Abstract
It is unclear to what extent pre-existing antibody-mediated immunity shapes influenza virus infection in humans. Similarly, the influence of previous history of influenza vaccination on ...disease severity and clinical outcome is not well understood. In here, we aimed to determine the balance of pre-existing antibodies against the hemagglutinin (HA) and neuraminidase (NA) protein of influenza virus that correlates with protection in humans. We measured hemagglutination inhibition (HI) titers and anti-HA (stalk and full-length) and anti-NA antibodies at the onset of the influenza infection on a cohort of H1N1/Cal09 influenza virus-infected patients (solid organ transplant recipients, SOTRs). Results demonstrated that the antecedent of TIV vaccination was the only controllable factor associated with lower risk of severity of disease in influenza virus-infected SOTRs. The presence of lower respiratory symptoms (LRS) significantly determined disease outcome at hospital admission (severe vs. mild, 9, 75% vs. 19, 32·1%, OR 95% 6·3, p=0·01). Moreover, a predicted probability curve for both anti-HA full-length and stalk (OR 0·13, p=0·02 and OR 0·06, p=0·03, respectively) demonstrated that the probability of developing LRS decreased with increasing assay log-values. However, multivariate logit model adjusted for HI, anti-HA (full-length and stalk) and anti-NA titers demonstrated that only anti-HA stalk antibodies were independently associated with influenza severity. Our study demonstrated that when HI antibodies fail to confer protection from symptomatic influenza infection, pre-existing HA stalk antibodies protected against severe disease in SOTRs.
Introduction
Reevaluation of donor criteria, including age, is needed to combat organ shortages, lengthy wait times, and anticipated recipient mortality rates. The purpose of this study was to ...evaluate donor and recipient (D/R) age combinations and patient and graft survival outcomes.
Methods
Single-organ, living donor kidney transplantations (LDKTs) from 2012 to 2018 were retrospectively reviewed. Donors and recipients were placed into “older” and “younger” age categories of 50 years and above or below age 50, then analyzed with SPSS version 25.
Results
We performed 347 LDKTs. Younger-to-older pairings had significantly higher rates of smoking in recipient (53.6%) and hepatitis C (5.5%), but shorter hospital stays (5.3 days). Older-to-younger pairings had the longest hospital stays (7.4 days) but the shortest cold ischemic time (2.3 hours). Notably, there was no significant variance in delayed graft function (first-week dialysis) between groups. Regarding complication rates, only bleeding within 30 days, highest in older-to-older pairings (7.7%), and renal complications, highest in older-to-younger pairings, significantly varied between groups. Interestingly, though younger-to-older cases had the longest mean graft survival time, older kidneys lasted 537 days longer in older recipients than in younger recipients.
Discussion
These results indicate there is not a one-size-fits-all approach when considering outcomes of donor/recipient age-pairings in LDKT, as significant correlations did not consistently favor one age-pairing over others. Regardless of age-pairing, LDKT provides gold standard treatment and expands the availability of organs. Future research into the impact of age-pairing on specific variables, national or multicenter studies, and protocol development for evaluating donor/recipient age-pairings is needed.
Concerns that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may cause new-onset diabetes persist in an ...evolving research landscape, and precise risk assessment is hampered by, at times, conflicting evidence. Here, leveraging comprehensive single-cell analyses of in vitro SARS-CoV-2-infected human pancreatic islets, we demonstrate that productive infection is strictly dependent on the SARS-CoV-2 entry receptor ACE2 and targets practically all pancreatic cell types. Importantly, the infection remains highly circumscribed and largely non-cytopathic and, despite a high viral burden in infected subsets, promotes only modest cellular perturbations and inflammatory responses. Similar experimental outcomes are also observed after islet infection with endemic coronaviruses. Thus, the limits of pancreatic SARS-CoV-2 infection, even under in vitro conditions of enhanced virus exposure, challenge the proposition that in vivo targeting of β cells by SARS-CoV-2 precipitates new-onset diabetes. Whether restricted pancreatic damage and immunological alterations accrued by COVID-19 increase cumulative diabetes risk, however, remains to be evaluated.
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•SARS-CoV-2 infection targets practically all human pancreatic cell types in vitro•Productive SARS-CoV-2 infection of islet cells is strictly dependent on ACE2•Extent and consequences of pancreatic SARS-CoV-2 infection are notably restrained•Islets are also permissive to in vitro infection with endemic human coronaviruses
Assessing the risk of SARS-CoV-2-induced new-onset diabetes requires integration of multiple complementary lines of investigation. Here, van der Heide et al. demonstrate that the specific limits of in vitro pancreatic SARS-CoV-2 infection suggest at best a minor, if any, role of virus-induced β cell damage directly promoting new-onset diabetes.
Abstract
Background
Infections with extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae is an emerging problem leading to poor clinical outcomes and increased mortality. The purpose of ...this study was to determine the prevalence, risk factors and outcomes of ESBL-producing E. coli (EC) in bloodstream infections (BSIs) of neutropenic patients with hematological malignancies and compare the difference with Non-ESBL producing EC.
Methods
Through an IRB approved protocol, a retrospective cohort study was conducted at the H. Lee Moffitt Cancer Center from January, 2007 till October, 2017. Of the 310 records, who had +ive blood cultures for E. Coli, a total of 63 neutropenic patients with hematological malignancies were identified based on the bloodstream infections with ESBL-EC and Non ESBL EC. Data included demographics, underlying malignancy, type of bone marrow transplant, duration of neutropenia, antibiotics use pre and post culture, length of hospital stay, severity of infection, ventilator use, and mortality data.
Results
A total of 310 cases with hematological malignancy and neutropenia were reviewed, 63 were identified as +ive blood culture for E. coli. Out of the 63 cases, 17 were ESBL-EC +ive and 46 were non-ESBL-EC. The prevalence of ESBL-EC was highest in the year 2015 (29.4%) and decreased in the subsequent years (Figure 1). The mean ages of the two groups were 53.59 ±12.4 and 60.82 ± 11.1, respectively. The average length of stay for the ESBL-EC group was 26.59 ± 11.2 days, longer than the non-ESBL EC group 21.96 ± 11.2. Days of neutropenia in non-ESBL vs. ESBL EC were 9 days ± 8.3, and 19 days ± 22.0, respectively, P < 0.01). No differences were observed in the 30–60 day mortality and other outcomes listed in Table 1.
Conclusion
The prevalence of ESBL-EC was observed to be higher in patients who were neutropenic for longer duration, were older and resulted in longer hospital stay. Early identification and empirical therapy in neutropenic patients suspected to have ESBL-EC infection is crucial. Also, the infection with ESBL-EC was higher in the year 2015 and decreased in the subsequent years. After higher rates, perhaps infection control, lab reporting changes, antibiotic stewardship and transmission-based precautions might have played a role.
Disclosures
All authors: No reported disclosures.
The nonstructural protein 1 (Nsp1) of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a virulence factor that targets multiple cellular pathways to inhibit host gene expression and ...antiviral response. However, the underlying mechanisms of the various Nsp1-mediated functions and their contributions to SARS-CoV-2 virulence remain unclear. Among the targets of Nsp1 is the mRNA (messenger ribonucleic acid) export receptor NXF1-NXT1, which mediates nuclear export of mRNAs from the nucleus to the cytoplasm. Based on Nsp1 crystal structure, we generated mutants on Nsp1 surfaces and identified an acidic N-terminal patch that is critical for interaction with NXF1-NXT1. Photoactivatable Nsp1 probe reveals the RNA Recognition Motif (RRM) domain of NXF1 as an Nsp1 N-terminal binding site. By mutating the Nsp1 N-terminal acidic patch, we identified a separation-of-function mutant of Nsp1 that retains its translation inhibitory function but substantially loses its interaction with NXF1 and reverts Nsp1-mediated mRNA export inhibition. We then generated a recombinant (r)SARS-CoV-2 mutant on the Nsp1 N-terminal acidic patch and found that this surface is key to promote NXF1 binding and inhibition of host mRNA nuclear export, viral replication, and pathogenicity in vivo. Thus, these findings provide a mechanistic understanding of Nsp1-mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS-CoV-2.
SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs ...evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.
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•Systems analyses reveal the host-selective forces that drive SARS-CoV-2 evolution•Variants modulate viral protein levels, phosphorylation, and virus-host complexes•Variants converge on innate immune suppression by modulating viral proteins•Understanding innate/adaptive immune balance will aid future pandemic preparedness
Systems proteomic and genomic analyses reveal that SARS-CoV-2 variants of concern respond to the selective forces of the host immune response by modulating viral protein expression, phosphorylation, and virus-host protein-protein interactions. Variants have converged on similar strategies for innate and adaptive immune evasions, suggesting implications for predicting viral transmission and tackling future viral pandemics.
The domesticated donkey, derived from the African wild ass, has played a crucial role in human history for over 5,000 years, serving as a working and pack animal. However, donkeys often suffer from ...skin wounds and injuries due to various factors, including equipment use, road accidents, and lack of veterinary care. Wound healing is a complex process involving inflammation, proliferation, and maturation phases, with impaired cell proliferation potentially delaying healing. Equines, including donkeys, are particularly susceptible to traumatic skin wounds, with limb wounds healing more slowly due to factors such as tissue loss, contamination, and excessive skin tension. In such cases, wound healing by second intention is common but can lead to complications. Chitosan, a biopolymer derived from the shells of crustaceans, has shown promise in promoting wound healing. It helps with tissue granulation, collagen deposition, and tissue regeneration, while also preventing wound contamination and maintaining a sterile environment. Honey, with its antimicrobial, anti-inflammatory, and antioxidant properties, is another natural remedy that accelerates wound healing and is often used in combination with chitosan for optimal results. This biologically-based approaches hold potential for improving the healing of donkey wounds and preventing infections, offering safer and more effective alternatives to traditional wound care.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting ...nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.
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•SARS-CoV-2 ORF6 antagonizes IFN-induced signaling during infection•ORF6 binds Nup98-Rae1 and selectively inhibits nucleocytoplasmic trafficking•ORF6 expression contributes to SARS-CoV-2 pathogenesis•The D61L polymorphism disrupts ORF6 protein functions at the NPC
Kehrer, Cupic et al. dissect the role of ORF6 in the host response to SARS-CoV-2 infection. ORF6 is an innate immune antagonist that binds to Nup98-Rae1 and suppresses host gene expression by selectively inhibiting nucleocytoplasmic trafficking. ORF6 loss-of-function mutations result in SARS-CoV-2 attenuation both in vitro and in vivo.
Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder that causes decreased immunity and increased susceptibility to infections. It affects B lymphocyte differentiation, ...resulting in predominantly bacterial and less frequently viral, fungal, and protozoal infections. The respiratory and gastrointestinal tracts where antibody defences are essential are usually affected. Individuals with CVID are also predisposed to developing lymphoid and gastrointestinal malignancies. We present two cases with rare infectious and oncological complications of CVID, including a patient with
comple
infection and ovarian cancer, and another patient with group B
empyema of the lung with acute myeloid leukaemia. The main objective of this study is to highlight how CVID-induced hypogammaglobulinaemia can lead to rare infections and malignancies. The management of these complications can vary according to severity, but an awareness of their existence is crucial to diagnose them promptly in an already immunocompromised CVID patient.
Abstract
Background
COVID-19 disease became a global health care crisis and was declared pandemic by WHO in March 2020. Little is known how the immunosuppressive medications impact the mortality rate ...in Solid Organ Transplant (SOT) recipients. There is also minimal data regarding the incidence of transplanted graft failure or rejection that could be attributed to the COVID-19 infection itself or its complications and management. Our study aims to investigate the management of COVID-19 infection, outcome of the infection, transplant failure and rejection rates in SOT recipients.
Methods
We conducted a retrospective cohort study of all consecutive SOT recipients who were admitted to our transplant center from March 2020 to April 2021 with COVID-19 infection. Data was collected from the electronic medical records after receiving Institutional Review Board approval. Table 1Characteristics of the Population in the two groups
Table 2 Type of Transplants in the two groups
Results
A total of 135 patients met the inclusion criteria. After the diagnosis of COVID -19 infection, 31% recipients had decrease in the dose of immunosuppressive medications (change group) and 69% had no changes in the dose (no change group). Out of the 73 Kidney Transplant recipients 33% were in the change group compared to 14% of liver, 25% of heart and 27% of lung transplant recipients. Of the total 42 recipients in the change group, 28.6% required Intensive Care Unit (ICU) level care significantly higher compared to 7.5% in the no change group (p-value < 0.005). Mechanical ventilation was required in 14.3% of the patients in the change group and 6.5% in the no change group (p-value < 0.5). Out of the total, 85.7% patients in the change group survived compared to 94.6% in the no change group (p-value < 0.1). Overall, the transplant rejection rate was higher in the change group compared to the no change group (p-value < 0.5). Table 3Comparison of the Outcomes in the two groups
Figure 1 Kaplan – Meier Curve for survival
Figure 2 Kaplan – Meier Curve with Cox Regression for survival
Conclusion
Our study showed a significantly higher ICU admission rate and mortality in SOT recipients who had their immune suppression reduced at the time of COVID-19 diagnosis. The same group also had a higher risk of rejection of transplanted graft. More studies with larger sample size needs to be done to further understand the management of immunosuppressive drugs in the SOT recipients with COIVD-19 infection.
Disclosures
All Authors: No reported disclosures.
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