Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES).

BACKGROUND: Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery. METHODS: We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major noncardiac surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery. RESULTS: A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to noncardiac surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, P<0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, P=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, P<0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]). CONCLUSIONS: Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before noncardiac surgery.

Plastic ingestion by green turtles (Chelonia mydas) over 33 years along the coast of Texas, USA.

Despite exponential growth of anthropogenic marine debris in recent decades, plastic ingestion by marine turtles in the Gulf of Mexico is not well understood. Gastrointestinal tracts were examined from 464 green turtles that stranded in Texas between 1987 and 2019, and 226 turtles ingested plastic (48.7%). This number doubled from 32.5% in 1987-1999 to 65.5% in 2019, but mass of ingested items was lowest in 2019. No turtles showed evidence of death directly related to plastic ingestion. Compared to other regions, plastic ingestion was low. Small turtles (<25 cm straight carapace length) ingested plastic more frequently and in greater amounts than larger turtles. Small turtles also ingested more hard plastic while larger turtles ingested more sheet-like and thread-like plastics, which may correspond to size-based habitat shifts. This is among the largest marine turtle ingestion studies to date and demonstrates an increasing prevalence of plastic ingestion.

Contamination of multiuse eyedrop bottles by exhaled air from patients wearing face masks during the COVID-19 pandemic: Schlieren imaging analysis.

PURPOSE: To determine whether mask-induced redirected exhaled air through the superior mask gap contacts multiuse eyedrop bottles during drop administration and the efficacy of interventions to reduce such exposure. SETTING: Academic ophthalmology center. DESIGN: Interventional analysis. METHODS: Schlieren airflow imaging was taken of an examinee wearing frequently used face masks and enacting common clinical scenarios-with and without manual occlusion of the superior mask gap and/or neck extension-and maximum visible vertical breath plume height was quantified. Bottle height during eyedrop administration was measured for 4 ophthalmologists during instillation to 8 eyes of 4 subjects. RESULTS: Breath plume height (mean ± SD 275.5 ± 16.3 mm) was significantly greater than mean bottle height (13.9 ± 4.7 mm; P < .01). Plume height was reduced with manual mask occlusion vs without (P < .01) and was also lower than mean bottle height with manual mask occlusion (P < .01) but not in the absence of occlusion (P < .01). Neck extension alone did not adequately redirect liberated breath to prevent contact with a bottle. CONCLUSIONS: Exhaled air liberated from commonly worn patient face masks was able to contact multiuse eyedrop bottles during eyedrop administration. These findings have important patient safety implications during the coronavirus disease 2019 pandemic and with other respiratory pathogens because these multiuse bottles could potentially serve as vectors of disease. Occlusion of the superior mask gap significantly reduces breath contamination and should be strongly considered by eyecare providers during drop administration in eye clinics.

An evaluation of bird and bat mortality at wind turbines in the Northeastern United States.

Wind energy offers substantial environmental benefits, but wind facilities can negatively impact wildlife, including birds and bats. Researchers and managers have made major efforts to chronicle bird and bat mortality associated with wind facilities, but few studies have examined the patterns and underlying mechanisms of spatial patterns of fatalities at wind facilities. Understanding the horizontal fall distance between a carcass and the nearest turbine pole is important in designing effective search protocols and estimating total mortality. We explored patterns in taxonomic composition and fall distance of bird and bat carcasses at wind facilities in the Northeastern United States using publicly available data and data submitted to the US Fish and Wildlife Service under scientific collecting and special purpose utility permits for collection and study of migratory birds. Forty-four wind facilities reported 2,039 bird fatalities spanning 128 species and 22 facilities reported 418 bat fatalities spanning five species. Relative to long-distance migratory birds, short-distance migrants were found farther from turbines. Body mass of birds and bats positively influenced fall distance. Turbine size positively influenced fall distance of birds and bats when analyzed collectively and of birds when analyzed separately from bats. This suggests that as turbines increase in size, a greater search radius will be necessary to detect carcasses. Bird and bat fall distance distributions were notably multimodal, but only birds exhibited a high peak near turbine bases, a novel finding we attribute to collisions with turbine poles in addition to blades. This phenomenon varied across bird species, with potential implications for the accuracy of mortality estimates. Although pole collisions for birds is intuitive, this phenomenon has not been formally recognized. This finding may warrant an updated view of turbines as a collision threat to birds because they are a tall structure, and not strictly as a function of their motion.

The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation.

Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portend poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the proinflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. In this study, we manipulated three putative nuclear localization (NLS1 to -3) and two potential nuclear export signals (NES1 and -2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, MSH3 with this deletion (Δ27bp MSH3) localizes to the cytoplasm, suggesting that NLS1 function in Δ27bp MSH3 is compromised. Overall, MSH3's shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammation-associated neoplastic processes.

Prognostic role of diastolic dysfunction in patients undergoing transcatheter aortic valve replacement.

OBJECTIVES: Prior studies have shown that left ventricular diastolic dysfunction (DD) is associated with increased mortality after surgical aortic valve replacement but studies on transcatheter aortic valve replacement (TAVR) are limited and have not taken into account mitral annular calcification (MAC), which limits the use of mitral valve annular tissue Doppler imaging. We performed a single-center retrospective analysis to better evaluate the role of baseline DD on outcomes after TAVR. METHODS: After excluding patients with atrial fibrillation, mitral valve prostheses and significant mitral stenosis, 359 consecutive TAVR patients were included in the study. Moderate-to-severe MAC was present in 58% of the patients. We classified patients into severe versus nonsevere DD based on the evaluation of elevated left ventricular filling pressure. The outcome measure was all-cause mortality or heart failure hospitalization. RESULTS: Over a mean follow-up time of 13 months, severe DD was associated with an increased risk for the outcome measure (HR 2.02 [1.23-3.30], p = .005). However, this association was lost in a propensity-matched cohort. In multivariate analysis, STS score was the only independent predictor of all cause mortality of heart failure hospitalization (HR 1.1 [1.05-1.15], p < .001). CONCLUSIONS: We evaluated the role of baseline DD on outcomes after TAVR by taking into account the presence of MAC. Severe DD was associated with increased all-cause mortality or heart failure hospitalization but not independently of other structural parameters and known predictors of the outcome measure.

Subclinical atrial fibrillation detection with a floating atrial sensing dipole in single lead implantable cardioverter-defibrillator systems: Results of the SENSE trial.

INTRODUCTION: Subclinical atrial fibrillation (AF), in the form of cardiac implantable device-detected atrial high rate episodes (AHREs), has been associated with increased thromboembolism. An implantable cardioverter-defibrillator (ICD) lead with a floating atrial dipole may permit a single lead (DX) ICD system to detect AHREs. We sought to assess the utility of the DX ICD system for subclinical AF detection in patients, with a prospective multicenter, cohort-controlled trial. METHODS AND RESULTS: One hundred fifty patients without prior history of AF (age 59 ± 13 years; 108 [72%] male) were enrolled into the DX cohort and implanted with a Biotronik DX ICD system at eight centers. Age-, sex-, and left ventricular ejection fraction-matched single- and dual-chamber ICD cohorts were derived from a Cornell database and from the IMPACT trial, respectively. The primary endpoint were AHRE detection at 12 months. During median 12 months follow-up, AHREs were detected in 19 (13%) patients in the DX, 8 (5.3%) in the single-chamber, and 19 (13%) in the dual-chamber cohorts. The rate of AHRE detection was significantly higher in the DX cohort compared to the single-chamber cohort (P = .026), but not significantly different compared to the dual-chamber cohort. There were no inappropriate ICD therapies in the DX cohort. At 12 months, only 3.0% of patients in the DX cohort had sensed atrial amplitudes less than 1.0 mV. CONCLUSION: Use of a DX ICD lead allows subclinical AF detection with a single lead DX system that is superior to that of a conventional single-chamber ICD system.

Regional isolation in the right atrium with disruption of intra-atrial conduction after catheter ablation of atrial tachycardia.

BACKGROUND: Ablation of atrial tachycardia (AT) that occurs after cardiac surgery or prior ablation often requires complex lesion sets. In combination with the pre-existing atrial scar, these lesion sets may result in inadvertent intra-atrial conduction block. This study reports the phenomenon of incidental isolation of right atrial (RA) regions that occurs secondary to AT ablation, which in some cases results in profound bradycardia due to sinus exit block. METHODS AND RESULTS: Intracardiac electrograms were examined in consecutive patients who underwent AT ablation in the RA. Cases of localized isolation of the RA were defined as areas that developed electrical dissociation during ablation. Of 132 patients having ablation in both the RA free wall and the cavotricuspid isthmus (CTI), 10 (7.6%) developed unintentional isolation of the lateral RA. Five of these patients had prior mitral valve surgery, comprising 12.2% of all 41 patients with mitral surgery who underwent ablation in the CTI and the RA free wall. All patients with regional isolation had a pre-existing scar in the lateral wall of the RA. In six patients, isolation of the lateral RA resulted in profound bradycardia due to exit block from the peri-sinus node myocardium. CONCLUSIONS: Complex ablation lesions in patients with prior valve surgery, prior ablation, or atrial myopathy may result in unintended localized conduction block in the RA. In some cases, isolation of the lateral RA can result in complete sinus exit block with profound bradycardia requiring pacemaker implantation.

Impact of Mitral Regurgitation Severity and Cause on Effort Tolerance-Integrated Stress Myocardial Perfusion Imaging and Echocardiographic Assessment of Patients With Known or Suspected Coronary Artery Disease Undergoing Exercise Treadmill Testing.

Background Mitral regurgitation ( MR ) has the potential to impede exercise capacity; it is uncertain whether this is because of regurgitation itself or the underlying cause of valvular insufficiency. Methods and Results The population comprised 3267 patients who underwent exercise treadmill myocardial perfusion imaging and transthoracic echocardiography within 6±8 days. MR was present in 28%, including 176 patients (5%) with moderate or greater MR . Left ventricular systolic function significantly decreased and chamber size increased in relation to MR , paralleling increments in stress and rest myocardial perfusion deficits (all P<0.001). Exercise tolerance (metabolic equivalents of task) decreased stepwise in relation to graded MR severity ( P<0.05). Workload was significantly lower with mild versus no MR (mean±SD, 9.8±3.0 versus 10.1±3.0; P=0.02); magnitude of workload reduction significantly increased among patients with advanced versus those with mild MR (mean±SD, 8.6±3.0 versus 9.8±3.0; P<0.001). MR -associated exercise impairment was accompanied by lower heart rate and blood pressure augmentation and greater dyspnea (all P<0.05). Both functional and nonfunctional MR subgroups demonstrated significantly decreased effort tolerance in relation to MR severity ( P≤0.01); impairment was greater with functional MR ( P=0.04) corresponding to more advanced left ventricular dysfunction and dilation (both P<0.001). Functional MR predicted reduced metabolic equivalent of task-based effort (B=-0.39 [95% CI, -0.62 to -0.17]; P=0.001) independent of MR severity. Among the overall cohort, advanced (moderate or greater) MR was associated with reduced effort tolerance (B=-1.36 [95% CI, -1.80 to -0.93]; P<0.001) and remained significant ( P=0.01) after controlling for age, clinical indexes, stress perfusion defects, and left ventricular dysfunction. Conclusions MR impairs exercise tolerance independent of left ventricular ischemia, dysfunction, and clinical indexes. Magnitude of exercise impairment parallels severity of MR .

Improving implantable cardioverter defibrillator deactivation discussions in admitted patients made DNR and comfort care.

Background: Unintended shocks from implantable cardioverter defibrillators (ICDs) are often distressing to patients and family members, particularly at the end of life. Unfortunately, a large proportion of ICDs remain active at the time of death among do not resuscitate (DNR) and comfort care patients. Methods: We designed standardised teaching sessions for providers and implemented a novel decision tool in the electronic medical record (EMR) to improve the frequency of discussions surrounding ICD deactivation over a 6-month period. The intended population was patients on inpatient medicine and cardiology services made DNR and/or comfort care. These rates were compared with retrospective data from 6 months prior to our interventions. Results: After our interventions, the rates of discussions regarding deactivation of ICDs improved from 50% to 93% in comfort care patients and from 32% to 70% in DNR patients. The rates of deactivated ICDs improved from 45% to 73% in comfort care patients and from 29% to 40% in DNR patients. Conclusion: Standardised education of healthcare providers and decision support tools and reminders in the EMR system are effective ways to increase awareness, discussion and deactivation of ICDs in comfort care and DNR patients.

Reversible Conjunctival Pigmentation Associated With Prostaglandin Use.

A 54-year-old Indian male with a diagnosis of ocular hypertension was started on a prostaglandin analog (PGA) in both eyes to lower intraocular pressure. Six years later, he developed progressively increasing bilateral limbal conjunctival hyperpigmentation. Travoprost was discontinued and replaced with brinzolamide and over the next year, the patient's conjunctival pigmentation improved significantly in both the eyes. This case report documents with slit-lamp photography the first case of conjunctival pigmentation associated with PGA use that has been shown to have reversal with discontinuation of the PGA. Because of the widespread use of PGAs, and the evolving nature of the conjunctival pigmentation, clinicians should be aware of this reversible condition when considering biopsy or removal of conjunctival melanocytic lesions.

Cataract surgery in the glaucoma patient.

To summarize the role of cataract surgery in the glaucoma patient, in terms of the effect on intraocular pressure (IOP) as well as diagnostic and therapeutic considerations for those with both conditions. Recent evidence suggests that cataract extraction may produce a significant and sustained IOP reduction in individuals with open-angle glaucoma, ocular hypertension, and angle-closure glaucoma. Cataract removal may improve the practitioner's ability to interpret perimetric testing, and re-establishing perimetric and optic nerve imaging baselines is recommended after cataract surgery. The sequence of cataract surgery relative to glaucoma surgery impacts the likelihood of complications and surgical success. There are multiple benefits to perform cataract surgery prior to glaucoma surgery while cataract surgery after trabeculectomy increases the risk of subsequent filtration failure. As "minimally invasive glaucoma surgeries" continue to improve in terms of efficacy, there is an evolving role for combined cataract and glaucoma surgery in patients with early to moderate stages of glaucoma.

Interleukin 6 alters localization of hMSH3, leading to DNA mismatch repair defects in colorectal cancer cells.

BACKGROUND & AIMS: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is the most common DNA mismatch repair defect in colorectal cancers, observed in approximately 60% of specimens. This acquired genotype correlates with metastasis and poor outcomes for patients, and is associated with intra-epithelial inflammation and heterogeneous nuclear levels of the mismatch repair protein hMSH3. Inflammation and accompanying oxidative stress can cause hMSH3 to change its intracellular location, but little is known about the source of oxidative stress in cancer cells. We investigated whether cytokines mediate this process. METHODS: We analyzed levels of interleukin 6 (IL6) and its receptor (IL6R) in human colon and lung cancer cell lines by flow cytometry and enzyme-linked immunosorbent assay; proteins were localized by immunofluorescence and immunoblot analyses. IL6 signaling was blocked with antibodies against IL6, soluble glycoprotein 130 Fc fragments, and the signal transducers and activators of transcription 3 inhibitor NSC74859; a constitutively active form of STAT3 was expressed in colon and lung cancer cell lines to replicate IL6R signaling. EMAST was detected by DNA fragment analysis. Immunohistochemistry was used to examine levels of IL6 in 20 colorectal tumor and adjacent nontumor tissues. RESULTS: Incubation of colon and lung cancer cell lines with IL6, but not other cytokines, caused hMSH3, but no other mismatch repair proteins, to move from the nucleus to the cytosol after generation of oxidative stress; inhibition of IL6 signaling prevented this shift. Expression of constitutively active STAT3 also caused hMSH3 to translocate from the nucleus to the cytoplasm in cancer cell lines. Incubation of cells with IL6 led to tetranucleotide frameshifts, the signature for EMAST. EMAST-positive colorectal tumors had significantly higher levels of IL6 than EMAST-negative tumors. CONCLUSIONS: IL6 signaling disrupts the nuclear localization of hMSH3 and DNA repair, leading to EMAST in cancer cell lines. Inflammatory cytokines might therefore promote genetic alterations in human cancer cells.

Activation of the endoplasmic reticulum unfolded protein response by lipid disequilibrium without disturbed proteostasis in vivo.

The Mediator is a conserved transcriptional coregulator complex required for eukaryotic gene expression. In Caenorhabditis elegans, the Mediator subunit mdt-15 is essential for the expression of genes involved in fatty acid metabolism and ingestion-associated stress responses. mdt-15 loss of function causes defects in reproduction and mobility and shortens lifespan. In the present study, we find that worms with mutated or depleted mdt-15 (mdt-15 worms) exhibit decreased membrane phospholipid desaturation, especially in phosphatidylcholine. Accordingly, mdt-15 worms exhibit disturbed endoplasmic reticulum (ER) homeostasis, as indicated by a constitutively activated ER unfolded protein response (UPR(ER)). Activation of this stress response is only partially the consequence of reduced membrane lipid desaturation, implicating other mdt-15-regulated processes in maintaining ER homeostasis. Interestingly, mdt-15 inactivation or depletion of the lipid metabolism enzymes stearoyl-CoA-desaturases (SCD) and S-adenosyl methionine synthetase (sams-1) activates the UPR(ER) without promoting misfolded protein aggregates. Moreover, these worms exhibit wild-type sensitivity to chemically induced protein misfolding, and they do not display synthetic lethality with mutations in UPR(ER) genes, which cause protein misfolding. Therefore, the constitutively activated UPR(ER) in mdt-15, SCD, and sams-1 worms is not the consequence of proteotoxic stress but likely is the direct result of changes in ER membrane fluidity and composition. Together, our data suggest that the UPR(ER) is induced directly upon membrane disequilibrium and thus monitors altered ER homeostasis.

Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib.

PURPOSE: To investigate elevated intraocular pressures (IOP) (defined by a measurement >25 mmHg at a follow-up visit) after an intravitreal injection of anti-vascular endothelial growth factor agents for age-related macular degeneration. METHODS: Retrospective review of medical records. RESULTS: A total of 127 patients (155 eyes) received an intravitreal injection of anti-vascular endothelial growth factor agents (bevacizumab, ranibizumab, or pegaptanib) ranging from 1 to 39 injections for more than a period of 30 to 1759 days. Among this population, 12 patients (14 eyes; 9.4%) developed elevated IOP >25 mmHg. Of these, 7 patients (5.5%) developed sustained elevated IOP (IOP >25 mmHg on 2 separate visits requiring glaucoma medication or surgery), of which 8 eyes required topical medications and 1 eye underwent glaucoma surgery. Mean IOP of injected eyes receiving intravitreal injection was 15.2 ± 2.4 mmHg, and the mean IOP was 14.9 ± 2.6 mmHg for noninjected eyes. Among eyes that had elevated IOPs, there was no association with injection frequency, number of injections, or anti-vascular endothelial growth factor agent used. CONCLUSION: Elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon. No association with patient demographics or injection history was identified in the authors' study population.

Polybasic KKR motif in the cytoplasmic tail of Nipah virus fusion protein modulates membrane fusion by inside-out signaling.

The cytoplasmic tails of the envelope proteins from multiple viruses are known to contain determinants that affect their fusogenic capacities. Here we report that specific residues in the cytoplasmic tail of the Nipah virus fusion protein (NiV-F) modulate its fusogenic activity. Truncation of the cytoplasmic tail of NiV-F greatly inhibited cell-cell fusion. Deletion and alanine scan analysis identified a tribasic KKR motif in the membrane-adjacent region as important for modulating cell-cell fusion. The K1A mutation increased fusion 5.5-fold, while the K2A and R3A mutations decreased fusion 3- to 5-fold. These results were corroborated in a reverse-pseudotyped viral entry assay, where receptor-pseudotyped reporter virus was used to infect cells expressing wild-type or mutant NiV envelope glycoproteins. Differential monoclonal antibody binding data indicated that hyper- or hypofusogenic mutations in the KKR motif affected the ectodomain conformation of NiV-F, which in turn resulted in faster or slower six-helix bundle formation, respectively. However, we also present evidence that the hypofusogenic phenotypes of the K2A and R3A mutants were effected via distinct mechanisms. Interestingly, the K2A mutant was also markedly excluded from lipid rafts, where approximately 20% of wild-type F and the other mutants can be found. Finally, we found a strong negative correlation between the relative fusogenic capacities of these cytoplasmic-tail mutants and the avidities of NiV-F and NiV-G interactions (P = 0.007, r(2) = 0.82). In toto, our data suggest that inside-out signaling by specific residues in the cytoplasmic tail of NiV-F can modulate its fusogenicity by multiple distinct mechanisms.

N-glycans on Nipah virus fusion protein protect against neutralization but reduce membrane fusion and viral entry.

Nipah virus (NiV) is a deadly emerging paramyxovirus. The NiV attachment (NiV-G) and fusion (NiV-F) envelope glycoproteins mediate both syncytium formation and viral entry. Specific N-glycans on paramyxovirus fusion proteins are generally required for proper conformational integrity and biological function. However, removal of individual N-glycans on NiV-F had little negative effect on processing or fusogenicity and has even resulted in slightly increased fusogenicity. Here, we report that in both syncytium formation and viral entry assays, removal of multiple N-glycans on NiV-F resulted in marked increases in fusogenicity (>5-fold) but also resulted in increased sensitivity to neutralization by NiV-F-specific antisera. The mechanism underlying the hyperfusogenicity of these NiV-F N-glycan mutants is likely due to more-robust six-helix bundle formation, as these mutants showed increased fusion kinetics and were more resistant to neutralization by a fusion-inhibitory reagent based on the C-terminal heptad repeat region of NiV-F. Finally, we demonstrate that the fusogenicities of the NiV-F N-glycan mutants were inversely correlated with the relative avidities of NiV-F's interactions with NiV-G, providing support for the attachment protein "displacement" model of paramyxovirus fusion. Our results indicate that N-glycans on NiV-F protect NiV from antibody neutralization, suggest that this "shielding" role comes together with limiting cell-cell fusion and viral entry efficiencies, and point to the mechanisms underlying the hyperfusogenicity of these N-glycan mutants. These features underscore the varied roles that N-glycans on NiV-F play in the pathobiology of NiV entry but also shed light on the general mechanisms of paramyxovirus fusion with host cells.