Mural Wnt/ß-catenin signaling regulates Lama2 expression to promote neurovascular unit maturation.

Neurovascular unit and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are crucial for these processes, yet the signaling pathway(s) that regulate their expression remain unknown. Here, we show that mural cells have active Wnt/ß-catenin signaling during central nervous system development in mice. Bulk RNA sequencing and validation using postnatal day 10 and 14 wild-type versus adenomatosis polyposis coli downregulated 1 (Apcdd1-/-) mouse retinas revealed that Lama2 mRNA and protein levels are increased in mutant vasculature with higher Wnt/ß-catenin signaling. Mural cells are the main source of Lama2, and Wnt/ß-catenin activation induces Lama2 expression in mural cells in vitro. Markers of mature astrocytes, including aquaporin 4 (a water channel in astrocyte endfeet) and integrin-α6 (a laminin receptor), are upregulated in Apcdd1-/- retinas with higher Lama2 vBM deposition. Thus, the Wnt/ß-catenin pathway regulates Lama2 expression in mural cells to promote neurovascular unit and barrier maturation.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Oral antivirals for COVID-19 among patients with cancer.

PURPOSE: Immunocompromised individuals, such as those diagnosed with cancer, are at a significantly higher risk for severe illness and mortality when infected with SARS-CoV-2 (COVID-19) than the general population. Two oral antiviral treatments are approved for COVID-19: Paxlovid® (nirmatrelvir/ritonavir) and Lagevrio® (molnupiravir). There is a paucity of data regarding the benefit from these antivirals among immunocompromised patients with cancer, and recent studies have questioned their efficacy among vaccinated patients, even those with risk factors for severe COVID-19. METHODS: We evaluated the efficacy and safety of nirmatrelvir/ritonavir and molnupiravir in preventing severe illness and death using our database of 457 patients with cancer and COVID-19 from Brown University-affiliated hospitals. RESULTS: Sixty-seven patients received nirmatrelvir/ritonavir or molnupiravir and were compared to 45 concurrent controls who received no antiviral treatment despite being eligible to receive it. Administration of nirmatrelvir/ritonavir or molnupiravir was associated with improved survival and lower 90-day all-cause and COVID-19-attributed mortality (p < 0.05) and with lower peak O2 requirements (ordinal odds ratio [OR] 1.52, 95% confidence interval [CI] 0.92-2.56). CONCLUSION: Acknowledging the small size of our sample as a limitation, we concluded that early antiviral treatment might be beneficial to immunocompromised individuals, particularly those with cancer, when infected with SARS-CoV-2. Larger-scale, well-stratified studies are needed in this patient population.

Progressive Multifocal Leukoencephalopathy Unmasked by Teclistamab in a Refractory Multiple Myeloma Patient.

This case report describes the development of Progressive Multifocal Leukoencephalopathy (PML) in a 72-year-old male with relapsed/refractory multiple myeloma (RRMM), following a single dose of teclistamab amidst a COVID-19 infection. Shortly after starting teclistamab treatment, the patient developed symptoms, including fever, altered mental status, and right-sided paresis. A diagnosis of PML was confirmed through the detection of JC virus PCR in the cerebrospinal fluid. Our report emphasizes the occurrence of PML after only one dose of teclistamab and highlights teclistamab's potential for severe infectious complications, despite its promise in treating RRMM.

Cytomegalovirus infection and cardiovascular outcomes in abdominal organ transplant recipients: A systematic review and meta-analysis.

INTRODUCTION: Despite advancements in Cytomegalovirus (CMV) management, its impact on graft function, mortality, and cardiovascular (CV) health of organ transplant recipients (OTR) remains a significant concern. We investigated the association between CMV infection and CV events (CVE) in organ (other than heart) transplant recipients. METHODS: We conducted a comprehensive literature search in PubMed and EMBASE, including studies that reported on CMV infection or disease and post-transplantation CVE. Studies of heart transplant recipients were excluded. RESULTS: We screened 3875 abstracts and 12 clinical studies were included in the final analysis, mainly in kidney and liver transplant recipients. A significant association was observed between CMV infection and an increased risk of CVE, with a pooled unadjusted hazard ratio (HR) of 1.99 (95% Confidence Intervals [CI] 1.45-2.73) for CMV infection and 1.59 (95% CI 1.21-2.10) for CMV disease. Pooled adjusted HR were 2.17 (95% CI 1.47-3.20) and 1.77 (95% CI 0.83-3.76), respectively. Heterogeneity was low (I2 = 0%) for CMV infection, suggesting consistent association across studies, and moderate-to-high for CMVdisease (I2 = 50% for unadjusted, 53% for adjusted HR). DISCUSSION: We found a significant association between CMV infection and CV risk in abdominal OTR, underscoring the importance of proactive CMV surveillance and early treatment. Future research should aim for more standardized methodologies to fully elucidate the relationship between CMV and CV outcomes, potentially informing novel preventive and therapeutic strategies that could benefit the CV health of OTR.

Oral antivirals for COVID-19 among patients with cancer.

Purpose: Immunocompromised individuals, such as those diagnosed with cancer, are at a significantly higher risk for severe illness and mortality when infected with SARS-CoV-2 (COVID-19) than the general population. Two oral antiviral treatments are approved for COVID-19: Paxlovid® (nirmatrelvir/ritonavir) and Lagevrio® (molnupiravir). There is a paucity of data regarding the benefit from these antivirals among immunocompromised patients with cancer, and recent studies have questioned their efficacy among vaccinated patients, even those with risk factors for severe COVID-19. Methods: We evaluated the efficacy and safety of nirmatrelvir/ritonavir and molnupiravir in preventing severe illness and death using our database of 457 patients with cancer and COVID-19 from Brown University-affiliated hospitals. 67 patients received nirmatrelvir/ritonavir or molnupiravir and were compared to 56 concurrent controls who received no antiviral treatment despite being eligible to receive it. Results: Administration of nirmatrelvir/ritonavir or molnupiravir was associated with improved survival and lower 90-day all-cause and COVID-19-attributed mortality (p<0.05) and with lower peak O2 requirements (ordinal odds ratio [OR] 1.52, 95% confidence interval [CI] 0.92-2.56). Conclusion: Acknowledging the small size of our sample as a limitation, we concluded that early antiviral treatment might be beneficial to immunocompromised individuals, particularly those with cancer, when infected with SARS-CoV-2. Larger-scale, well-stratified studies are needed in this patient population.

Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/ß-catenin signaling.

Interactions among neuronal, glial and vascular components are crucial for retinal angiogenesis and blood-retinal barrier (BRB) maturation. Although synaptic dysfunction precedes vascular abnormalities in many retinal pathologies, how neuronal activity, specifically glutamatergic activity, regulates retinal angiogenesis and BRB maturation remains unclear. Using in vivo genetic studies in mice, single-cell RNA-sequencing and functional validation, we show that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1 -/- retinas where neurons fail to release glutamate. In contrast, deep plexus angiogenesis and paracellular BRB maturation are accelerated in Gnat1 -/- retinas where constitutively depolarized rods release excessive glutamate. Norrin expression and endothelial Norrin/ß-catenin signaling are downregulated in Vglut1 -/- retinas, and upregulated in Gnat1 -/- retinas. Pharmacological activation of endothelial Norrin/ß-catenin signaling in Vglut1 -/- retinas rescued defects in deep plexus angiogenesis and paracellular BRB maturation. Our findings demonstrate that glutamatergic neuronal activity regulates retinal angiogenesis and BRB maturation by modulating endothelial Norrin/ß-catenin signaling.

Glutamatergic neuronal activity regulates angiogenesis and blood-retinal barrier maturation via Norrin/ß-catenin signaling.

Interactions among neuronal, glial, and vascular components are crucial for retinal angiogenesis and blood-retinal barrier (BRB) maturation. Although synaptic dysfunction precedes vascular abnormalities in many retinal pathologies, how neuronal activity, specifically glutamatergic activity, regulates retinal angiogenesis and BRB maturation remains unclear. Using in vivo genetic studies in mice, single-cell RNA sequencing (scRNA-seq), and functional validation, we show that deep plexus angiogenesis and paracellular BRB maturation are delayed in Vglut1-/- retinas where neurons fail to release glutamate. By contrast, deep plexus angiogenesis and paracellular BRB maturation are accelerated in Gnat1-/- retinas, where constitutively depolarized rods release excessive glutamate. Norrin expression and endothelial Norrin/ß-catenin signaling are downregulated in Vglut1-/- retinas and upregulated in Gnat1-/- retinas. Pharmacological activation of endothelial Norrin/ß-catenin signaling in Vglut1-/- retinas rescues defects in deep plexus angiogenesis and paracellular BRB maturation. Our findings demonstrate that glutamatergic neuronal activity regulates retinal angiogenesis and BRB maturation by modulating endothelial Norrin/ß-catenin signaling.

Outpatient anti-spike monoclonal antibody administration is associated with decreased morbidity and mortality among patients with cancer and COVID-19.

BACKGROUND: Patients with cancer have many comorbidities that increase their risk of death from Coronavirus disease 2019 (COVID-19). Anti-spike monoclonal antibodies (mAbs) reduce the risk of hospitalization or death from COVID-19 in the general population. To our knowledge, no studies have focused on the clinical efficacy of mAbs compared to no outpatient treatment exclusively among patients with solid tumors and hematologic malignancies, who are often excluded from clinical trials. METHODS: We studied patients with cancer who had COVID-19 between 11.9.2020 and 7.21.2022 and received mAbs in an outpatient setting. We compared hospitalization and mortality rates to those of patients with cancer concurrently diagnosed with COVID-19, who were eligible for mAbs, but did not receive any outpatient treatment. RESULTS: 63 patients received mAbs and 89 no outpatient treatment. Administration of mAbs was associated with lower 90-day hospitalization (20.6% vs. 60.7%, p<0.001), all-cause (6.3% vs. 19.1%, p=0.025) and COVID-19-attributed (3.2% vs. 14.6%, p=0.019) mortality rates, and lower peak O2 requirements (ordinal Odds Ratio [OR]=0.33, 95%Confidence Intervals [CI]=0.20-0.53). Administration of mAbs (aHR 0.21, p<0.001), age (≥ 60 years, adjusted Hazard Ratio [aHR] 1.86, p=0.033), and metastases (aHR 0.41, p=0.007) were independently associated with hospitalization. mAb treatment remained significantly associated with all-cause (aHR 0.27, p=0.019) and COVID-19-attributed (aHR 0.19, p=0.031) mortality, after adjustment for other factors. CONCLUSIONS: mAb administration was associated with improved clinical outcomes among vulnerable patients with cancer and COVID-19. With no mAbs approved currently for treatment against the prevalent circulating variants, the development of new mAbs should be a research priority.

Outpatient anti-spike monoclonal antibody administration is associated with decreased morbidity and mortality among patients with cancer and COVID-19.

Patients with cancer have many comorbidities that increase their risk of death from Coronavirus disease 2019 (COVID-19). Anti-spike monoclonal antibodies (mAbs) reduce the risk of hospitalization or death from COVID-19 in the general population. To our knowledge, no studies have focused on the clinical efficacy of mAbs compared to no outpatient treatment exclusively among patients with solid tumors and hematologic malignancies, who are often excluded from clinical trials. We studied patients with cancer who had COVID-19 between 11.9.2020 and 7.21.2022 and received mAbs in an outpatient setting. We compared hospitalization and mortality rates to those of patients with cancer concurrently diagnosed with COVID-19, who were eligible for mAbs, but did not receive any outpatient treatment. 63 patients received mAbs and 89 no outpatient treatment. Administration of mAbs was associated with lower 90-day hospitalization (20.6% vs. 60.7%, p <0.001), all-cause (6.3% vs. 19.1%, p 0.025) and COVID-19-attributed (3.2% vs. 14.6%, p 0.019) mortality rates, and lower peak O2 requirements (ordinal Odds Ratio [OR] = 0.33, 95% Confidence Intervals [CI] = 0.20-0.53). Administration of mAbs (aHR 0.21, p <0.001), age (≥ 60 years, adjusted Hazard Ratio [aHR] 1.86, p=0.033), and metastases (aHR 0.41, p 0.007) were independently associated with hospitalization. mAb treatment remained significantly associated with all-cause (aHR 0.27, p 0.019) and COVID-19-attributed (aHR 0.19, p 0.031) mortality, after adjustment for other factors. mAb administration was associated with improved clinical outcomes among vulnerable patients with cancer and COVID-19. With no mAbs approved currently for treatment against the prevalent circulating variants, the development of new mAbs should be a research priority.

Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis.

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

mRNA Vaccination Decreases COVID-19-Associated Morbidity and Mortality Among Organ Transplant Recipients: A Contemporary Cohort Study.

Background: Organ transplant recipients (OTRs) are less protected from vaccination than immunocompetent hosts. Additional vaccine doses have shown increased immunogenicity. Few studies have assessed their clinical efficacy, particularly against Omicron variants, as most included patients from earlier phases of the pandemic, with higher base mortality rates. Methods: We studied adult OTRs who had coronavirus disease 2019 (COVID-19) between 12/15/21 and 5/25/22. We compared clinical outcomes between those who had received 2 or ≥3 doses of an mRNA vaccine and concurrent unvaccinated controls. Results: Among 103 OTRs, vaccination was associated with lower 90-day mortality (unvaccinated vs 2 vs ≥3 doses: 25% vs 7% vs 3%; P = .003), hospital (unvaccinated vs 2 vs ≥3 doses: 56% vs 37% vs 27%; P = .018) and intensive care unit (ICU; unvaccinated vs 2 vs ≥3 doses: 25% vs 15% vs 3%; P = .001) admission rates, and peak O2 requirements (ordinal scale Kendall's tau b = -0.309 [lower scores, ie, O2 requirements with more vaccine doses]; P = .003). Age (age >60 years: adjusted hazard ratio [aHR], 7.73; P = .016; administration of antispike monoclonal antibody: aHR, 0.17; P = .042) and vaccination, especially with ≥3 doses (aHR, 0.105; P = .01), were independently associated with 90-day mortality. Black (P = .021) and Hispanic (P = .016) OTRs were underrepresented among the vaccinated, especially in the ≥3-dose group. Conclusions: Despite lower mRNA vaccine efficacy in OTRs and against Omicron variants, vaccination protects this vulnerable patient population from severe COVID-19 and death. Ethnic and racial disparities in health care have been exacerbated by the COVID-19 pandemic and warrant better community outreach efforts.