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Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. Although intrahost evolution has been documented, direct evidence of subsequent transmission and continued stepwise adaptation is lacking. Here we describe sequential persistent SARS-CoV-2 infections in three individuals that led to the emergence, forward transmission, and continued evolution of a new Omicron sublineage, BA.1.23, over an eight-month period. The initially transmitted BA.1.23 variant encoded seven additional amino acid substitutions within the spike protein (E96D, R346T, L455W, K458M, A484V, H681R, A688V), and displayed substantial resistance to neutralization by sera from boosted and/or Omicron BA.1-infected study participants. Subsequent continued BA.1.23 replication resulted in additional substitutions in the spike protein (S254F, N448S, F456L, M458K, F981L, S982L) as well as in five other virus proteins. Our findings demonstrate not only that the Omicron BA.1 lineage can diverge further from its already exceptionally mutated genome but also that patients with persistent infections can transmit these viral variants. Thus, there is, an urgent need to implement strategies to prevent prolonged SARS-CoV-2 replication and to limit the spread of newly emerging, neutralization-resistant variants in vulnerable patients. There is limited understanding of SARS-CoV-2 intra-host evolution and subsequent transmission and adaptations in the context of persistent infection. Here, the authors describe sequential persistent SARS-CoV-2 infections that led to the emergence, transmission and further evolution of a novel Omicron BA.1.23 lineage.

Background: Insulinoma-associated protein 1 (INSM1) has been considered as a novel immunostain for neuroendocrine tumors (NETs) and is hypothesized to be more reliable than first-generation NET biomarkers, such as CGA (chromogranin A), SYP (synaptophysin) and CD56 (neural cell adhesion molecule). In this review, we summarize existing literature on INSM1′s reliability as an immunostain for detection of various NETs, its results in comparison to first-generation NET biomarkers, and its expression in both non-NETs and benign tissues/cells on cytology specimens (cell blocks/smears).

There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of χ 2 tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3·6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22·4%) given antivirals later (p=0·007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009–10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. None.

TAM receptors (TYRO3, AXL, and MERTK) comprise a family of homologous receptor tyrosine kinases (RTK) that are expressed across a range of liquid and solid tumors where they contribute to both oncogenic signaling to promote tumor proliferation and survival, as well as expressed on myeloid and immune cells where they function to suppress host anti-tumor immunity. In recent years, several strategies have been employed to inhibit TAM kinases, most notably small molecule tyrosine kinase inhibitors and inhibitory neutralizing monoclonal antibodies (mAbs) that block receptor dimerization. Targeted protein degraders (TPD) use the ubiquitin proteasome pathway to redirect E3 ubiquitin ligase activity and target specific proteins for degradation. Here we employ first-in-class TPDs specific for MERTK/TAMs that consist of a cereblon E3 ligase binder linked to a tyrosine kinase inhibitor targeting MERTK and/or AXL and TYRO3. A series of MERTK TPDs were designed and investigated for their capacity to selectively degrade MERTK chimeric receptors, reduce surface expression on primary efferocytic bone marrow-derived macrophages, and impact on functional reduction in efferocytosis (clearance of apoptotic cells). We demonstrate proof-of-concept and establish that TPDs can be tailored to either selectivity degrades MERTK or concurrently degrade multiple TAMs and modulate receptor expression in vitro and in vivo . This work demonstrates the utility of proteome editing, enabled by tool degraders developed here towards dissecting the therapeutically relevant pathway biology in preclinical models, and the ability for TPDs to degrade transmembrane proteins. These data also provide proof of concept that TPDs may serve as a viable therapeutic strategy for targeting MERTK and other TAMs and that this technology could be expanded to other therapeutically relevant transmembrane proteins.

Background: Immunocompromised adults may experience severe COVID-19 outcomes, necessitating a multifaceted treatment approach. Studies from the Delta period showed benefit from monoclonal antibody (mAb) therapy that was most pronounced among anti-spike IgG seronegative individuals. With widespread vaccination and shifting SARS-CoV-2 variants in the Omicron period, clinical predictors of anti-spike IgG seronegativity, and impacts on clinical outcomes, remain incompletely characterized. Objectives: We describe outcomes from a cohort of immunocompromised adults with COVID-19 stratified by anti-spike IgG serostatus and receipt of mAb therapy during the Omicron period to evaluate clinical impact. Design: This was a retrospective study of immunocompromised adults with mild-moderate COVID-19 presenting between December 2021 and October 2022. Methods: Charts were reviewed to assess anti-spike IgG serostatus, receipt of mAb therapy, and 28-day outcomes including conventional oxygen use, high-flow oxygen use, mechanical ventilation, and death. Results: A total of 276 individuals were included, of whom 252 (91%) were partially or fully vaccinated, 190 (69%) were anti-spike IgG seropositive, and 225 (82%) received mAb therapy. A majority were solid organ transplant recipients (169, 61%), with anti-spike IgG seronegatively significantly associated with mycophenolate-based immunosuppression or comorbid chronic kidney disease. Conventional oxygen use among seropositive patients receiving mAb, seronegative patients receiving mAb, seropositive patients not receiving mAb, and seronegative patients not receiving mAb were 2/154 (1%), 5/71 (7%), 6/36 (17%), and 4/15 (27%), respectively. Across the cohort, high-flow oxygen use, mechanical ventilation, and death occurred in 6 (2%), 4 (3%), and 3 (1%) individuals, respectively. Conclusion: Clinical outcomes in a predominantly vaccinated, immunocompromised cohort with mild–moderate COVID-19 during the Omicron period appeared to vary with anti-spike IgG serostatus and receipt of mAb therapy. Observed trends would benefit from prospective studies during future iterations of COVID-19 therapeutics to inform treatment decisions for immunocompromised adults.

Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics \"emergency hematopoiesis,\" a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

Background Healthcare-associated infections pose a potentially fatal threat to patients worldwide and Staphylococcus aureus is one of the most common causes of healthcare-associated infections. S. aureus is a common commensal pathogen and a frequent cause of bacteremia, with studies demonstrating that nasal and blood isolates from single patients match more than 80% of the time. Here we report on a contemporary collection of colonizing isolates from those with methicillin-resistant S. aureus (MRSA) bloodstream infections to evaluate the diversity within hosts, and detail the clinical features associated with concomitant nasal colonization. Methods Swabs of the bilateral anterior nares were obtained from patients diagnosed with MRSA bacteremia. A single colony culture from the blood and an average of 6 colonies from the nares were evaluated for MRSA growth. For the nares cultures, we typed multiple isolates for staphylococcal protein A ( spa ) and derived the clonal complexes. Demographic and clinical data were obtained retrospectively from the electronic medical record system and analysed using univariate and multivariable regression models. Results Over an 11-month period, 68 patients were diagnosed with MRSA bloodstream infection, 53 were swabbed, and 37 (70%) were colonized with MRSA in the anterior nares. We performed molecular typing on 213 nasal colonies. Spa types and clonal complexes found in the blood were also detected in the nares in 95% of the cases. We also found that 11% of patients carried more than one clone of MRSA in the nares. Male sex and history of prior hospitalization within the past 90 days increased odds for MRSA colonization. Conclusion The molecular epidemiological landscape of colonization in the setting of invasive disease is diverse and defining the interplay between colonization and invasive disease is critical to combating invasive MRSA disease.

Background Whole-genome sequencing (WGS) is increasingly used to map the spread of bacterial and viral pathogens in nosocomial settings. A limiting factor for more widespread adoption of WGS for hospital infection prevention practices is the availability of standardized tools for genomic epidemiology. Methods We developed the Pathogen Sequencing Phylogenomic Outbreak Toolkit (PathoSPOT) to automate integration of genomic and medical record data for rapid detection and tracing of nosocomial outbreaks. To demonstrate its capabilities, we applied PathoSPOT to complete genome surveillance data of 197 MRSA bacteremia cases from two hospitals during a 2-year period. Results PathoSPOT identified 8 clonal clusters encompassing 33 patients (16.8% of cases), none of which had been recognized by standard practices. The largest cluster corresponded to a prolonged outbreak of a hospital-associated MRSA clone among 16 adults, spanning 9 wards over a period of 21 months. Analysis of precise timeline and location data with our toolkit suggested that an initial exposure event in a single ward led to infection and long-term colonization of multiple patients, followed by transmissions to other patients during recurrent hospitalizations. Conclusions We demonstrate that PathoSPOT genomic surveillance enables the detection of complex transmission chains that are not readily apparent from epidemiological data and that contribute significantly to morbidity and mortality, enabling more effective intervention strategies.

Candida auris is a globally emerging fungal pathogen that is associated with healthcare-related infections. The accurate and rapid detection of C. auris is crucial for effective infection prevention, control, and patient management. This study aimed to validate the analytical and diagnostic performance of the DiaSorin Molecular C. auris Detection Kit. The analytical specificity, sensitivity, and reproducibility of the assay were evaluated. The limit of detection (LOD) was determined to be 266 CFU/µL using the ZeptoMetrix Candida auris Z485 strain and standard calibration curves. The assay demonstrated high analytical specificity and showed no amplification against a diverse panel of bacteria and fungi. Clinical validation was conducted using deidentified residual axillary/groin surveillance culture specimens from C. auris culture-positive and culture-negative patients. The DiaSorin Molecular Detection Kit exhibited 100% agreement in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) when compared to cultures coupled with MALDI-TOF identification. Intra- and inter-reproducibility testing demonstrated consistent and reliable diagnostic performance. This validated assay offers rapid and accurate detection of C. auris, facilitating timely implementation of infection control measures and appropriate patient care. The DiaSorin Molecular C. auris Detection Kit has the potential to aid in controlling the outbreaks caused by this emerging fungal pathogen. Providing a reliable diagnostic tool can contribute to the effective management and containment of C. auris infections in healthcare settings and ultimately improve patient outcomes.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), poses a global health challenge and is responsible for over a million deaths each year. Current treatment is lengthy and complex, and new, abbreviated regimens are urgently needed. Mtb adapts to nutrient starvation, a condition experienced during host infection, by shifting its metabolism and becoming tolerant to the killing activity of bactericidal antibiotics. An improved understanding of the mechanisms mediating antibiotic tolerance in Mtb can serve as the basis for developing more effective therapies. We performed a forward genetic screen to identify candidate Mtb genes involved in tolerance to the two key first-line antibiotics, rifampin and isoniazid, under nutrient-rich and nutrient-starved conditions. In nutrient-rich conditions, we found 220 mutants with differential antibiotic susceptibility (218 in the rifampin screen and 2 in the isoniazid screen). Following Mtb adaptation to nutrient starvation, 82 mutants showed differential antibiotic susceptibility (80 in the rifampin screen and 2 in the isoniazid screen). Using targeted mutagenesis, we validated the rifampin-hypersusceptible phenotype under nutrient starvation in Mtb mutants lacking the following genes: ercc3, moeA1, rv0049, and rv2179c. These findings shed light on potential therapeutic targets, which could help shorten the duration and complexity of antitubercular regimens.