Two review authors independently screened the search results and extracted data. We assessed risk of bias with the Cochrane 'Risk of bias' tool. We conducted meta-analysis for two outcomes (overall survival and improvement in LVEF) with two adult trials. Other meta-analyses were not possible because only three relevant trials were included, and researchers analysed markedly different populations and used different outcome measures., Main Results: In this update we added two trials to the two previously included trials. A quasi-randomised trial was previously included due to a paucity of evidence from randomised trials; however, with the addition of two new randomised trials, it was removed from this update. For two adult trials, the overall risk of bias was unclear with very low-certainty evidence for all outcomes. The first trial studied 62 adults with recent-onset dilated cardiomyopathy randomly assigned to receive IVIG or an equivalent volume of 0.1% albumin in a blinded fashion. The effect on event-free survival between groups was uncertain (risk ratio (RR) of any event 1.76, 95% confidence interval (CI) 0.48 to 6.40). The second trial studied 41 adults with acute myocarditis randomised to either high-dose IVIG (1 to 2 g/kg over two days) or no treatment. The IVIG group reported greater survival time after 60 days (no raw data, P < 0.01), but the evidence is uncertain. We pooled the reported number of deaths in both trials, with no evidence of a difference between groups (RR 0.91, 95% CI 0.23 to 3.62, I 2 = 31%, very low-certainty evidence). The evidence on the effect of IVIG treatment on LVEF (pooled mean difference (MD) -0.01, 95% CI -0.06 to 0.05) after 12 months and an unknown time frame is uncertain. The results for functional capacity, assessed by peak oxygen consumption at 12 months, were uncertain (MD -0.80, 95% CI -4.57 to 2.97). The results for infusion-related side effects were also uncertain due to a very large CI (RR 20.29, 95% CI 1.25 to 329.93). Lastly, there was uncertain evidence addressing failure to attain complete recovery (RR 0.46, 95% CI 0.19 to 1.14).  Evidence for improvement in LVEDD, left ventricular shortening fraction, and hospitalisation status in adults was not reported.  In the single included paediatric trial, the overall risk of bias was low with very low-certainty evidence for all outcomes. The trial included 86 children in Egypt presenting with acute myocarditis. Children were randomly assigned to 1 g/kg IVIG daily for two consecutive days or placebo followed by echocardiography one and six months post randomisation for recording of LVEDD and LVSF. The evidence for overall survival after six months was uncertain (risk of death RR 0.48, 95% CI 0.20 to 1.15). The evidence was also uncertain for improvement in LVEDD and LVSF after six months (LVEDD MD -4.00, 95% CI -9.52 to 1.52; LVSF no raw data).  Evidence for improvement in LVEF, functional capacity, side effects, complete recovery, and hospitalisation status in children was not reported.  AUTHORS' CONCLUSIONS: Evidence from two trials of very low certainty and with unclear risk of bias provides contradictory evidence on the use of IVIG in the treatment of adults with presumed viral myocarditis. One trial reported that use of IVIG results in longer survival time after 60 days, whilst the other trial found that IVIG does not provide an appreciable benefit. The evidence of a difference in event-free or overall survival, LVEDD, or LVSF is of very low certainty in a single paediatric trial with a low risk of bias. Until higher-quality studies with low risk of bias and larger sample sizes have demonstrated benefit in a particular group of patients, the evidence for treatment with IVIG for presumed viral myocarditis is uncertain. Further studies of the pathophysiology of myocarditis would lead to improved diagnostic criteria, which would facilitate future research., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Hodgkin (HL) and non-Hodgkin lymphoma (NHL) represent a spectrum of lymphoid malignancies that are often curable with currently applied treatment regimens; however, 15%-30% of lymphoma patients still suffer from relapsed or refractory (rel/ref) disease. Although hematopoietic stem cell transplantation (HSCT) improves outcomes of second-line therapy for lymphoma in childhood, the complication rates in this group of patients, especially infectious complications (IC), remain unclear., Objective: The aim of this population-based cohort study was a retrospective analysis of incidence, epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in primary or rel/ref lymphoma patients, both HL and NHL., Patients and Methods: We subdivided lymphoma patients into three groups: patients with primary conventional chemotherapy/radiotherapy regimens (group A), patients with rel/ref lymphoma treated with second-line chemotherapy (group B), and rel/ref lymphoma patients who underwent HSCT (group C). The medical records of the patients were biannually reported by each pediatric oncology center, and the data were analyzed centrally., Results: Within 637 patients with primary lymphoma, at least one IC was diagnosed in 255 (40.0%), among 52 patients with rel/ref lymphoma 24 (46.2%) ICs were observed, and in transplanted group, 28 (57.1%) out of 49 children were diagnosed with IC (P = .151). The distribution of etiology of IC differed between the patient groups (A, B, C), with a predominance of BI in group A (85.6% vs 72.0% and 47.9%, respectively), VI in group C (9% and 16.0% vs 46.6%, respectively), and IFD in group B (5.4% vs 12.0% vs 5.5%, respectively). Overall, 500 (68.0%) episodes of bacterial IC were diagnosed in the entire group. Apart from HL patients treated with chemotherapy, in all the other subgroups of patients Gram-positives were predominant. The rate of multidrug-resistant bacteria was high, especially for Gram-negatives (41.1% in group A, 62.5% in group B, and 84.6% in group C). The infection-related mortality was comparable for each group., Conclusions: The incidence of IC was comparable during first- and second-line chemotherapy and after HSCT, but their profile was different for primary or re/ref lymphoma and depended on the type of therapy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: During the ongoing COVID-19 outbreak, co-circulation of other common respiratory viruses can potentially result in co-infections; however, reported rates of co-infections for SARS-CoV-2 vary. We sought to evaluate the prevalence and etiology of all community acquired viral respiratory infections requiring hospitalization during an ongoing COVID-19 outbreak, with a focus on co-infection rates and clinical outcomes., Methods: Over a 10-week period, all admissions to our institution, the largest tertiary hospital in Singapore, were screened for respiratory symptoms, and COVID-19 as well as a panel of common respiratory viral pathogens were systematically tested for. Information was collated on clinical outcomes, including requirement for mechanical ventilation and in hospital mortality., Results: One-fifth (19.3%, 736/3807) of hospitalized inpatients with respiratory symptoms had a PCR-proven viral respiratory infection; of which 58.5% (431/736) tested positive for SARS-CoV-2 and 42.2% (311/736) tested positive for other common respiratory viruses. The rate of co-infection with SARS-CoV-2 was 1.4% (6/431); all patients with co-infection had mild disease and stayed in communal settings. The in-hospital mortality rate and proportion of COVID-19 patients requiring invasive ventilation was low, at around 1% of patients; these rates were lower than patients with other community-acquired respiratory viruses admitted over the same period (p < 0.01)., Conclusion: Even amidst an ongoing COVID-19 outbreak, common respiratory viruses still accounted for a substantial proportion of hospitalizations. Coinfections with SARS-CoV-2 were rare, with no observed increase in morbidity or mortality., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Improved identification of bacterial and viral infections would reduce morbidity from sepsis, reduce antibiotic overuse, and lower healthcare costs. Here, we develop a generalizable host-gene-expression-based classifier for acute bacterial and viral infections. We use training data (N = 1069) from 18 retrospective transcriptomic studies. Using only 29 preselected host mRNAs, we train a neural-network classifier with a bacterial-vs-other area under the receiver-operating characteristic curve (AUROC) 0.92 (95% CI 0.90-0.93) and a viral-vs-other AUROC 0.92 (95% CI 0.90-0.93). We then apply this classifier, inflammatix-bacterial-viral-noninfected-version 1 (IMX-BVN-1), without retraining, to an independent cohort (N = 163). In this cohort, IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.86 (95% CI 0.77-0.93), and viral-vs.-other 0.85 (95% CI 0.76-0.93). In patients enrolled within 36 h of hospital admission (N = 70), IMX-BVN-1 AUROCs are: bacterial-vs.-other 0.92 (95% CI 0.83-0.99), and viral-vs.-other 0.91 (95% CI 0.82-0.98). With further study, IMX-BVN-1 could provide a tool for assessing patients with suspected infection and sepsis at hospital admission.

Objective: To analyze the role that infections play on the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) outcome., Methods: A retrospective study of adult patients with AAV diagnosed in a tertiary center. Clinical features, laboratory findings, treatment, relapses, major infections, and outcome were evaluated., Results: Included were 132 patients [51 microscopic polyangiitis (MPA), 52 granulomatosis with polyangiitis (GPA), 29 eosinophilic GPA (EGPA)] with a mean followup of 140 (96-228) months. ANCA were positive in 85% of cases. A total of 300 major infections, mainly bacterial (85%), occurred in 60% patients during the followup. Lower respiratory tract (64%) and urinary tract infections (11%) were the most frequent, followed by bacteremia (10%). A total of 7.3% opportunistic infections were observed, most due to systemic mycosis. Up to 46% of all opportunistic infections took place in the first year of diagnosis, and 55% of them under cyclophosphamide (CYC) treatment. Bacterial infections were associated with Birmingham Vasculitis Activity Score (version 3) > 15 at the disease onset, a total cumulative CYC dose > 8.65 g, dialysis, and development of leukopenia during the followup. Leukopenia was the only factor independently related to opportunistic infections. Forty-four patients died, half from infection. Patients who had major infections had an increased mortality from any cause., Conclusion: Our results confirm that major infections are the main cause of death in patients with AAV.

Viral respiratory infections (VRIs) contribute to the morbidity and transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and strategies to prevent and treat VRIs are warranted. We monitored VRIs before and after transplant in children undergoing allogeneic HSCT with nasopharyngeal aspirates (NPA) and assessed the impact on clinical outcome. Between 2007 and 2017, 585 children underwent 620 allogeneic HSCT procedures. Out of 75 patients with a positive NPA screen (12%), transplant was delayed in 25 cases (33%), while 53 children started conditioning with a VRI. Patients undergoing HSCT with a positive NPA screen had a significantly lower overall survival (54% vs. 79%) and increased TRM (26% vs. 7%) compared to patients with a negative NPA. Patients with a positive NPA who delayed transplant and cleared the virus before conditioning had improved overall survival (90%) and lower TRM (5%). Pre-HSCT positive NPA was the only significant risk factor for progression to a lower respiratory tract infection and was a major risk factor for TRM. Transplant delay, whenever feasible, in case of a positive NPA screen for VRIs can positively impact on survival of children undergoing HSCT., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

In host-parasite co-evolution, parasites are assumed to have an advantage owing to their shorter generation time. Evolution of pathogens within the lifetime of a host individual is implicated as a strong selective force in the evolution of sex and aging in the host. However, this assumption or its testable predictions have not been examined empirically. We classified infectious bacteria and viruses into those that can have continued longterm existence on the host body (group 1) versus those that have only a short-term interaction during an active infection (group 2). We surveyed the literature for age-specific incidence data about infections from both the groups. The age trends of the two groups show contrasting patterns. The incidence of infections by all group 1 pathogens showed a 2.28- to 28-fold increase in older ages. In group 2, 6 out of the 9 pathogens showed a significant declining trend in incidence with age. In both groups, there was greater mortality or morbidity among the infected in the old-age classes. These patterns are better explained by pathogen evolution than by age-related decline in immunity.

Aim: Myocarditis and cardiomyopathy impose a substantial economic burden on society. Many studies have examined the effects of various predictors on the prognosis of these diseases, such as the left ventricular systolic function, the New York Heart Association glomerular filtration rate, the QT interval, and the presence of viruses. In the present study, we conducted a meta-analysis of cohort studies to investigate the significance of the presence of viruses in the myocardial tissue on the prognosis of these diseases., Methods: The Embase, PubMed, and Cochrane library databases were searched for relevant literature that had been published between January 1, 1964 and August 14, 2018. The inclusion criteria were patients over 18 years of age, suspected myocarditis or dilated cardiomyopathy, accepted myocardial biopsy, and the detection of virus in the myocardial tissue., Results: In total, 10 studies met the inclusion criteria. These studies included 1006 patients with suspected myocarditis or idiopathic heart disease for whom the primary endpoint was all-cause death, heart transplant, or re-hospitalization due to fatal arrhythmia and heart failure. There was no significant difference in the prognosis of virus-positive and virus-negative patients with myocarditis or dilated cardiomyopathy confirmed by endomyocardial biopsy (EMB) [hazard ratio (HR) = 1.40, 95% confidence interval (CI) = 0.93-2.12, P = 0.11]. However, virus-negative patients had a better prognosis following nonspecific treatment (HR = 1.40, 95% CI = 1.06-1.86, P = 0.02) and right ventricular biopsy (HR = 2.08, 95% CI = 1.07-4.04, P = 0.03)., Conclusions: The presence of a virus did not worsen the long-term prognosis of patients with suspected myocarditis or dilated cardiomyopathy. However, virus-positive patients who did not undergo specific treatment or who underwent right ventricular biopsy did have a worse prognosis. Thus, the early diagnosis of the presence of viral infection in the myocardium will improve the prognosis of patients., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2019 Wen-Hao Chen et al.)

Foodborne viral diseases are a major public health threat and pose a huge burden on the economies of both developed and developing countries. Enteric viruses are the causative agents of most foodborne illnesses and outbreaks. Egypt is classified by WHO among the regions with intermediate to high endemicity for various enteric viruses. This is manifested by the high prevalence rates of different enteric virus infections among Egyptian population such as Hepatitis A and E viruses, human rotaviruses, human noroviruses, human astroviruses, and human adenovirus. Recently, a number of foodborne gastroenteritis and acute hepatitis outbreaks have occurred in the US, Canada, Australia, and the European Union countries. Some of these outbreaks were attributed to the consumption of minimally processed foods imported from Egypt indicating the possibility that Egyptian foods may also be partially responsible for high prevalence of enteric virus infections among Egyptian population. In the absence of official foodborne-pathogen surveillance systems, evaluating the virological safety of Egyptian foods is a difficult task. In this review, we aim to provide a preliminary evaluation of the virological safety of Egyptian foods. A comprehensive review of prevalence studies on enteric virus infections shows hyperendemicity of several enteric viruses in Egypt and provides strong evidence of implication of Egyptian foods in these infections. We also address possible environmental risk factors that may lead to the contamination of Egyptian foods with enteric viruses. In addition, we describe potential obstacles to any plan that might be considered for improving the virological safety of Egyptian foods.

Introduction: Over 19% of deceased organ donors are labeled increased risk for disease transmission (IRD) for viral blood-borne disease transmission. Many potential organ recipients need to decide between accepting an IRD organ offer and waiting for a non-IRD organ., Methods: Using machine learning and simulation, we built transplant and waitlist survival models and compared the survival for patients accepting IRD organ offers or waiting for non-IRD organs for the heart, liver, and lung. The simulation consisted of generating 20 000 different scenarios of a recipient either receiving an IRD organ or waiting and receiving a non-IRD organ., Results: In the simulations, the 5-year survival probabilities of heart, liver, and lung recipients who accepted IRD organ offers increased on average by 10.2%, 12.7%, and 7.2%, respectively, compared with receiving a non-IRD organ after average wait times (190, 228, and 223 days, respectively). When the estimated waitlist time was at least 5 days for the liver, and 1 day for the heart and lung, 50% or more of the simulations resulted in a higher chance of 5-year survival when the patient received an IRD organ versus when the patient remained on the waitlist. We also developed a simple equation to estimate the benefits, in terms of 5-year survival probabilities, of receiving an IRD organ versus waiting for a non-IRD organ, for a particular set of recipient/donor characteristics., Conclusion: For all three organs, the majority of patients are predicted to have higher 5-year survival accepting an IRD organ offer compared with waiting for a non-IRD organ., (© 2019 The Authors. Transplant Infectious Disease published by Wiley Periodicals, Inc.)

Objective: To study the association between mode of conception and offspring infectious morbidity risk., Design: Population-based cohort study., Setting: Regional university medical center., Patient(s): All singleton infants born between the years 1991 and 2014 and discharged alive from the hospital., Intervention(s): Follow-up time in the study was calculated from birth to an event, defined as the first offspring hospitalization with any infectious morbidity. All infectious diagnoses were compared between the study groups, and a multivariable survival model was created to study the association between mode of conception and offspring pediatric hospitalization with infectious morbidity, and adjusting for confounding or clinically significant variables., Main Outcome Measure(s): First offspring pediatric hospitalization with infectious morbidity., Result(s): During the study period, 242,187 newborns met the inclusion criteria: 2,603 (1.1%) of which were conceived after undergoing IVF, 1,172 (0.7%) after ovulation induction (OI), and 237,863 (98.3%) were conceived spontaneously. Mothers receiving fertility treatments were older and with higher rates of preterm births and low birthweights. The hospitalizations rates per 1,000 person years of follow-up were 16.34/1,000 person years, 11.61/1,000 person years, and 10.19/1,000 person years, among the IVF, OI, and spontaneously conceived offspring, respectively. The adjusted hazard ratios were 1.26 (95% confidence interval 1.13-1.42) and 1.14 (95% confidence interval 1.00-1.38), for the IVF and OI compared with the spontaneously conceived offspring, respectively. The model adjusted for preterm delivery, birthweight, maternal age, hypertension, diabetes, and cesarean section., Conclusion(s): Higher risk for infectious morbidity was found among offspring conceived after fertility treatments compared with spontaneously conceived offspring., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Some strains of Bacillus Calmette-Guérin (BCG) vaccine not only confer protection against disseminated forms of tuberculosis, but also reduce all-cause mortality by the induction of protection against infections with non-related pathogens., Objectives: We review evidence for non-specific protection induced by BCG vaccination against viral infections, discuss possible mechanisms of action, and summarize implications for vaccination policies and vaccine discovery., Sources: Relevant studies retrieved from PubMed and clinicaltrials.gov., Content: Numerous epidemiological, clinical and immunological studies demonstrate that BCG vaccination impacts the immune response to subsequent infections, resulting in reduced morbidity and mortality. Important lines of evidence indicating that BCG protects against viral pathogens comes from experimental studies in mice showing that BCG offers protection against various DNA and RNA viruses, including herpes and influenza viruses. Recently, the effect of BCG on an experimental viral infection in humans has been demonstrated. These effects are thought to be mediated via the induction of innate immune memory and heterologous lymphocyte activation, resulting in enhanced cytokine production, macrophage activity, T-cell responses and antibody titres., Implications: The discovery of innate immune memory has greatly improved our understanding of the mechanisms underlying the non-specific effects induced by BCG vaccination. However, a full understanding of the molecular mechanisms that underlie this phenomenon is still evolving. By identifying the factors that impact the non-specific effects of BCG, we will take an important step towards novel therapeutic options and vaccination strategies, which might lead to a reduction in severe morbidity and mortality associated with viral infections., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Mannose-binding lectin (MBL) is a key component of innate immunity. Low serum MBL levels, related to promoter polymorphism and structural variants, have been associated with an increased risk of infection. The aim of this work was to analyse the incidence and severity of infections and mortality in relation to the MBL2 genotype and MBL levels in patients underwent allogeneic haematopoietic stem cell transplantation (Allo-HSCT)., Results: This was a prospective cohort study of 72 consecutive patients underwent Allo-HSCT between January 2007 and June 2009 in a tertiary referral centre. Three periods were considered in the patients' follow-up: the early period (0-30 days after Allo-HSCT), the intermediate period (30-100 days after Allo-HSCT) and the late period (> 100 days after Allo-HSCT). A commercial line probe assay for MBL2 genotyping and an ELISA Kit were used to measure MBL levels. A total of 220 episodes of infection were collected in the 72 patients. No association between donor or recipient MBL2 genotype and infection was found. The first episode of infection presented earlier in patients with pre-transplant MBL levels of < 1000 ng/ml (median 6d vs 8d, p = 0.036). MBL levels < 1000 ng/ml in the pre-transplant period (risk ratio (RR) 2.48, 95% CI 1.00-6.13), neutropenic period (0-30 days, RR 3.28, 95% CI 1.53-7.06) and intermediate period (30-100 days, RR 2.37, 95% CI 1.15-4.90) were associated with increased risk of virus infection. No association with bacterial or fungal disease was found. Mortality was associated with pre-transplant MBL levels < 1000 ng/ml (hazard ratio 5.55, 95% CI 1.17-26.30, p = 0.03) but not with MBL2 genotype., Conclusions: Patients who underwent Allo-HSCT with low pre-transplant MBL levels presented the first episode of infection earlier and had an increased risk of viral infections and mortality in the first 6 months post-transplant. Thus, pre-transplant MBL levels would be important in predicting susceptibility to viral infections and mortality and might be considered a biomarker to be included in the pre-transplantation risk assessment.

We did a global review to synthesise data on the prevalence, harms, and interventions for stimulant use, focusing specifically on the use of cocaine and amphetamines. Modelling estimated the effect of cocaine and amphetamine use on mortality, suicidality, and blood borne virus incidence. The estimated global prevalence of cocaine use was 0·4% and amphetamine use was 0·7%, with dependence affecting 16% of people who used cocaine and 11% of those who used amphetamine. Stimulant use was associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. No effective pharmacotherapies are available that reduce stimulant use, and the available psychosocial interventions (except for contingency management) had a weak overall effect. Generic approaches can address mental health and blood borne virus infection risk if better tailored to mitigate the harms associated with stimulant use. Substantial and sustained investment is needed to develop more effective interventions to reduce stimulant use., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To identify parents' prioritised outcomes by combining qualitative findings from two trial feasibility studies of interventions for paediatric suspected severe infection., Design: Qualitative synthesis combining parent interview data from the Fluids in Shock (FiSh) and Fever feasibility studies. Parents had experience of their child being admitted to a UK emergency department or intensive care unit with a suspected infection., Participants: n=: 85 parents. FiSh study: n=41 parents, 37 mothers, 4 fathers, 7 were bereaved. Fever study: n=44 parents, 33 mothers, 11 fathers, 7 were bereaved., Results: In addition to survival, parents prioritised short-term outcomes including: organ and physiological functioning (eg, heart rate, breathing rate and temperature); their child looking and/or behaving more like their normal self; and length of time on treatments or mechanical support. Longer term prioritised outcomes included effects of illness on child health and development. We found that parents' prioritisation of outcomes was influenced by their experience of their child's illness, survival and the point at which they are asked about outcomes of importance in the course of their child's illness., Conclusions: Findings provide insight into parent prioritised outcomes to inform the design of future trials investigating treatments for paediatric suspected or proven severe infection as well as core outcome set development work., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Respiratory viruses other than rhinovirus or respiratory syncytial virus, including human metapneumovirus, influenza virus, and human bocavirus, are important pathogens in acute wheezing illness and asthma exacerbations in young children. Whether infection with these viruses in early life is associated with recurrent wheezing and/or asthma is not fully investigated, although there are data to suggest children with human metapneumovirus lower respiratory tract infection may have a higher likelihood of subsequent and recurrent wheezing several years after initial infection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/aim: The aim of this study was to determine the accuracy of severity scores for predicting the 28-day mortality among adults with severe acute respiratory infection (SARI) admitted to the emergency department., Materials and Methods: This study included 159 consecutive adult patients with SARI admitted to the emergency department of a tertiary hospital. A standard form was filled out in order to record demographic information, clinical parameters, laboratory tests, and radiographic findings of the patients. CURB-65, PSI, SIRS, qSOFA, SOFA and APACHE II scores were compared between the survivor and nonsurvivor groups., Results: Of 159 patients included in the study, 38.4% were positive for respiratory viruses and 28.3% were positive for influenza viruses. 35.8% of the patients were admitted to an intensive care unit (ICU) and the mortality rate was 36.5%. The area under the receiver operating characteristic curve of CURB-65, PSI, SIRS criteria, qSOFA, SOFA and APACHE II scores were 0.717, 0.712, 0.607, 0.683, 0.755, and 0.748, respectively in predicting mortality and 0.759, 0.744, 0.583, 0.728, 0.741, and 0.731, respectively in predicting ICU admission., Conclusion: SOFA and APACHE II were more accurate than SIRS in predicting the 28-day mortality among adults with SARI. There was no significant difference among these scores in terms of other multivariate comparisons., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

In this study, ridgetail white prawns- Exopalaemon carinicauda -were infected per os (PO) with debris of Penaeus vannamei infected with shrimp hemocyte iridescent virus (SHIV 20141215), a strain of decapod iridescent virus 1 (DIV1), and via intramuscular injection (IM with raw extracts of SHIV 20141215. The infected E. carinicauda showed obvious clinical symptoms, including weakness, empty gut and stomach, pale hepatopancreas, and partial death with mean cumulative mortalities of 42.5% and 70.8% by nonlinear regression, respectively. Results of TaqMan probe-based real-time quantitative PCR showed that the moribund and surviving individuals with clinical signs of infected E. carinicauda were DIV1-positive. Histological examination showed that there were darkly eosinophilic and cytoplasmic inclusions, of which some were surrounded with or contained tiny basophilic staining, and pyknosis in hemocytes in hepatopancreatic sinus, hematopoietic cells, cuticular epithelium, etc. On the slides of in situ DIG-labeling-loop-mediated DNA amplification (ISDL), positive signals were observed in hematopoietic tissue, stomach, cuticular epithelium, and hepatopancreatic sinus of infected prawns from both PO and IM groups. Transmission electron microscopy (TEM) of ultrathin sections showed that icosahedral DIV1 particles existed in hepatopancreatic sinus and gills of the infected E. carinicauda from the PO group. The viral particles were also observed in hepatopancreatic sinus, gills, pereiopods, muscles, and uropods of the infected E. carinicauda from the IM group. The assembled virions, which mostly distributed along the edge of the cytoplasmic virogenic stromata near cellular membrane of infected cells, were enveloped and approximately 150 nm in diameter. The results of molecular tests, histopathological examination, ISDL, and TEM confirmed that E. carinicauda is a susceptible host of DIV1. This study also indicated that E. carinicauda showed some degree of tolerance to the infection with DIV1 per os challenge mimicking natural pathway.

It has been reported that B7H1 and B7H3 play a role in graft-versus-host disease (GVHD), the major cause of treatment-related mortality (TRM) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) patients; however, the prognostic value of these factors has not been defined. We retrospectively collected 64 haplo-HSCT patients in our hospital from 2013 to 2014, as well as 38 HLA-matched-HSCT patients during the same period as the control group. We analyzed B7H1, B7H3, PD1, soluble CD25, ST2 and TNFR1 at 0 day, + 7 days, + 14 days and + 28 days after HSCT. The + 7 days/+ 14 days B7H1/B7H3 and + 28 days ST2 serum levels were higher in patients with aGVHD who underwent haplo-HSCT. Moreover, + 7 days B7H1/B7H3 serum levels were predictive of grade III-IV aGVHD (B7H1: AUC = 0.830, P < 0.001; B7H3: AUC = 0.775, P = 0.001). Haplo-HSCT patients with higher + 7 days B7H1/B7H3 or + 28 days ST2 serum levels had poor GVHD-related mortality (GRM) (B7H1: P < 0.001; B7H3: P = 0.002; ST2: P = 0.047). Multivariate analysis revealed that the + 7 days B7H1 serum level (P = 0.041), as well as viral infection (P = 0.015) and donor age (P = 0.012), could independently predict GRM. Collectively, we found that + 7 days B7H1/B7H3 serum levels can predict grade III-IV aGVHD, while only the + 7 days B7H1 serum level, together with viral infection and donor age, could independently predict GRM in patients with haplo-HSCT.

There is a paucity of studies examining the relation between high psychological distress and infectious disease in the general population. We examined this association in a large multi-cohort study drawn from the general population. The analytic sample comprised 104,923 men and women (age, 47.3 ± 17.4 year; 45.7% men) in which psychological distress symptoms was assessed using the 12-item version of the General Health Questionnaire. There were 1535 deaths attributed to infectious diseases during 971,220 person-years of follow up (mean 9.3; range 0.1-17.1 years). A dose-response association between GHQ-12 score and all infectious disease mortality was observed after adjusting for age, sex, survey year, occupational social class, longstanding illness, smoking, alcohol, and physical activity (per SD increase, hazard ratio = 1.24; 95% CI, 1.20-1.28). A similar pattern was apparent for viral infections (1.23; 1.14, 1.33) and pneumonia (1.20; 1.13, 1.28), but weaker for bacterial infections (1.09; 1.00, 1.19). In conclusion, psychological distress is associated with higher risk of infectious disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Respiratory virus infections (RVIs) pose a threat to children undergoing hematopoietic stem cell transplantation (HSCT). In this era of sensitive molecular diagnostics, the incidence and outcome of HSCT recipients who are hospitalized with RVI (H-RVI) are not well described., Methods: A retrospective observational cohort of pediatric HSCT recipients (between January 2010 and June 2013) was assembled from 9 US pediatric transplant centers. Their medical charts were reviewed for H-RVI events within 1 year after their transplant. An H-RVI diagnosis required respiratory signs or symptoms plus viral detection (human rhinovirus/enterovirus, human metapneumovirus, influenza, parainfluenza, coronaviruses, and/or respiratory syncytial virus). The incidence of H-RVI was calculated, and the association of baseline HSCT factors with subsequent pulmonary complications and death was assessed., Results: Among 1560 HSCT recipients, 259 (16.6%) acquired at least 1 H-RVI within 1 year after their transplant. The median age of the patients with an H-RVI was lower than that of patients without an H-RVI (4.8 vs 7.1 years; P < .001). Among the patients with a first H-RVI, 48% required some respiratory support, and 14% suffered significant pulmonary sequelae. The all-cause and attributable case-fatality rates within 3 months of H-RVI onset were 11% and 5.4%, respectively. Multivariate logistic regression revealed that H-RVI onset within 60 days of HSCT, steroid use in the 7 days before H-RVI onset, and the need for respiratory support at H-RVI onset were associated with subsequent morbidity or death., Conclusion: Results of this multicenter cohort study suggest that H-RVIs are relatively common in pediatric HSCT recipients and contribute to significant morbidity and death. These data should help inform interventional studies specific to each viral pathogen.

Pathogen burden is a construct developed to assess the cumulative effects of multiple, persistent pathogens on morbidity and mortality. Despite the likely biological wear and tear on multiple body systems caused by persistent infections, few studies have examined the impact of total pathogen burden on such outcomes and specifically on preclinical markers of dysfunction. Using data from two waves of the National Health and Nutrition Examination Survey, we compared three alternative methods for measuring pathogen burden, composed of mainly persistent viral infections, using a cumulative deficits index (CDI) as an outcome: single pathogen associations, a pathogen burden summary score and latent class analyses. We found significant heterogeneity in the distribution of the CDI by age, sex, race/ethnicity and education. There was an association between pathogen burden and the CDI by all three metrics. The latent class classification of pathogen burden showed particularly strong associations with the CDI; these associations remained after controlling for age, sex, body mass index, smoking, race/ethnicity and education. Our results suggest that pathogen burden may influence early clinical indicators of poor health as measured by the CDI. Our results are salient since we were able to detect these associations in a relatively young population. These findings suggest that reducing pathogen burden and the specific pathogens that drive the CDI may provide a target for preventing the early development of age-related physiological changes.

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 provides an up-to-date analysis of the burden of diarrhoea in 195 countries. This study assesses cases, deaths, and aetiologies in 1990-2016 and assesses how the burden of diarrhoea has changed in people of all ages., Methods: We modelled diarrhoea mortality with a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We modelled diarrhoea incidence with a compartmental meta-regression tool that enforces an association between incidence and prevalence, and relies on scientific literature, population representative surveys, and health-care data. Diarrhoea deaths and episodes were attributed to 13 pathogens by use of a counterfactual population attributable fraction approach. Diarrhoea risk factors are also based on counterfactual estimates of risk exposure and the association between the risk and diarrhoea. Each modelled estimate accounted for uncertainty., Findings: In 2016, diarrhoea was the eighth leading cause of death among all ages (1 655 944 deaths, 95% uncertainty interval [UI] 1 244 073-2 366 552) and the fifth leading cause of death among children younger than 5 years (446 000 deaths, 390 894-504 613). Rotavirus was the leading aetiology for diarrhoea mortality among children younger than 5 years (128 515 deaths, 105 138-155 133) and among all ages (228 047 deaths, 183 526-292 737). Childhood wasting (low weight-for-height score), unsafe water, and unsafe sanitation were the leading risk factors for diarrhoea, responsible for 80·4% (95% UI 68·2-85·0), 72·1% (34·0-91·4), and 56·4% (49·3-62·7) of diarrhoea deaths in children younger than 5 years, respectively. Prevention of wasting in 1762 children (95% UI 1521-2170) could avert one death from diarrhoea., Interpretation: Substantial progress has been made globally in reducing the burden of diarrhoeal diseases, driven by decreases in several primary risk factors. However, this reduction has not been equal across locations, and burden among adults older than 70 years requires attention., Funding: Bill & Melinda Gates Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Lower respiratory infections are a leading cause of morbidity and mortality around the world. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, provides an up-to-date analysis of the burden of lower respiratory infections in 195 countries. This study assesses cases, deaths, and aetiologies spanning the past 26 years and shows how the burden of lower respiratory infection has changed in people of all ages., Methods: We used three separate modelling strategies for lower respiratory infections in GBD 2016: a Bayesian hierarchical ensemble modelling platform (Cause of Death Ensemble model), which uses vital registration, verbal autopsy data, and surveillance system data to predict mortality due to lower respiratory infections; a compartmental meta-regression tool (DisMod-MR), which uses scientific literature, population representative surveys, and health-care data to predict incidence, prevalence, and mortality; and modelling of counterfactual estimates of the population attributable fraction of lower respiratory infection episodes due to Streptococcus pneumoniae, Haemophilus influenzae type b, influenza, and respiratory syncytial virus. We calculated each modelled estimate for each age, sex, year, and location. We modelled the exposure level in a population for a given risk factor using DisMod-MR and a spatio-temporal Gaussian process regression, and assessed the effectiveness of targeted interventions for each risk factor in children younger than 5 years. We also did a decomposition analysis of the change in LRI deaths from 2000-16 using the risk factors associated with LRI in GBD 2016., Findings: In 2016, lower respiratory infections caused 652 572 deaths (95% uncertainty interval [UI] 586 475-720 612) in children younger than 5 years (under-5s), 1 080 958 deaths (943 749-1 170 638) in adults older than 70 years, and 2 377 697 deaths (2 145 584-2 512 809) in people of all ages, worldwide. Streptococcus pneumoniae was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more deaths than all other aetiologies combined in 2016 (1 189 937 deaths, 95% UI 690 445-1 770 660). Childhood wasting remains the leading risk factor for lower respiratory infection mortality among children younger than 5 years, responsible for 61·4% of lower respiratory infection deaths in 2016 (95% UI 45·7-69·6). Interventions to improve wasting, household air pollution, ambient particulate matter pollution, and expanded antibiotic use could avert one under-5 death due to lower respiratory infection for every 4000 children treated in the countries with the highest lower respiratory infection burden., Interpretation: Our findings show substantial progress in the reduction of lower respiratory infection burden, but this progress has not been equal across locations, has been driven by decreases in several primary risk factors, and might require more effort among elderly adults. By highlighting regions and populations with the highest burden, and the risk factors that could have the greatest effect, funders, policy makers, and programme implementers can more effectively reduce lower respiratory infections among the world's most susceptible populations., Funding: Bill & Melinda Gates Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The metabolite-sensing G protein-coupled receptors (GPCRs) bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. However, the roles of metabolite-sensing GPCRs in viral infection are not well characterized. Here, we identified metabolite-sensing GPCR TGR5 as an interferon (IFN)-stimulated gene (ISG) which had increased expression following viral infection or IFN-β stimulation in a STAT1-dependent manner. Most importantly, overexpression of TGR5 or treatment with the modified bile acid INT-777 broadly protected host cells from vesicular stomatitis virus (VSV), newcastle disease virus (NDV) and herpes simplex virus type 1 (HSV-1) infection. Furthermore, VSV and HSV-1 replication was increased significantly in Tgr5 -deficient macrophages and the VSV distribution in liver, spleen and lungs was increased in Tgr5 -deficient mice during VSV infection. Accordingly, Tgr5 -deficient mice were much more susceptible to VSV infection than wild-type mice. Mechanistically, TGR5 facilitates type I interferon (IFN-I) production through the AKT/IRF3-signaling pathway, which is crucial in promoting antiviral innate immunity. Taken together, our data reveal a positive feedback loop regulating IRF3 signaling and suggest a potential therapeutic role for metabolite-sensing GPCRs in controlling viral diseases.

Introduction: Our objectives are to (1) describe the pathogens, site, timing and risk factors for acquired infection during neonatal and pediatric ECMO and (2) explore the association between acquired infection and mortality., Methods: Secondary analysis of prospective data collected by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. Clinical factors associated with acquired infection were assessed with multivariable Cox regression. Factors associated with mortality were assessed with logistic regression., Results: Of 481 patients, 247 (51.3%) were neonates and 400 (83.2%) received venoarterial ECMO. Eighty (16.6%) patients acquired one or more infections during ECMO; 60 (12.5%) patients had bacterial, 21 (4.4%) had fungal and 11 (2.3%) had viral infections. The site of infection included respiratory for 53 (11.0%) patients, bloodstream for 21 (4.4%), urine for 20 (4.2%) and other for 7 (1.5%). Candida species were most common. Median time to infection was 5.2 days (IQR 2.3, 9.6). On multivariable analysis, a greater number of procedures for ECMO cannula placement was independently associated with increased risk of acquired infection during ECMO (Hazard Ratio 2.13 (95% CI 1.22, 3.72), p<0.01) and receiving ECMO in a neonatal ICU compared to a pediatric or cardiac ICU was associated with decreased risk (Hazard Ratio pediatric ICU 4.25 (95% CI 2.20, 8.20), cardiac ICU 2.91 (95% CI 1.48, 5.71), neonatal ICU as reference, p<0.001). Acquired infection was not independently associated with mortality., Conclusion: ECMO procedures and location may contribute to acquired infection risk; however, acquired infection did not predict mortality in this study.

Death due to infectious diseases is a major health concern worldwide. This is of particular concern in developing countries where poor-socio economic status and a lack of healthcare resources contribute to the high burden of disease. In some cases death due to infection can be acute and aggressive, and death may occur without a diagnosis whilst the person is still alive. These deaths may ultimately lead to a medico-legal autopsy being performed. There are various mechanisms by which sudden death due to infection may occur. In addition, there are many risk factors associated with sudden death due to infection, which differ between infants and older individuals. However, it is unclear which pathogens and risk factors are most frequently associated with sudden death due to infection. Therefore a systematic review of articles and case reports published between 1 January 2000 and 30 June 2016 was undertaken in order to (1) explore the relationship between pathogens and their causative role and (2) identify the relationship between predisposing and/or risk factors associated with sudden death due to infection. Major databases were searched and after critical appraisal 143 articles were identified. It was found that respiratory infections and deaths involving bacterial pathogens were most commonly associated with these deaths. In addition the most common risk factors in infants were exposure to tobacco smoke and co-sleeping. In adults the most common risk factors were co-morbid conditions and illnesses. This information aids in a better understanding of these deaths and highlights the need for more research in this field, particularly in developing countries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia., Methods: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples., Findings: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs., Interpretation: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal., Funding: Bill & Melinda Gates Foundation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Tick-borne encephalitis (TBE) is the main tick-borne viral infection in Eurasia. Its manifestations range from inapparent infections and fevers with complete recovery to debilitating or fatal encephalitis. The basis of this heterogeneity is largely unknown, but part of this variation is likely due to host genetic. We have previously found that BALB/c mice exhibit intermediate susceptibility to the infection of TBE virus (TBEV), STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, carrying 12.5% of the STS genome on the background of the BALB/c genome is even more susceptible than BALB/c. Importantly, mouse orthologs of human TBE controlling genes Oas1b, Cd209, Tlr3, Ccr5, Ifnl3 and Il10, are in CcS-11 localized on segments derived from the strain BALB/c, so they are identical in BALB/c and CcS-11. As they cannot be responsible for the phenotypic difference of the two strains, we searched for the responsible STS-derived gene-locus. Of course the STS-derived genes in CcS-11 may operate through regulating or epigenetically modifying these non-polymorphic genes of BALB/c origin., Methods: To determine the location of the STS genes responsible for susceptibility of CcS-11, we analyzed survival of TBEV-infected F 2 hybrids between BALB/c and CcS-11. CcS-11 carries STS-derived segments on eight chromosomes. These were genotyped in the F 2 hybrid mice and their linkage with survival was tested by binary trait interval mapping. We have sequenced genomes of BALB/c and STS using next generation sequencing and performed bioinformatics analysis of the chromosomal segment exhibiting linkage with TBEV survival., Results: Linkage analysis revealed a novel suggestive survival-controlling locus on chromosome 7 linked to marker D7Nds5 (44.2 Mb). Analysis of this locus for polymorphisms between BALB/c and STS that change RNA stability and genes' functions led to detection of 9 potential candidate genes: Cd33, Klk1b22, Siglece, Klk1b16, Fut2, Grwd1, Abcc6, Otog, and Mkrn3. One of them, Cd33, carried a nonsense mutation in the STS strain., Conclusions: The robust genetic system of recombinant congenic strains of mice enabled detection of a novel suggestive locus on chromosome 7. This locus contains 9 candidate genes, which will be focus of future studies not only in mice but also in humans.