Safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2

Summary Background We used the RNActive® technology platform (CureVac N.V., Tübingen, Germany) to prepare CVnCoV, a COVID-19 vaccine containing sequence-optimized mRNA coding for a stabilized form of SARS-CoV‑2 spike (S) protein encapsulated in lipid nanoparticles (LNP). Methods This is an interim analysis of a dosage escalation phase 1 study in healthy 18–60-year-old volunteers in Hannover, Munich and Tübingen, Germany, and Ghent, Belgium. After giving 2 intramuscular doses of CVnCoV or placebo 28 days apart we assessed solicited local and systemic adverse events (AE) for 7 days and unsolicited AEs for 28 days after each vaccination. Immunogenicity was measured as enzyme-linked immunosorbent assay (ELISA) IgG antibodies to SARS-CoV‑2 S‑protein and receptor binding domain (RBD), and SARS-CoV‑2 neutralizing titers (MN50). Results In 245 volunteers who received 2 CVnCoV vaccinations (2 μg, n = 47, 4 μg, n = 48, 6 μg, n = 46, 8 μg, n = 44, 12 μg, n = 28) or placebo (n = 32) there were no vaccine-related serious AEs. Dosage-dependent increases in frequency and severity of solicited systemic AEs, and to a lesser extent local AEs, were mainly mild or moderate and transient in duration. Dosage-dependent increases in IgG antibodies to S‑protein and RBD and MN50 were evident in all groups 2 weeks after the second dose when 100% (23/23) seroconverted to S‑protein or RBD, and 83% (19/23) seroconverted for MN50 in the 12 μg group. Responses to 12 μg were comparable to those observed in convalescent sera from known COVID-19 patients. Conclusion In this study 2 CVnCoV doses were safe, with acceptable reactogenicity and 12 μg dosages elicited levels of immune responses that overlapped those observed in convalescent sera.

Dosage escalation of antenatal steroids in preterm twin pregnancies does not improve long-term outcome

Objectives To analyze long-term effects of antenatal betamethasone (≤16 mg, =24 mg and >24 mg) in preterm twins on infant and childhood morbidity. Methods Retrospective cohort study among 198 preterm twins. Three follow up time points, including a total of 84 outcomes, were evaluated: first neonatal examination after birth and in the neonatal period up to 10 days after birth using data from the clinic charts; examination from the 21st to the 24th month of life and examination from the 60th to the 64th months, using data from copies of the children’s examination booklets sent back by the parents. Dosage-dependent and sex-specific long-term effects of antenatal betamethasone treatment on neonatal, infant and early childhood development and morbidity up to 5.3 years of age were analyzed. Results Dosage escalation of >24 mg was not associated with improved neonatal, infant or early child hood outcome, independent of twin pair structure. In contrast, higher doses >24 mg were significantly linked to increased rates of congenital infections (OR 5.867, 95% CI 1.895–18.167). Male sex as a factor was obvious for lower rates of apnea-bradycardia-syndrome in neonates, higher rates of no free steps after 15 months in infancy and highest rates of motor clumsiness in early childhood. Conclusions Betamethasone dosage escalation >24 mg in twins born between 23+5 and 33+6 weeks of gestation did not improve neonatal, infant or early childhood morbidity. In contrast, higher doses >24 mg total dose resulted in significantly higher rates of congenital infections and are not recommended. For males, 24 mg betamethasone appears to be the preferable dose.

COVID-19 and Its Implications for Thrombosis and Anticoagulation

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in extracorporeal membrane oxygenation (ECMO) devices, acute limb ischemia, and isolated strokes, all in the face of prophylactic and even therapeutic anticoagulation, are features of novel coronavirus disease 2019 (COVID-19) coagulopathy. It seems well established at this time that a COVID-19 patient deemed sick enough to be hospitalized, should receive at least prophylactic dose anticoagulation. However, should some hospitalized patients have dosage escalation to intermediate dose? Should some be considered for full-dose anticoagulation without a measurable thromboembolic event and how should that anticoagulation be monitored? Should patients receive postdischarge anticoagulation and with what medication and for how long? What thrombotic issues are related to the various medications being used to treat this coagulopathy? Is antiphospholipid antibody part of this syndrome? What is the significance of isolated ischemic stroke and limb ischemia in this disorder and how does this interface with the rest of the clinical and laboratory features of this disorder? The aims of this article are to explore these questions and interpret the available data based on the current evidence.

Hypokalemia associated with mifepristone use in the treatment of Cushing’s syndrome

Summary Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia. Learning points: Mifepristone, a potent antagonist of glucocorticoid receptors, has a high risk of adrenal insufficiency, despite high cortisol levels. Mifepristone is associated with hypokalemia due to spill-over effect of cortisol on unopposed mineralocorticoid receptors. Given the lack of a biochemical parameter to assess improvement, the dosing of mifepristone is based on clinical progress. Patients on mifepristone require anticipation of toxicity, especially when the dose is escalated. The half-life of mifepristone is 85 h, requiring prolonged monitoring for toxicity, even after the medication is held.

Population Pharmacokinetics of Anidulafungin in Critically Ill Patients

ABSTRACT A two-compartment pharmacokinetic (PK) population model of anidulafungin was fitted to PK data from 23 critically ill patients (age, 65 years [range, 28 to 81 years]; total body weight [TBW], 75 kg [range, 54 to 168 kg]). TBW was associated with clearance and incorporated into a final population PK model. Simulations suggested that patients with higher TBWs had less-extensive MIC coverage. Dosage escalation may be warranted in patients with high TBWs to ensure optimal drug exposures for treatment of Candida albicans and Candida glabrata infections.