INTRAVENOUS VITAMIN C SUPPLEMENTATION IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS: SALUTARY IMPACT ON CLINICAL OUTCOMES.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (SCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic hematopoietic stem cell transplant (HSCT) were evaluated in a phase I/II trial and clinical outcomes compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies were enrolled in a phase 2 clinical trial, receiving IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HSCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C: these include 10/10 HLA-MRD and MUD (n=48) and 9/10 HLA MUD recipients (n=7). All patients enrolled were deficient in vitamin C at day 0 and had restoration to normal levels for the remainder of the course. Vitamin C recipients had lower non-relapse mortality (11% vs. 25%, p-value = 0.07) and consequently, improved survival compared to historical controls (82% vs 62% p=0.06), with no attributable grade 3 and 4 toxicities to vitamin C. Patients with myeloid malignancies had improved survival (83% vs. 54%, p=0.02) and non-relapse mortality (NRM) (10% vs. 37%, p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HSCT the administration of IV vitamin C is safe and reduces non-relapse mortality improving overall survival. Randomized trials are needed to confirm the utility of this easily available and inexpensive therapy.

Intravenous Vitamin C Supplementation in Allogeneic Hematopoietic Cell Transplant Recipients: Salutary Impact on Clinical Outcomes.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (HCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic HCT were evaluated in a phase I/II trial. Clinical outcomes were compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies received IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C. All patients were deficient in vitamin C at day 0. Vitamin C recipients had lower non-relapse mortality (NRM) (p = 0.07) and improved survival compared to historical controls (p=0.06), with no attributable grade 3 and 4 toxicities. Vitamin C recipients had similar relapse rate and acute graft versus host disease (GVHD) (p=0.35), but lower severe chronic GVHD (p=0.35). Patients with myeloid malignancies had improved survival (p=0.02) and NRM (p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HCT the administration of IV vitamin C is safe and reduces non-relapse mortality and chronic GVHD improving overall survival.

The Interplay between α-Synuclein and Microglia in α-Synucleinopathies.

Synucleinopathies are a set of devastating neurodegenerative diseases that share a pathologic accumulation of the protein α-synuclein (α-syn). This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown, microglia, the resident immune cells of the central nervous system (CNS), have been consistently implicated in the pathogenesis of synucleinopathies. Microglia are generally believed to be neuroprotective in the early stages of α-syn accumulation and contribute to further neurodegeneration in chronic disease states. While the molecular mechanisms by which microglia achieve this role are still being investigated, here we highlight the major findings to date. In this review, we describe how structural varieties of inherently disordered α-syn result in varied microglial receptor-mediated interactions. We also summarize which microglial receptors enable cellular recognition and uptake of α-syn. Lastly, we review the downstream effects of α-syn processing within microglia, including spread to other brain regions resulting in neuroinflammation and neurodegeneration in chronic disease states. Understanding the mechanism of microglial interactions with α-syn is vital to conceptualizing molecular targets for novel therapeutic interventions. In addition, given the significant diversity in the pathophysiology of synucleinopathies, such molecular interactions are vital in gauging all potential pathways of neurodegeneration in the disease state.

Microbial Profile and Clinical Outcomes of Fungal Keratitis at a Single-Center Tertiary Care Hospital.

PURPOSE: To evaluate baseline characteristics, microbiological spectrum, management, and outcomes of patients with culture-proven fungal keratitis. METHODS: Retrospective review of all patients with culture-proven fungal keratitis seen over 6 years at a tertiary referral center. RESULTS: The present study included 62 eyes from 62 patients. Infection with filamentous organisms was more common than with yeast (66.1% vs 27.4%). The most common filamentous organisms were Fusarium (17.7%) and Aspergillus (16.1%), while the most common yeast was Candida (24.2%). The main predisposing factor for filamentous keratitis was contact lens use. Yeast keratitis is most associated with an immunocompromised host and ocular surface disease. Corneal perforation (20.0%) and surgical interventions (46.8%) were common, with 27.4% of eyes requiring at least one penetrating keratoplasty. Filamentous keratitis is more likely than yeast keratitis to require urgent penetrating keratoplasty or enucleation and to receive more than one topical and systemic antifungal agent. Visual outcomes were poor with nearly half of the eyes remaining at 20/200 or worse upon resolution of infection. Worse visual outcomes were associated with poor vision at presentation and a history of ocular surface disease. Antifungal susceptibility testing was not routinely performed, but it demonstrated a relatively high minimum inhibitory concentration for at least one antifungal drug in 90% of cases when performed (16.1%) and guided the direction of treatment for 80% of the cases. CONCLUSION: Fungal keratitis is visually devastating. Infections with filamentous fungi predominated over yeast and were generally treated more aggressively both medically and surgically. Filamentous and yeast keratitis had similar durations of infections and visual outcomes. Antifungal susceptibility testing influenced treatment in 80% of cases in which it was performed.

Protection against SARS-CoV-2 Beta variant in mRNA-1273 vaccine-boosted nonhuman primates.

Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.ß, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.

Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates.

Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 µg of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.ß (heterologous), which encompasses the spike sequence of the B.1.351 (beta or ß) variant. Reciprocal ID 50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the ß variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost ß-specific reciprocal ID 50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the ß variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations. ONE-SENTENCE SUMMARY: mRNA-1273 boosted nonhuman primates have increased immune responses and are protected against SARS-CoV-2 beta infection.

Lymphocyte Activation Gene 3 (Lag3) Contributes to α-Synucleinopathy in α-Synuclein Transgenic Mice.

Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson's disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.

Delayed diagnoses of Acanthamoeba keratitis at a tertiary care medical centre.

PURPOSE: To determine the prevalence and reasons for delays in diagnosis in patients with Acanthamoeba keratitis (AK) presenting to Wilmer Eye Institute, Baltimore, Maryland. METHODS: This retrospective study analysed all patients with culture-positive AK seen between 2012 and 2019 at a tertiary referral centre. Patient demographic information, clinical history, risk factors, symptom duration, referral patterns, slit lamp examination findings, visual acuity and need for surgery were collected. RESULTS: The study included 45 eyes of 43 patients. On average, patients were symptomatic for 52.6 days before culture collection. Thirty-one percent of patients were diagnosed within 28 days of symptom onset while 69% were diagnosed after 28 days. Before presentation to a tertiary care centre, 69% of patients were evaluated by an ophthalmologist outside of this institution and 27% were evaluated by a provider other than an ophthalmologist. AK was most commonly misdiagnosed as herpetic keratitis, occurring in 38% of patients. The strongest risk factor for AK was contact lens use. Only 11% of patients presented with the classic ring infiltrate and 82% had pain. Patients with an early versus late diagnosis had a mean Snellen visual acuity (VA) of 20/224 versus 20/296 at presentation (p = 0.33) and a mean Snellen VA of 20/91 versus 20/240 at final visit (p = 0.07). 11% of patients required a therapeutic penetrating keratoplasty. CONCLUSION: Delayed diagnosis of AK in our cohort occurred due to a misdiagnosis as herpetic keratitis, non-specific clinical signs including the lack of pain in a number of patients, and a delay in referral to a tertiary care centre. Any contact lens wearer with an atypical keratitis should be referred promptly for Acanthamoeba cultures.