Search

International audience; Background: Besides the prototypical hepatitis B virus (HBV) infectious particle, which contains a full-length double-stranded DNA (flDNA), additional circulating virus-like particles, which carry pregenomic RNA (pgRNA), spliced1RNA (sp1RNA) or spliced-derived DNA (defDNA) forms have been described. We aimed to determine the level of these four circulating forms in patients and to evaluate their impact on viral lifecycle.Methods: Chronic HBV untreated patients (n = 162), included in the HEPATHER cohort, were investigated. Pangenomic qPCRs were set up to quantify the four circulating forms of HBV nucleic acids (HBVnaf). In vitro infection assays were performed to address the impact of HBVnaf.Results: Hierarchical clustering individualized two clusters of HBVnaf diversity among patients: (1) cluster 1 (C1) showing a predominance of flDNA; (2) cluster 2 (C2) showing various proportions of the different forms. HBeAg-positive chronic hepatitis phase and higher viral load (7.0 ± 6.4 vs 6.6 ± 6.2 Log10 copies/ml; p < 0.001) characterized C2 compared to C1 patients. Among the different HBVnaf, pgRNA was more prevalent in C1 patients with high vs low HBV viral load (22.1% ± 2.5% vs 4.1% ± 1.8% of HBVnaf, p < 0.0001) but remained highly prevalent in C2 patients, whatever the level of replication. C2 patients samples used in infection assays showed that: (1) HBVnaf secretion was independent of the viral strain; (2) the viral cycle efficiency differed according to the proportion of HBVnaf in the inoculum, independently of cccDNA formation. Inoculum enrichment before infection suggests that pgRNA-containing particles drive this impact on viral replication.Conclusion: Besides the critical role of HBV replication in circulating HBVnaf diversity, our data highlight an impact of this diversity on the dynamics of viral cycle.Clinical trial registration: Patients were included from a prospective multicenter French national cohort (ANRS CO22 HEPATHER, NCT01953458).

BackgroundStaphylococcus aureus dominates the lung microbiota of children with cystic fibrosis (CF) and persistent clones are able to establish chronic infection for years, having a direct deleterious impact on lung function. However, in this context, the exact contribution of S. aureus to the decline in respiratory function in children with CF is not elucidated.MethodsTo investigate the contribution of persistent S. aureus clones in CF disease, we undertook the analysis of sequential isogenic isolates recovered from 15 young CF patients.ResultsUsing an air-liquid infection model, we observed a strong correlation between S. aureus adaption in the lung (late isolates), low toxicity, and proinflammatory cytokine secretion. Conversely, early isolates appeared to be highly cytotoxic but did not promote cytokine secretion. We found that cytokine secretion was dependent on staphylococcal protein A (Spa), which was selectively expressed in late compared to early isolates as a consequence of dysfunctional agr quorum-sensing system. Finally, we demonstrated the involvement of TNF-α receptor 1 signaling in the inflammatory response of airway epithelial cells to these lung-adapted S. aureus isolates.ConclusionsOur results suggest an unexpected direct role of bacterial lung adaptation in the progression of chronic lung disease by promoting a proinflammatory response through acquired agr dysfunction.

Activation and viral control of the innate immune response are hallmarks of hepatitis C virus (HCV) infection and are major determinants of spontaneous clearance or progression to chronic infection and liver disease. In this review, we provide a contemporary overview of how HCV is sensed by the host cell to trigger innate immune activation and the mechanisms deployed by the virus to evade this response. Type I and III interferons (IFNs) are crucial mediators of antiviral innate immunity against HCV, and we specifically highlight the importance of IFN-λ host genetics for the outcome of HCV infection. Last, we focus on the proinflammatory responses elicited by HCV infection and describe our current understanding of how interleukin (IL)-1β signaling and cross talk between the IL-1β and IFN signaling pathways lead to sustained inflammation and increased risk of liver pathology.

Background: Although surgical stabilization for rib fractures (SSRF) has been adopted widely over the past decade, little information is available regarding the prevalence and outcomes of post-operative surgical site infection (SSI). We hypothesized that SSI after SSRF is uncommon but morbid. Patients and Methods: Patients undergoing SSRF at a level 1 trauma center from 2010-2020 were reviewed. The primary outcome was the prevalence of SSI, documented by clinical examination, radiography, systemic markers of infection, and microbiology. Results: Of 228 patients undergoing SSRF, 167 (73.2%) were male, the median age was 53 years (P25-P75; 41-63 years), injury severity score (ISS) was 19 (P25-P75, 13-26), with a median of eight fractured ribs (P25-P75, 6-11). All stabilization plates were titanium. SSRF was typically performed on post-injury day one (P25-P75, 0-2 days) after trauma. All patients received antibiotic agents within 30 minutes of incision, and a median of four ribs (P25-P75, 3-6) were repaired. Four (1.8%) patients developed an SSI and all underwent implant removal. Two patients required implant removal within 30 days (on post-operative day seven and 17) and two for chronic infection at seven and 17 months after SSRF. The causative organism was methicillin-sensitive Staphylococcus aureus (MSSA) bacteria in all patients. After implant removal, three patients received intravenous and oral antibiotic agents, ranging from two to six weeks, without recurrent infection. No patient required additional SSRF. Conclusions: Surgical site infection after SSRF is rare but morbid and can become symptomatic within one week to 17 months. Implant removal results in complete recovery.

Objective: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. Methods: Four cohortswith participantswhoinitiatedARTduring acute infection or during chronic infectionwere enrolled in a cross-sectional, noninterventional study.Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIVDNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. Results: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. Conclusion: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.

Background Norovirus (NoV) infection frequently progresses to chronic disease after kidney transplant (KTx). This study aims to assess potential risk factors helping to determine patients at risk of chronic NoV infection and to analyse the effect of NoV on allograft outcome. Additionally, we assessed the effectiveness of intravenous immunoglobulin (IVIg) therapy for chronic NoV infection. Methods The study enrolled 60 KTx patients requiring hospitalization because of NoV infection. Clinical parameters, severity of NoV infection and potential risk factors were evaluated. Outcome parameters were clinical symptoms, rehospitalizations, persistent shedding of virus and effects on allograft function. Results Patients were divided into 2 groups: 29 had acute NoV infection only, 31 progressed to chronic NoV infection. Chronic NoV infection was defined as a recurrence of clinical symptoms plus redetection of NoV in stool. Lymphocyte-depleting induction therapy and diabetes mellitus were independent risk factors for chronic infection. For patients with chronic NoV infection, length of stay in hospital was significantly prolonged (p= 0.024). Allograft function remained impaired in the chronic NoV group 6 and 12 months after initial admission.IVIg was administered to 18 patients with chronic NoV infection. No further clinical symptoms of NoV infection occurred in 13 (72%) of these patients. However, NoV was still detectable in stool specimens from 10 (77%) of these patients. Conclusions Chronic NoV infection is associated with reduced allograft function. Administration of IVIg to patients with chronic NoV infection seems beneficial in achieving freedom from clinical symptoms, despite limited effects on shedding of virus.

BACKGROUND: Periprosthetic shoulder infection (PSI) remains a devastating complication after reverse shoulder arthroplasty (RSA). Currently, scientific data related to the management of PSI are limited, and the optimal strategy and related clinical outcomes remain unclear. Guidelines from the Infectious Diseases Society of America for the management of periprosthetic joint infection are mainly based on data from patients after hip and knee arthroplasty. The aim of this study was to evaluate whether these guidelines are also valid for patients with PSI after RSA. In addition, the functional outcome according to the surgical intervention was assessed. METHODS: An RSA database was retrospectively reviewed to identify infections after primary and revision RSAs, diagnosed between 2004 and 2018. Data collected included age, sex, indication for RSA, causative pathogen, surgical and antimicrobial treatment, functional outcome, and recurrence. RESULTS: Thirty-six patients with a PSI were identified. Surgical treatment was subdivided into débridement and implant retention (DAIR) (n = 6, 17%); 1-stage revision (n = 1, 3%); 2-stage revision (n = 16, 44%); multiple-stage revision (>2 stages) (n = 7, 19%); definitive spacer implantation (n = 2, 6%); and resection arthroplasty (n = 4, 11%). The most common causative pathogens were Staphylococcus epidermidis (n = 11, 31%) and Cutibacterium acnes (n = 9, 25%). Recurrence was diagnosed in 4 patients (11%), all of whom were initially treated with a DAIR approach. The median follow-up period was 36 months (range, 24-132 months). CONCLUSION: PSI is typically caused by low-virulence pathogens, which often are diagnosed with a delay, resulting in chronic infection at the time of surgery. Our results indicate that treatment of patients with chronic PSI with DAIR has a high recurrence rate. In addition, implant exchange (ie, 1- and 2-stage exchange) does not compromise the functional result as compared with implant retention. Thus, patients with chronic PSI should be treated with implant exchange. Future research should further clarify which surgical strategy (ie, 1-stage vs. 2-stage exchange) has a better outcome overall. ispartof: JOURNAL OF SHOULDER AND ELBOW SURGERY vol:30 issue:11 pages:2514-2522 ispartof: location:United States status: published

Chagas disease is a neglected parasitosis caused by the protozoan parasite Trypanosoma cruzi. This infection is present in most Latin American countries, although, due to migratory movements, it is a growing cause for concern in non-endemic countries. The only two drugs currently available for its treatment-benznidazole and nifurtimox-were marketed 50 years ago. While they are very effective for acute and recent infection, and for the prevention of maternofoetal transmission, their efficacy declines in people who have chronic infection, especially those older than 18 years of age. In the presence of visceral involvement, parasiticidal treatment is of little or no value. The safety profile of both drugs is far from ideal, with frequent adverse events and high rates of drug discontinuation, mainly in adults. So far, new drugs and new strategies have not been shown to improve the results of the current nitroimidazoles, although the results are promising. In this review, we focus on the aspects that allow clinicians to make the best use of currently available drugs. In addition, we discuss new therapeutic options and ongoing research in the field.

The introduction of clotting factor concentrates has substantially improved the lives of people with clotting factor deficiencies. Unfortunately, the transmission of blood-borne viral infections through these plasma-derived products led to a huge epidemic of human immunodeficiency virus and viral hepatitis in people with haemophilia (PWH). In a significant proportion of PWH exposed to these viruses, the ensuing decades-long chronic infection resulted in excess morbidity and mortality. Fortunately, developments in the safety of blood products, as well as vaccination and highly effective antiviral treatments have improved the prospects of PWH. The present article reviews the background of the viral hepatitis epidemic in PWH, the natural history of hepatitis B and C infections and their long-term management.

Hepatitis C virus (HCV) chronic infection is associated with fibrosis progression, end-stage liver complications and HCC. Not surprisingly, HCV infection is a leading cause of liver-related morbidity and mortality worldwide. After sustained virological response (SVR), the risk of developing hepatocellular carcinoma is not completely eliminated in patients with established cirrhosis or with advanced fibrosis. Therefore, lifelong surveillance is currently recommended. This strategy is likely not universally cost-effective and harmless, considering that not all patients with advanced fibrosis have the same risk of developing HCC. Factors related to the severity of liver disease and its potential to improve after SVR, the molecular and epigenetic changes that occur during infection and other associated comorbidities might account for different risk levels and are likely essential for identifying patients who would benefit from screening programs after SVR. Efforts to develop predictive models and risk calculators, biomarkers and genetic panels and even deep learning models to estimate the individual risk of HCC have been made in the direct-acting antiviral agents era, when thousands of patients with advanced fibrosis and cirrhosis have reached SVR. These tools could help to identify patients with very low HCC risk in whom surveillance might not be justified. In this review, factors affecting the probability of HCC development after SVR, the benefits and risks of surveillance, suggested strategies to estimate individualized HCC risk and the current evidence to recommend lifelong surveillance are discussed.

Indications for pulmonary lobectomy in infants and children include cystic pulmonary adenomatoid malformation, congenital lobar emphysema, chronic infection, and malignancy. These procedures can now all be done thoracoscopically avoiding the short- and long-term morbidity of an open thoracotomy. In this article we describe the technique of thoracoscopic lobectomy as well as the preoperative and postoperative care.

Serum hepatitis B core antibody (anti-HBc) is associated with liver inflammation in chronic hepatitis B patients. This study aimed to investigate whether anti-HBc could serve as a predictor of significant liver inflammation in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infected patients with normal alanine aminotransferase (ALT) and detectable HBV DNA. Treatment-naive HBeAg-negative chronic HBV infected patients with normal ALT and detectable HBV DNA who underwent liver biopsy were retrospectively included from two medical centers. Liver inflammation grade was evaluated using the Scheuer scoring system and significant liver inflammation was defined as ≥G2. Serum anti-HBc levels were measured by commercial immunoassays (Abbott GmbH & Co. KG). A total of 117 patients were included and 50 (42.7%) patients showed significant liver inflammation. Serum anti-HBc levels in patients with significant liver inflammation were significantly higher than patients with no or mild liver inflammation (

Background Coccidioidomycosis is a systemic infection caused by dimorphic fungi Coccidioides spp. endemic to Southwestern United States and Central and South America. A history of residence and travel in these areas is essential for the diagnostic of coccidioidomycosis, which has highly variable symptoms ranging from asymptomatic to severe, disseminated infection, and even death. Immunocompromised patients of coccidioidomycosis experience a high risk of dissemination, chronic infection, and mortality. Meningitis is one of the most deleterious coccidioidomycosis and can cause various life-threatening complications. Case presentation Here we report a case of Coccidioides posadasii meningitis in a 49-year-old female who returned to China after one and a half years residence in Los Angeles, USA. The repeated routine cultures using CSF for bacteria or fungi were all negative. To hunt for an infectious etiology, the state-of-the-art technology metagenomic next-generation sequencing (mNGS) was then utilized, suggesting Coccidioides posadasii. Organizational pathological examination and polymerase-chain-reaction (PCR) results subsequently confirmed the mNGS detection. Conclusion To our knowledge, cases for coccidioidal meningitis have been rarely reported in China. While global travelling may spread this disease across continents and make the diagnosis more difficult. mNGS can detect almost all known pathogens with high sensitivity and specificity, especially for uncommon pathogen, such as Coccidioides posadasii in China.

Staphylococcus aureus – a major aetiological agent of bone and joint infection (BJI) – is associated with a high risk of relapse and chronicity, in part due to its ability to invade and persist in non-professional phagocytic bone cells such as osteoblasts. This intracellular reservoir protects S. aureus from the action of the immune system and most antibiotics. To date, the choice of antimicrobial strategies for BJI treatment mostly relies on standard susceptibility testing, bone penetration of antibiotics and their ‘antibiofilm’ activity. Despite the role of intracellular persistent S. aureus in the development of chronic infection, the ability of antibiotics to target the S. aureus intraosteoblastic reservoir is not considered in therapeutic choices but might represent a key determinant of treatment outcome. This review provides an overview of the intracellular pharmacokinetics of antistaphylococcal drugs used in the treatment of BJI and of their ability to target intraosteoblastic S. aureus. Thirteen studies focusing on the intraosteoblastic activity of antibiotics against S. aureus were reviewed, all relying on in vitro models of osteoblast infection. Despite varying incubation times, multiplicities of infection, bacterial strains, and the types of infected cell lines, rifamycins and fluoroquinolones remain the two most potent antimicrobial classes for intraosteoblastic S. aureus eradication, consistent with clinical data showing a superiority of this combination therapy in S. aureus orthopaedic device-related infections.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is usually a latent and asymptomatic malignancy caused by different aetiologies, which is a result of various aberrant molecular heterogeneity and often diagnosed at advanced stages. The incidence and prevalence have significantly increased because of sedentary lifestyle, diabetes, chronic infection with hepatotropic viruses and exposure to aflatoxins. Due to advanced intra‐ or extrahepatic metastasis, recurrence is very common even after radical resection. In this paper, we highlighted novel therapeutic modalities, such as molecular‐targeted therapies, targeted radionuclide therapies and epigenetic modification‐based therapies. These topics are trending headlines and their combination with cell‐based immunotherapies, and gene therapy has provided promising prospects for the future of HCC treatment. Moreover, a comprehensive overview of current and advanced therapeutic approaches is discussed and the advantages and limitations of each strategy are described. Finally, very recent and approved novel combined therapies and their promising results in HCC treatment have been introduced.

Hepatitis B virus (HBV) causes chronic infections that are associated with immune dysfunction. Though T cell impairment is perhaps the most prominent immune change contributing to viral persistence, HBV interaction with the innate immune system is also likely key, as the lack of effective innate immunity has functional consequences that promote chronic infection. In addition to an intrinsic ability to fight viral infections, the innate immune system also impacts T cell responses and other adaptive immune mechanisms critical for HBV control. Therefore, it is essential to understand the relationships between HBV and innate immunity, as these interactions may be useful immunotherapeutic targets to manage the infection.

Hepatitis B virus (HBV) chronically infects 257 million people and is one of the most important liver diseases worldwide. A unique feature of HBV infection in humans is that viral clearance heavily depends on the age at exposure. Recent studies demonstrated that the virus takes advantage of immature innate immunity, especially hepatic macrophages, and not-yet-stabilized gut microbiota in early life to establish a chronic infection. The liver contains resident and infiltrating myeloid cells involved in immune responses to pathogens. They influence both innate and adaptive sectors of the immune system and their interplay with HBV has only been noticed recently. Here, we discuss how interactions between gut microbiota and hepatic macrophages influence the outcomes of HBV infection. Understanding the underlying mechanism would pave the way for the treatment of chronic HBV infection.

Phytochemicals are promising antibacterials for the development of novel antibiofilm drugs, but their antibiofilm activity in physiologically relevant model systems is poorly characterized. As the host microenvironment can interfere with the activity of the phytochemicals, mimicking the complex environment found in biofilm associated infections is essential to predict the clinical potential of novel phytochemical-based antimicrobials. In the present study, we examined the antibiofilm activity of borneol, citral, and combinations of both as well as their Pickering emulsions against Staphylococcus aureus and Pseudomonas aeruginosa in an in vivo-like synthetic cystic fibrosis medium (SCFM2) model, an in vitro wound model (consisting of an artificial dermis and blood components at physiological levels), and an in vivo Galleria mellonella model. The Pickering emulsions demonstrated an enhanced biofilm inhibitory activity compared to both citral and the borneol/citral combination, reducing the minimum biofilm inhibitory concentration (MBIC) values up to 2 to 4 times against P. aeruginosa PAO1 and 2 to 8 times against S. aureus P8-AE1 in SCMF2. In addition, citral, the combination borneol/citral, and their Pickering emulsions can completely eliminate the established biofilm of S. aureus P8-AE1. The effectiveness of Pickering emulsions was also demonstrated in the wound model with a reduction of up to 4.8 log units in biofilm formation by S. aureus Mu50. Furthermore, citral and Pickering emulsions exhibited a significant degree of protection against S. aureus infection in the G. mellonella model. The present findings reveal the potential of citral- or borneol/citral-based Pickering emulsions as a type of alternative antibiofilm candidate to control pathogenicity in chronic infection. IMPORTANCE There is clearly an urgent need for novel formulations with antimicrobial and antibiofilm activity, but while there are plenty of studies investigating them using simple in vitro systems, there is a lack of studies in which (combinations of) phytochemicals are evaluated in relevant models that closely resemble the in vivo situation. Here, we examined the antibiofilm activity of borneol, citral, and their combination as well as Pickering emulsions (stabilized by solid particles) of these compounds. Activity was tested against Staphylococcus aureus and Pseudomonas aeruginosa in in vitro models mimicking cystic fibrosis sputum and wounds as well as in an in vivo Galleria mellonella model. The Pickering emulsions showed drastically increased antibiofilm activity compared to that of the compounds as such in both in vitro models and protected G. mellonella larvae from S. aureus-induced killing. Our data show that Pickering emulsions from phytochemicals are potentially useful for treating specific biofilm-related chronic infections.

BACKGROUND: This study sought to evaluate the effectiveness of locally developed external fixators (LDEF) as definitive treatment for open tibia diaphyseal fractures (OTDF) in Ivory Coast. METHODS: Gustilo I, II, and IIIA OTDFs of patients admitted within 24 hours of injury were prospectively included and treated with LDEF. The rates of union, mal-union, septic complications, as well as the functional results were assessed, in addition to the LDEF construct's integrity. Predictive factors of failure or poor results were assessed. RESULTS: Overall, 40 OTDF patients were admitted within 24 hours of injury. Gustilo I, II, and IIIA fractures were observed in three, 13, and 24 patients, respectively. Uneventful fracture healing was obtained in 29 cases, with an average union time of 8.47 months. Mal-union and non-union were registered in three and four cases, respectively. Pin-track infection (PTI) was observed in 13 cases and deep infection in seven. Infection resolved in all patients except four, who developed chronic osteomyelitis. None of the non-unions were associated with an infection. The overall functional result was satisfactory in 32 patients. PTI was the only predictive factor for chronic infection. Biplanar frames, when compared to monoplanar constructs, were associated with a significantly improved functional outcome. CONCLUSION: LDEF improved significantly the OTDF management, as it provided better stability and superior fracture healing rates than what is observed with the standard of care in the same environment. PTI remains an essential problem but with, hopefully, limited negative consequences.

Pseudomonas aeruginosa (PA) in patients with bronchiectasis (BE) is associated with a poor outcome and quality of life, and its presence is considered a marker of disease severity. This opportunistic pathogen is known for its ability to produce biofilms on biotic or abiotic surfaces and to survive environmental stress exerted by antimicrobials, inflammation, and nutrient or oxygen depletion. The presence of PA biofilms has been linked to chronic respiratory infection in cystic fibrosis but not in BE. There is considerable inconsistency in the reported infection/eradication rates of PA and chronic PA. In addition, inadequate antimicrobial treatment may potentiate the progression from intermittent to chronic infection and also the emergence of antibiotic resistance. A better comprehension of the pathophysiology of PA infections and its implications for BE is urgently needed. This can drive improvements in diagnostic accuracy, can move us toward a new consensus definition of chronic infection, can better define the follow-up of patients at risk of PA, and can achieve more successful eradication rates. In addition, the new technological advances regarding molecular diagnostics, -omics, and biomarkers require us to reconsider our traditional concepts.

Background Brucellosis causes a disabling human disease and loss of animals' lives. The clinical significance of Brucella bacteremia is still unclear and Brucella identification in blood culture is suboptimal. Methods This was a retrospective study conducted in Medina in Saudi Arabia from August 2016 to May 2019. We included cases with brucellosis symptoms and a positive culture or serological evidence for brucellosis, comparing bacteremic with non-bacteremic brucellosis cases for the rates of complications, infection relapses and brucellosis development. Also, we estimated blood culture positivity rates and the time to detect Brucella in an automatic blood culture instrument. Results Of the total number of 147 cases, 62 (42%) had a positive blood culture for Brucella, and the blood culture instrument (BACT/ALERT 3D) detected all positive blood cultures within 3 d of incubation. We found higher rates of chronic brucellosis in bacteremia than non-bacteremia cases (OR 7.25, 95% CI 1.41 to 37.23; p=0.018). Patients aged Conclusion Brucella bacteremia is an independent predictor for the development of chronic infection. Brucella bacteremia cases may need long follow-up periods and a more thorough evaluation to exclude deep-seated infection.

Infectious agents, including viruses and bacteria, are proposed to be involved in the pathogenesis of Alzheimer’s disease (AD). According to this hypothesis, these agents have capacity to evade the host immune system leading to chronic infection, inflammation, and subsequent deposition of Aβ and phosphorylated-tau in the brain. Co-existing proteinopathies and age-related pathologies are common in AD and the brains of elderly individuals, but whether these are also related to neuroinfections remain to be established. This study determined the prevalence and distribution of neurodegenerative proteinopathies in patients with infection-induced acute or chronic inflammation associated with herpes simplex virus (HSV) encephalitis (n = 13) and neurosyphilis (n = 23). The mean age at death in HSV patients was 53 ± 12 years (range 24–65 years) and survival was 9 days–6 years following initial infection. The mean age at death and survival in neurosyphilis patients was 60 ± 15 years (range 36–86 years) and 1–5 years, respectively. Neuronal tau-immunoreactivity and neurites were observed in 8 HSV patients and 19 neurosyphilis patients, and in approximately half of these, this was found in regions associated with inflammation and expanding beyond regions expected from the Braak stage of neurofibrillary degeneration. Five neurosyphilis patients had cortical ageing-related tau astrogliopathy. Aβ-plaques were found in 4 HSV patients and 11 neurosyphilis patients. Lewy bodies were observed in one HSV patient and two neurosyphilis patients. TDP-43 pathology was absent. These observations provide insights into deposition of neurodegenerative proteins in neuroinfections, which might have implications for COVID-19 patients with chronic and/or post-infectious neurological symptoms and encephalitis. Supplementary Information The online version contains supplementary material available at 10.1007/s00702-021-02371-7.

This study aims to evaluate differences in serum and fecal calprotectin in patients with HCV chronic hepatitis and COVID-19 infection and compare them to a control group. This observational study was performed between April 2020 and October 2020 in a single Internal Medicine center. We determined serum and fecal calprotectin, as well as levels of transaminases, C-reactive protein, ferritin, in 25 patients with COVID-19 infection, 30 patients with active HCV chronic infection and 38 patients with cured HCV infection. Serum levels of ALT, AST, C-reactive protein and ferritin were significantly higher in patients with COVID-19 infection (mean values of 127 IU/mL, 135 IU/mL, 123 mg/L and 1034 ng/mL, respectively) than in patients with active HCV infection (mean values of 68 IU/mL, 51 IU/mL, 17 mg/L and 528 ng/mL, respectively) or in patients with cured HCV infection (37 IU/mL, 29 IU/mL, 3.4 mg/L and 274 ng/mL, respectively). Also, serum and fecal calprotectin had increased concentrations in patients with COVID-19 (7.3 µg/mL and 394 µg/mg) versus patients with active hepatitis (2.4 µg/mL and 217 µg/mg) and patients with cured hepatitis (1.2 µg/mL and 38 µg/mg). Values were significantly higher in patients with digestive symptoms related to COVID-19. Serum and fecal calprotectin can be used as inflammatory markers in patients with active viral infections. In COVID-19, calprotectin concentrations can be correlated to the severity of disease, particularly in patients with digestive symptoms.

Background Trimodality therapy is a treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Thoracic radiation has both early (radiation pneumonitis) and late (chronic lung injury [CLI]) adverse effects on the lung. While CLI is expected to result in various problems in long-term survivors, these manifestations have not been precisely investigated. Methods We enrolled 112 LA-NSCLC patients who had received induction chemoradiotherapy followed by surgery, and then undergone follow-up computed tomography (CT) every 6 months for greater than 1 year. All chest CT images were reviewed to evaluate any injury of the pulmonary parenchyma. Results CLI at 1 year after surgery and its progression were observed in 94 (84%) and 38 (34%) patients, respectively. Progressive lung fibrosis as the first manifestation of CLI progression was most frequent after right middle and lower lobectomy. Cavity formation was the subsequent manifestation after progressive lung fibrosis , and chronic infection was the final stage of CLI. The cumulative rate of chronic infection was 76.4% at 10 years in patients with cavity formation. Ten patients with chronic infection included 7 cases of pulmonary aspergillosis and 2 cases of cavity infections with methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Among them, 4 patients required surgical interventions including completion pneumonectomy or fenestration. Conclusions CLI is a common incidence after trimodality therapy for LA-NSCLC. CLI frequently results in cavity formation, which is a precursor of highly refractory chronic infections requiring surgical intervention. Appropriate management needs to be established for CLI developing after trimodality therapy.

CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.

Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56− NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19)., This Review covers the role of natural killer cells in acute and chronic viral infections, with emphasis on human infections and insights from patients with primary immunodeficiencies affecting natural killer cells. It also describes the emerging data on how natural killer cells are involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Summary Chronic hepatitis B infection remains a serious global health threat, contributing to a large number of deaths through liver cirrhosis and hepatocellular carcinoma. Current treatment does not eradicate disease, and therefore new treatments are urgently needed. In acute hepatitis B virus (HBV) a strong immune response is necessary to clear the virus, but in chronic infection the immune response is weakened and dysfunctional. Therapeutic vaccination describes the process of inoculating individuals with a non‐infective form of viral antigen with the aim of inducing or boosting existing HBV‐specific immune responses, resulting in sustained control of HBV infection. In this review we outline the rationale for therapeutic vaccination in chronic HBV infection, discuss previous and ongoing trials of novel HBV therapeutic vaccine candidates and outline strategies to improve vaccine efficacy going forward., Hepatitis B virus (HBV) is a serious global health threat. Current treatments do not cure the disease. This review summaries the potential of therapeutic vaccination as a strategy to treat chronic HBV infection.

Background Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions. Methods Two sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART. Results The total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (6 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P P Conclusions Baseline total HIV-1 DNA and CD4+ T cell count are two independent predictors of total HIV-1 DNA after treatment. The derived model based on these two baseline factors provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

Large-scale comprehensive studies on HBV RNA in chronic hepatitis B are lacking. We aimed to study the HBV RNA profile and its correlation with other viral markers in patients with chronic hepatitis B who are treatment-naïve and patients receiving nucleos(t)ide analogues (NA).Biomarkers, including HBV RNA and hepatitis B core-related antigen (HBcrAg), were measured in 388 patients. Of these, 246 were treatment-naïve and were categorized into HBeAg-positive chronic infection (n = 41), HBeAg-positive chronic hepatitis (n = 81), HBeAg-negative chronic infection (n = 39), HBeAg-negative chronic hepatitis (n = 66), and HBsAg seroclearance (n = 19). These biomarkers were also measured in 142 patients who were NA-treated receiving tenofovir or entecavir at baseline, week 48, and week 96. The pattern of serum HBV RNA levels mirrored HBV DNA (1-2 logs higher than HBV RNA) and HBcrAg in patients who were treatment-naïve. HBV RNA correlated best with HBcrAg (r = 0.84) and to a lesser extent with HBV DNA (r = 0.737) (both P 0.001). In patients with HBsAg seroclearance, 15.8% and 15.8% had detectable serum HBV RNA and HBcrAg, respectively. NA treatment reduced serum HBV RNA by 1.46 logs and 1.77 logs at weeks 48 and 96, respectively. At week 96 of NA therapy, only 19.1% patients who were tenofovir-treated and 25.7% patients who were entecavir-treated had unquantifiable HBV RNA (P 0.05). In patients who were treated and had undetectable HBV DNA, 77.5% and 30% had quantifiable HBV RNA and HBcrAg, respectively.HBV RNA showed distinct and corresponding profiles in patients with HBV in different disease phases. HBV RNA and HBcrAg could be used to monitor residual transcriptional activities in patients with HBsAg seroclearance. NA led to reduction of serum HBV RNA. Monitoring of viral activities can still be achieved in patients with undetectable HBV DNA by serum HBV RNA.

Cystic fibrosis (CF) is a progressive autosomal recessive genetic disease that principally affects the respiratory and digestive systems. It is a chronic disease that has no cure. Symptoms often include chronic cough, lung infections, and shortness of breath. Children with cystic fibrosis present failure to thrive as manifested by low weight and height for age. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene that codes for a cell membrane protein of epithelial tissues and affects multiple organ systems in the human body. Mutations on the CFTR causes dysfunctional electrolyte regulation affecting intracellular water content. Defective CFTR function in airways produce a dehydrated and sticky mucus that leads the establishment of bacterial chronic infection that ultimate decrease the lung function. During the first decade of life, affected individuals are colonized principally by non typable Haemophilus influenzae and Staphylococcus aureus. During the second decade, Pseudomonas aeruginosa becomes the most dominant pathogen and persists throughout the remainder of their lives. In this work, we describe the mechanisms used by P. aeruginosa to adapt and persist in lungs of individuals with cystic fibrosis.

Background and Aim Etiologies of acute viral hepatitis in high-income countries change with migration of populations, lifestyle changes, and emergence of new pathogens. We analyzed etiologies, characteristics, and outcomes of patients with acute viral hepatitis at a tertiary hospital in Spain. Methods We analyzed data from all patients with acute hepatitis (n = 100; 71% male; median age, 42 years; 72% Spanish nationals), older than 16 years, diagnosed in the emergency department of an academic hospital in Barcelona, Spain, from January 2014 through December 2018. Blood samples were collected and patients with serum levels of alanine aminotransferase more than 10-fold the upper limit of normal and markers viral infection were considered to have acute viral hepatitis. We collected clinical information from patients, and samples were analyzed for IgM antibody to hepatitis B (HB) core antigen, HB surface antigen, antibody against hepatitis C virus (HCV), HCV RNA, IgM against hepatitis E virus (HEV), HEV RNA, and IgM against hepatitis A virus (HAV). Patients were followed until resolution of infections or evidence of chronic infection. Results The most common etiologies of acute hepatitis were HBV infection (28%), HEV infection (18%), HCV infection (17%), and HAV infection (14%). The main risk factors of the cohort were sexual risk contact and intravenous drug use; 79% of cases of HAV had sexual risk behavior. Twenty-nine percent of patients with acute HAV infection and 29% of patients with HBV infection were immigrants to Spain. Fifty-four patients were hospitalized; jaundice and HCV infection were associated with hospital admission. Three patients died (2 from acute liver failure related to acute HBV infection or HBV and HDV co-infection). Chronic infections developed in 5/28 patients (18%) with acute HBV infection and 7/17 patients (41%) with acute HCV infection. Conclusions Despite universal vaccination against HBV in Spain, HBV remains the most frequent cause of acute viral hepatitis in our emergency department. Almost one-third of cases of acute HBV and HAV infections were immigrants, possibly from countries with suboptimal vaccination programs. A high proportion of patients with acute hepatitis have HEV infection (18%); acute HAV infection was associated with sexual risk behavior.

Genetic recombination is a major evolutionary mechanism among RNA viruses, and it is common in coronaviruses, including those infecting humans. A few SARS-CoV-2 recombinants have been reported to date whose genome harbored combinations of mutations from different mutants or variants, but a single patient’s sample was analyzed, and the virus was not isolated. Here, we re-port the gradual creation of a hybrid genome of B.1.160 and Alpha variants in a lymphoma patient chronically infected for 14 months, and we isolated the recombinant virus. The hybrid genome was obtained by next-generation sequencing, and recombination sites were confirmed by PCR. This consisted of a parental B.1.160 backbone interspersed with two fragments, including the spike gene, from an Alpha variant. Analysis of seven sequential samples from the patient decoded the recombination steps, including the initial infection with a B.1.160 variant, then a concurrent infec-tion with this variant and an Alpha variant, the generation of hybrid genomes, and eventually the emergence of a predominant recombinant virus isolated at the end of the patient’s follow-up. This case exemplifies the recombination process of SARS-CoV-2 in real life, and it calls for intensifying genomic surveillance in patients coinfected with different SARS-CoV-2 variants, and more gener-ally with several RNA viruses, as this may lead to the creation of new viruses.

We aimed to determine the contribution of quantitative HBsAg in differentiating chronic infections from chronic hepatitis in HBeAg negative patients with HBV DNA 2000–20,000 IU/ml. A total of 79 untreated HBeAg negative patients were included. Patients were divided into 3 groups based on HBV DNA levels: group 1 (HBV DNA ≤ 2000 IU/ml), group 2 (HBV DNA: 2000–20,000 IU/ml) and group 3 (HBV DNA > 20,000 IU/ml). We collected serum from all patients for quantitative HBsAg analysis. We compared serum quantitative HBsAg levels with biochemical parameters, HBV DNA and liver biopsy results. In this study 46 patients were female and the mean age was 42 years. Serum quantitative HBsAg levels were found to be significantly lower in chronic infections compared with chronic hepatitis. There was a positive correlation between quantitative HBsAg and HBV DNA, ALT (alanine aminotransferase), HAI score (histological activity index), fibrosis score and disease stage. The cut-off level of quantitative HBsAg was determined as 4425 IU/ml to differentiate chronic infection from chronic hepatitis. With the test specificity of 95%, we found quantitative HBsAg cut-off values 1026 IU/ml and 20,346 IU/ml for the diagnosis of chronic infection and chronic hepatitis, respectively. Our study suggests that the quantitative HBsAg ≤ 1000 IU/ml limit value might be used for the diagnosis of chronic infection not only in HBV DNA ≤ 2000 IU/ml but also in patients with HBV DNA between 2000–20,000 IU/ml. In addition, antiviral treatment could be considered in patients with quantitative HBsAg > 20,000 IU/ml and HBV DNA > 2000 IU/ml without further examinations such as liver biopsy.

Background There is little evidence on techniques for management of peri-prosthetic infection (PJI) in the context of severe proximal femoral bone loss. Custom-made articulating spacers (CUMARS) utilising cemented femoral stems as spacers was described providing better bone support and longer survival compared to conventional articulating spacers. We retrospectively report our experience managing PJI by adaptation of this technique using long cemented femoral stems where bone loss precludes use of standard stems. Methods Patients undergoing 1st stage revision for infected primary and revision THA using a cemented long stem (> 205 mm) and standard all-polyethylene acetabulum between 2011 and 2018 were identified. After excluding other causes of revision (fractures or aseptic loosening), Twenty-one patients remained out of total 721 revisions. Medical records were assessed for demographics, initial microbiological and operative treatment, complications, eradication of infection and subsequent operations. 2nd stage revision was undertaken in the presence of pain or subsidence. Results Twenty-one patients underwent 1st stage revision with a cemented long femoral stem. Mean follow up was 3.9 years (range 1.7–7.2). Infection was eradicated in 15 (71.4%) patients. Two patients (9.5%) required repeat 1st stage and subsequently cleared their infection. Three patients (14.3%) had chronic infection and are on long term suppressive antibiotics. One patient (4.8%) was lost to follow up before 2 years. Complications occurred in seven patients (33%) during or after 1st stage revision. Where infection was cleared, 2nd stage revision was undertaken in 12 patients (76.5%) at average of 9 months post 1st stage. Five (23.8%) CUMARS constructs remained in-situ at an average of 3.8 years post-op (range 2.6–5.1). Conclusions Our technique can be used in the most taxing of reconstructive scenarios allowing mobility, local antibiotic delivery, maintenance of leg length and preserves bone and soft tissue, factors not afforded by alternative spacer options.

Two-stage revision is the current gold standard treatment for infected total hip arthroplasties (THA) with good clinical outcomes. Single-stage revision THA offers the advantage of only a single surgical intervention, potentially leading to improved functional outcomes. This study aimed to compare the differences in patient-reported outcome measures (PROMs) and complications between single and two-stage revision THA for chronic periprosthetic joint infection (PJI). A total of 159 consecutive revision THA patients for chronic PJI with complete pre-and post-operative patient-reported outcome measures (PROM) was investigated. A total of 46 patients with single-stage revision THA was matched to 92 patients following two-stage revision THA using propensity score matching, yielding a total of 136 propensity score-matched patients for analysis. Single and two-stage revision THA improved PROM scores post-operatively, with significantly higher PROMs for single-stage revision THA (HOOS-PS: 50.7 vs 46.4, p = 0.04; Physical SF 10A: 42.1 vs 36.6, p

Purpose of review The aim of this study was to highlight the profound changes in the cause in chronic liver disease in HIV-infected individuals. Recent findings Hepatitis C virus (HCV) has been transformed into a curable viral infection by highly effective treatments. This has resulted in elimination of chronic hepatitis C in HIV-coinfected individuals at least in resource-rich settings. Hepatitis B virus (HBV) has become a chronic infection, which is easily controlled by long-term therapy with HBV polymerase inhibitors. As a result, nonalcoholic steatohepatitis (NASH) has gained clinical importance. The obesity epidemic in the general population has also included people with HIV and weight gain has been associated with some newer antiretroviral drugs, such as HIV integrase inhibitors and tenofovir alafenamide fumarate. Medical treatment for obesity is a focus of intense research efforts, but currently, the only convincing therapeutic option in morbidly obese patients is bariatric surgery, which can also improve liver outcomes. The wider use of this approach has included HIV-infected individuals allowing to assess at least the safety aspects of bariatric surgery in this special population. Summary The shift from communicable to noncommunicable liver disease is changing the clinical practice in HIV-infected individuals. Research activities are focusing more on treatment of NASH and obesity, although a curative therapy for HBV infection would have a great clinical impact.

Chronic infection with hepatitis C virus (HCV) is one of the leading causes of liver disease globally, affecting approximately 71 million people. The majority of them are infected with genotype (GT) 1 but infections with GT3 are second in frequency. For many years, GT3 was considered to be less pathogenic compared to other GTs in the HCV family due to its favorable response to interferon (IFN)-based regimen. However, the growing evidence of a higher rate of steatosis, more rapid progression of liver fibrosis, and lower efficacy of antiviral treatment compared to infection with other HCV GTs has changed this conviction. This review presents the specifics of the course of GT3 infection and the development of therapeutic options for GT3-infected patients in the era of direct-acting antivirals (DAA). The way from a standard of care therapy with pegylated IFN-alpha (pegIFNα) and ribavirin (RBV) through a triple combination of pegIFNα + RBV and DAA to the highly potent IFN-free pangenotypic DAA regimens is discussed along with some treatment options which appeared to be dead ends. Although the implementation of highly effective pangenotypic regimens is the most recent stage of revolution in the treatment of GT3 infection, there is still room for improvement, especially in patients with liver cirrhosis and those who fail to respond to DAA therapies, particularly those containing inhibitors of HCV nonstructural protein 5A.

Introduction: Cognitive impairment has been reported in people living with HIV-1 (PLWH) with prior syphilis, while PLWH who present with incident syphilis have reduced blood CD4 T-lymphocyte and elevated HIV-1 RNA levels. However, the clinical, virological and neurocognitive effects of syphilis during acute HIV-1 (AHI) remain unknown. Methods: Pre-antiretroviral therapy laboratory outcomes and neurocognitive performance in a four-test battery in the SEARCH10/RV254 AHI cohort were compared according to syphilis status, determined by serum Treponema pallidum haemagglutination (TPHA), Venereal Disease Research Laboratory (VDRL) and syphilis treatment history. Impaired cognitive performance was defined as having z-scores ≤ −1 in at least two tests or ≤ −2 in at least one test. Results: Out of 595 AHI participants (97% male, median age of 26 years and estimated duration of HIV-1 infection of 19 days), 119 (20%) had history of syphilis (TPHA-positive), of whom 51 (9%) had untreated syphilis (TPHA-positive/VDRL-positive/without prior treatment). Compared with those without syphilis (TPHA-negative), individuals with untreated syphilis had higher CD8 T-lymphocyte levels but not higher plasma HIV-1 RNA or lower CD4 T-lymphocyte levels. Taking into account estimated duration of HIV-1 infection (P

Cigarette smoke is a potent proinflammatory trigger contributing to acute lung injury and the development of chronic lung diseases via mechanisms that include the impairment of inflammation resolution. We have previously demonstrated that secondhand smoke (SHS) exposure exacerbates bacterial infection-induced pulmonary inflammation and suppresses immune responses. It is now recognized that resolution of inflammation is a bioactive process mediated by lipid-derived specialized proresolving mediators that counterregulate proinflammatory signaling and promote resolution pathways. We therefore hypothesized that proresolving mediators could reduce the burden of inflammation due to chronic lung infection following SHS exposure and restore normal immune responses to respiratory pathogens. To address this question, we exposed mice to SHS followed by chronic infection with nontypeable Haemophilus influenzae (NTHI). Some groups of mice were treated with aspirin-triggered resolvin D1 (AT-RvD1) during the latter half of the smoke exposure period or during a period of smoking cessation and before infection. Treatment with AT-RvD1 markedly reduced the recruitment of neutrophils, macrophages, and T cells in lung tissue and bronchoalveolar lavage and levels of proinflammatory cytokines in the bronchoalveolar lavage. Additionally, treatment with AT-RvD1 improved Ab titers against the NTHI outer membrane lipoprotein Ag P6 following infection. Furthermore, treatment with AT-RvD1 prior to classically adjuvanted immunization with P6 increased Ag-specific Ab titers, resulting in rapid clearance of NTHI from the lungs after acute challenge. Collectively, we have demonstrated that AT-RvD1 potently reverses the detrimental effects of SHS on pulmonary inflammation and immunity and thus could be beneficial in reducing lung injury associated with smoke exposure and infection.

Although they globally cause viral gastroenteritis in children, astroviruses are understudied due to the lack of well-defined animal models. While murine astroviruses (muAstVs) chronically infect immunodeficient mice, a culture system and understanding of their pathogenesis is lacking. Here, we describe a platform to cultivate muAstV using air–liquid interface (ALI) cultures derived from mouse enteroids, which support apical infection and release. Chronic muAstV infection occurs predominantly in the small intestine and correlates with higher interferon-lambda (IFN-λ) expression. MuAstV stimulates IFN-λ production in ALI, recapitulating our in vivo findings. We demonstrate that goblet cells and enterocytes are targets for chronic muAstV infection in vivo, and that infection is enhanced by parasite co-infection or type 2 cytokine signaling. Depletion of goblet cells from ALI limits muAstV infection in vitro. During chronic infection, muAstV stimulates IFN-λ production in infected cells and induces ISGs throughout the intestinal epithelium in an IFN-λ-receptor-dependent manner. Collectively, our study provides insights into the cellular tropism and innate immune responses to muAstV and establishes an enteroid-based culture system to propagate muAstV in vitro.

BACKGROUND: There is growing concern about individuals reported to suffer repeat COVID-19 disease episodes, these in a small number of cases characterised as de novo infections with distinct sequences, indicative of insufficient protective immunity even in the short term. METHODS: Observational case series and case-control studies reporting 33 cases of recurrent, symptomatic, qRT-PCR positive COVID-19. Recurrent disease was defined as symptomatic recurrence after symptom-free clinical recovery, with release from isolation >14 days from the beginning of symptoms confirmed by qRT-PCR. The case control study-design compared this group of patients with a control group of 62 patients randomly selected from the same COVID-19 database. RESULTS: Of 33 recurrent COVID-19 patients, 26 were female and 30 were HCW. Mean time to recurrence was 50.5 days which was associated with being a HCW (OR 36.4 (p