Clinico-Epidemiologic Characteristics of Patients Reported in the Mycotic Infections in COVID-19 Registry.

We update results from the Mycotic Infections in COVID-19 (MUNCO) Registry, May-September 2021. Data collection from May to September 2021 yielded 728 cases from India, Nepal, Bangladesh, Thailand, and the United States. The cases consisted of mostly mucormycosis (97.6%), primarily rhinocerebral, and were analyzed to investigate clinical characteristics associated with negative outcomes. Patients were mostly diabetic (85%) and male (76%), with significant mortality (11.7%). All patients received treatment of coronavirus disease 2019 (COVID-19) as well as antifungal treatment. The crude mortality rate was 11.3% for mucormycosis and 22.7% formixed infections. This study demonstrates the utility of online databases in the collection of high-caliber data.

A Case of Latent Plasmodium Falciparum Malaria in a Patient With Coexisting Systemic Lupus Erythematosus (SLE) and Neuromyelitis Optica Spectrum Disorder (NMOSD).

Malaria is a global health concern with high morbidity and mortality. It is often attributed to the Plasmodium (P.) falciparum species, particularly in sub-Saharan Africa, and it normally has an incubation period of seven to 14 days. Dormant disease secondary to P. vivax and P. ovale is well-reported, yet only a handful of cases report dormant malaria secondary to P. falciparum. Even though malaria is significantly less common in the United States in comparison to other parts of the world, it is still a growing concern given international travel from endemic regions and a growing immunocompromised population. Here, we present a case of Plasmodium falciparum malaria in a patient with systemic lupus erythematosus (SLE) with neuromyelitis optica spectrum disorder (NMOSD) and renal transplant without travel to sub-Saharan Africa in 10 years.

Altered Mental Status: An Important but Overlooked Presenting Symptom of COVID-19 in Older Adults.

OBJECTIVES: To determine whether altered mental status (AMS) as a presenting symptom in older adults with COVID-19 is independently associated with adverse outcomes. METHODS: A retrospective single center observational study of admitted patients (n = 421) age greater than 60 and a positive COVID-19 test. Outcomes included mortality, intubation, acute respiratory distress syndrome, acute kidney injury, and acute cardiac injury. Multivariate regression analysis was used to determine if presenting with AMS was associated with adverse outcomes. RESULTS: There was an increased risk of mortality (RR 1.29, 95% CI 1.05-1.57), intubation (RR 1.52, 95% CI 1.09-2.12) and AKI (RR 1.42, 95% CI 1.13-1.78) in patients that presented with AMS. CONCLUSIONS: During a global pandemic, prognostic indicators are vital to help guide the clinical course of patients, reduce healthcare cost, and preserve life. Our study suggests that AMS can play a major role in diagnostic algorithms in older adults with COVID-19.

Non-invasive positive pressure ventilation versus endotracheal intubation in treatment of COVID-19 patients requiring ventilatory support.

IMPORTANCE: Initial guidelines recommended prompt endotracheal intubation rather than non-invasive ventilation (NIV) for COVID-19 patients requiring ventilator support. There is insufficient data comparing the impact of intubation versus NIV on patient-centered outcomes of these patients. OBJECTIVE: To compare all-cause 30-day mortality for hospitalized COVID-19 patients with respiratory failure who underwent intubation first, intubation after NIV, or NIV only. DESIGN: Retrospective study of patients admitted in March and April of 2020. SETTING: A teaching hospital in Brooklyn, New York City. PARTICIPANTS: Adult COVID-19 confirmed patients who required ventilator support (non-invasive ventilation and/or endotracheal intubation) at discretion of treating physician, were included. EXPOSURES: Patients were categorized into three exposure groups: intubation-first, intubation after NIV, or NIV-only. PRIMARY OUTCOME: 30-day all-cause mortality, a predetermined outcome measured by multivariable logistic regression. Data are presented with medians and interquartile ranges, or percentages with 95% confidence intervals, for continuous and categorical variables, respectively. Covariates for the model were age, sex, qSOFA score ≥ 2, presenting oxygen saturation, vasopressor use, and greater than three comorbidities. A secondary multivariable model compared mortality of all patients that received NIV (intubation after NIV and NIV-only) with the intubation-first group. RESULTS: A total of 222 were enrolled. Overall mortality was 77.5% (95%CI, 72-83%). Mortality for intubation-first group was 82% (95%CI, 73-89%; 75/91), for Intubation after NIV was 84% (95%CI, 70-92%; 37/44), and for NIV-only was 69% (95%CI, 59-78%; 60/87). In multivariable analysis, NIV-only was associated with decreased all-cause mortality (odds ratio [OR]: 0.30, 95%CI, 0.13-0.69). No difference in mortality was observed between intubation-first and intubation after NIV. Secondary analysis found all patients who received NIV to have lower mortality than patients who were intubated only (OR: 0.44, 95%CI, 0.21-0.95). CONCLUSIONS & RELEVANCE: Utilization of NIV as the initial intervention in COVID-19 patients requiring ventilatory support is associated with significant survival benefit. For patients intubated after NIV, the mortality rate is not worse than those who undergo intubation as their initial intervention.

The impact of obesity on COVID-19 complications: a retrospective cohort study.

BACKGROUND: Obesity is an epidemic in New York City, the global epicenter of the coronavirus pandemic. Previous studies suggest that obesity is a possible risk factor for adverse outcomes in COVID-19. OBJECTIVE: To elucidate the association between obesity and COVID-19 outcomes. DESIGN: Retrospective cohort study of COVID-19 hospitalized patients tested between March 10 and April 13, 2020. SETTING: SUNY Downstate Health Sciences University, a COVID-only hospital in New York. PARTICIPANTS: In total, 684 patients were tested for COVID-19 and 504 were analyzed. Patients were categorized into three groups by BMI: normal (BMI 18.50-24.99), overweight (BMI 25.00-29.99), and obese (BMI ≥ 30.00). MEASUREMENTS: Primary outcome was 30-day in-hospital mortality, and secondary outcomes were intubation, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and acute cardiac injury (ACI). RESULTS: There were 139 patients (27%) with normal BMI, 150 patients who were overweight (30%), and 215 patients with obesity (43%). After controlling for age, gender, diabetes, hypertension, and qSOFA score, there was a significantly increased risk of mortality in the overweight (RR 1.4, 95% CI 1.1-1.9) and obese groups (RR 1.3, 95% CI 1.0-1.7) compared with those with normal BMI. Similarly, there was a significantly increased relative risk for intubation in the overweight (RR 2.0, 95% CI 1.2-3.3) and obese groups (RR 2.4, 95% CI 1.5-4.0) compared with those with normal BMI. Obesity did not affect rates of AKI, ACI, or ARDS. Furthermore, obesity appears to significantly increase the risk of mortality in males (RR 1.4, 95% CI 1.0-2.0, P = 0.03), but not in females (RR 1.2, 95% CI 0.77-1.9, P = 0.40). CONCLUSION: This study reveals that patients with overweight and obesity who have COVID-19 are at increased risk for mortality and intubation compared to those with normal BMI. These findings support the hypothesis that obesity is a risk factor for COVID-19 complications and should be a consideration in management of COVID-19.

The juxtamembrane linker in neutral sphingomyelinase-2 functions as an intramolecular allosteric switch that activates the enzyme.

Neutral sphingomyelinase 2 (nSMase2) produces the bioactive lipid ceramide and has important roles in neurodegeneration, cancer, and exosome formation. Although nSMase2 has low basal activity, it is fully activated by phosphatidylserine (PS). Previous work showed that interdomain interactions within nSMase2 are needed for PS activation. Here, we use multiple approaches, including small angle X-ray scattering, hydrogen-deuterium exchange-MS, circular dichroism and thermal shift assays, and membrane yeast two-hybrid assays, to define the mechanism mediating this interdomain interactions within nSMase2. In contrast to what we previously assumed, we demonstrate that PS binding at the N-terminal and juxtamembrane regions of nSMase2 rather acts as a conformational switch leading to interdomain interactions that are critical to enzyme activation. Our work assigns a unique function for a class of linkers of lipid-activated, membrane-associated proteins. It indicates that the linker actively participates in the activation mechanism via intramolecular interactions, unlike the canonical linkers that typically aid protein dimerization or localization.

Structure of human nSMase2 reveals an interdomain allosteric activation mechanism for ceramide generation.

Neutral sphingomyelinase 2 (nSMase2, product of the SMPD3 gene) is a key enzyme for ceramide generation that is involved in regulating cellular stress responses and exosome-mediated intercellular communication. nSMase2 is activated by diverse stimuli, including the anionic phospholipid phosphatidylserine. Phosphatidylserine binds to an integral-membrane N-terminal domain (NTD); however, how the NTD activates the C-terminal catalytic domain is unclear. Here, we identify the complete catalytic domain of nSMase2, which was misannotated because of a large insertion. We find the soluble catalytic domain interacts directly with the membrane-associated NTD, which serves as both a membrane anchor and an allosteric activator. The juxtamembrane region, which links the NTD and the catalytic domain, is necessary and sufficient for activation. Furthermore, we provide a mechanistic basis for this phenomenon using the crystal structure of the human nSMase2 catalytic domain determined at 1.85-Å resolution. The structure reveals a DNase-I-type fold with a hydrophobic track leading to the active site that is blocked by an evolutionarily conserved motif which we term the "DK switch." Structural analysis of nSMase2 and the extended N-SMase family shows that the DK switch can adopt different conformations to reposition a universally conserved Asp (D) residue involved in catalysis. Mutation of this Asp residue in nSMase2 disrupts catalysis, allosteric activation, stimulation by phosphatidylserine, and pharmacological inhibition by the lipid-competitive inhibitor GW4869. Taken together, these results demonstrate that the DK switch regulates ceramide generation by nSMase2 and is governed by an allosteric interdomain interaction at the membrane interface.