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As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.

Seasonal human coronaviruses (HCoVs) are the causative agents of more than 15% of common cold cases each year. However, compared with more virulent HCoVs such as SARS-CoV-2, there has been limited research on these viruses. We compared the replication of HCoV-NL63 (NL63) and HCoV-229E (229E). Additionally, we examined their interactions with interferon signaling and related innate immune pathways in lung-derived cell lines and primary nasal epithelial cultures. 229E replicates efficiently in each of these culture systems, with significant dsRNA-induced pathway induction only in nasal cells. In contrast, NL63 replicates efficiently only in nasal cell cultures but induces innate immune pathways in all three culture systems. Moreover, the conserved CoV innate immune antagonist endoribonuclease U aids in evading these responses in 229E infection. This study expands our understanding of common-cold HCoV-host interactions and provides insight into differences between seasonal and lethal HCoVs.

Amyloidosis is characterized by the tissue deposition of insoluble fibrils derived from misfolded proteins. This case report describes a Hispanic man diagnosed with both monoclonal gammopathy of undetermined significance (MGUS) and wild-type transthyretin amyloidosis (ATTR) cardiac amyloidosis. The diagnosis was made using a combination of serological tests and multimodality cardiac imaging. The report highlights the importance of multimodality imaging in diagnosing cardiac amyloidosis, especially in cases where MGUS is also present. The patient presented with shortness of breath and was found to have cardiac abnormalities through electrocardiogram, echocardiogram, and cardiac magnetic resonance (CMR). A technetium-99m pyrophosphate (Tc-99m PYP) scan confirmed the presence of ATTR cardiac amyloidosis. Bone marrow biopsy confirmed MGUS. The patient was treated with diuretics and remained asymptomatic during follow-up. The report emphasizes the need for accurate diagnosis to differentiate between AL, ATTR, and MGUS due to their distinct clinical courses and treatments.

Introduction Surgery is considered the treatment of choice for patients with large, symptomatic brain metastases. This report describes a series of patients treated with upfront two-session radiosurgery rather than surgery for large brain metastases from breast and lung histology. Methods From October 2016 to January 2019, 10 consecutive patients with neurologic symptoms from large brain metastases producing mass effects underwent two sessions of radiosurgical treatments 30 days apart. The response was assessed by imaging and clinical evaluations.  Results Ten patients had a total of 36 tumors; of these, 22 lesions with a mean volume of 12.3 ml (range, 7-78.4 ml) underwent two-session radiosurgery. The mean prescription dose for the first treatment was 13 Gy (range, 9-18 Gy) to the 50% isodose line, and the intratumoral mean dose was 17.9 Gy (12-22.9). All 10 patients had neurological symptoms, with a mean Karnofsky physical score (KPS) of 60 (range, 50-70) on the day of treatment. None of these patients required neurosurgical or emergency consultation related to worsening of neurological symptoms between the first and second treatments. At 30 days, the mean KPS was 80 and maintained at 80 at the last follow-up (range, 60-100; P=0.002), and mean lesion volume was 4.1 ml (range, 1.3-70 ml). The mean prescription dose for the second treatment was 12 Gy (range, 9-18 Gy) to the 50% isodose line, and the intratumoral mean dose was 17.9 Gy (11-22.4). The mean overall survival was 24 months (range, 3-32 months). At last follow-up, three patients (30%) had died, two of systemic progression and one of tumor progression, and at one year, local tumor control was 91% and 19 (86%) lesions showed documented local control at last follow up. In those tumors that progressed, the mean time to progression was eight months (range, 5-20 months), and the mean time to surgery was nine months (range, 5-32 months). Conclusion Two-session radiosurgery proved to be a safe treatment for patients with large, symptomatic metastases in this series. Neurological worsening after radiosurgery for large lesions of breast and lung histology may be an infrequent event. This strategy in radiosurgery may have neurological benefits for these patients providing adequate local tumor control while reducing the need of upfront surgery at diagnosis.

A series of tests were carried out to study the combined effect of plastic fiber, metal fiber, and the optimum percentage of natural hydraulic lime (NHL) in gravelly soils with clays. The methodology employed was to incorporate lime percentages of 2, 4, 6, 8, and 12% by weight into the natural soil, determining the optimum lime content by UCS test. Then, combinations of 0.5PF5MF8NHL, 1PF10MF8NHL, 2.5PF15MF8NHL, and 3.5PF20MF8NHL, respectively, were made to replace the natural soil. The PFs had a dimension of 40 mm long and 5 mm wide, and the MFs had a dimension of 100 mm long and 5 mm wide. The latter underwent chemical treatment before being included in the soil itself. Various tests such as Atterberg limits, compaction, California bearing capacity (CBR), and unconfined compressive strength (UCS) were performed to understand the impact of the additives on the soil. As novel results, the soil does not present plasticity when fibers are combined with NHL. In addition, both the optimum moisture content and maximum dry density show inversely proportional values of significant reduction and increase as a function of the combinations. On the other hand, the 1.5PF10MF8NHL combination showed an improvement in strength gain in the CBR of 152.11% and the UCS test of 759.80% at 28 days. However, the remaining combinations showed improvement, but not as significant as 1.5PF10MF8NHL. It is concluded that the combination of the three additives together has a significant positive impact on the mechanical properties of gravelly soil with clays, achieving successful stabilization.

Current serology tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies mainly take the form of enzyme-linked immunosorbent assays, chemiluminescent microparticle immunoassays or lateral flow assays, which are either laborious, expensive or lacking sufficient sensitivity and scalability. Here we present the development and validation of a rapid, low-cost, solution-based assay to detect antibodies in serum, plasma, whole blood and to a lesser extent saliva, using rationally designed split luciferase antibody biosensors. This new assay, which generates quantitative results in 30 min, substantially reduces the complexity and improves the scalability of coronavirus disease 2019 (COVID-19) antibody tests. This assay is well-suited for point-of-care, broad population testing, and applications in low-resource settings, for monitoring host humoral responses to vaccination or viral infection. A rapid, split luciferase test for SARS-CoV-2 antibodies in blood and saliva compatible with lyophilization and use in low-resource settings.

BACKGROUNDThe presence and reactivation of chronic viral infections, such as EBV, CMV, and HIV, have been proposed as potential contributors to long COVID (LC), but studies in well-characterized postacute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited.METHODSIn a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status) and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms.RESULTSWe observed that LC symptoms, such as fatigue and neurocognitive dysfunction, at a median of 4 months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) or high nuclear antigen (EBNA) IgG levels but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (early antigen-diffuse IgG positivity) was most strongly associated with fatigue (OR = 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).CONCLUSIONOverall, these findings suggest differential effects of chronic viral coinfections on the likelihood of developing LC and association with distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted.TRIAL REGISTRATIONLong-term Impact of Infection with Novel Coronavirus; ClinicalTrials.gov NCT04362150.FUNDINGThis work was supported by NIH/National Institute of Allergy and Infectious Diseases grants (3R01AI141003-03S1, R01AI158013, and K24AI145806); the Zuckerberg San Francisco General Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine; and the UCSF-Bay Area Center for AIDS Research (P30-AI027763).

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity. Of 12 serology assays tested, four detect antibodies in more than 80% of patients with COVID-19.

Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123 + cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5–0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07–0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ). In a phase 1 trial followed by translational analyses, patients with acute myeloid leukemia (AML) treated with chimeric antigen receptor (CAR) T cell therapy targeting CD123 experienced high levels of cytokine release syndrome and short-lived clinical responses, probably due to CAR T cell-derived cytokines increasing the viability of AML blasts and antigen persistence.

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35–56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71–120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.