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Although the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.

BACKGROUND: Up to 85% of patients with sickle cell disease (SCD) will develop gallstones by their third decade. Cholecystectomy is the most commonly performed procedure in these patients. Cholecystectomy is recommended for patients with SCD with symptomatic cholelithiasis and leads to lower morbidity. No contemporary large studies have evaluated this recommendation or associated clinical outcomes. This study evaluates clinical outcomes after cholecystectomy in patients with SCD and cholelithiasis with specific advanced clinical presentations. STUDY DESIGN: The Nationwide Inpatient Sample was queried for patients with SCD and gallbladder disease between 2006 and 2015. Patients were divided into groups based on their disease presentation, including uncomplicated cholelithiasis, acute and chronic cholecystitis, and gallstone pancreatitis. Clinical outcomes associated with disease presentation were analyzed. Statistical analysis was performed using the Student’s t-test, chi-square test, ANOVA, and logistic regression. RESULTS: There were 6,662 patients with SCD who presented with cholelithiasis. Median age was 20 (interquartile range 16 to 34) years and 54% were female patients. Cholecystectomy was performed in 1,779 patients with SCD with the most common indication being chronic cholecystitis (44%), followed by uncomplicated cholelithiasis (27%), acute cholecystitis (21%), and choledocholithiasis or gallstone pancreatitis (8%). On multivariable regression, advanced clinical presentation was the strongest predictor of perioperative vaso-occlusive crisis, which was the most common complication. Patients undergoing cholecystectomy for uncomplicated cholelithiasis were at lower risk than those with acute cholecystitis (odds ratio [OR] 2.37; 95% CI 1.64 to 3.41), chronic cholecystitis (OR 1.74; 95% CI 1.26 to 2.4), and choledocholithiasis or gallstone pancreatitis (OR 2.24; 95% CI 1.41 to 3.57). CONCLUSIONS: Seventy-three percent of patients with SCD have advanced clinical presentation at the time of their cholecystectomy. After cholecystectomy, perioperative vaso-occlusive events were significantly increased in patients with advanced clinical presentation. These data support screening abdominal ultrasounds and early cholecystectomy for cholelithiasis in patients with SCD.

Niacin, an important component of a balanced diet, is central to lipid metabolism. Occasionally used to treat hyperlipidemia, niacin is widely available without a prescription, making its use often unknown to treating physicians. Severe hepatotoxicity has been reported with niacin use. In the following report, we describe a case of hospitalization for acute decompensated cirrhosis with cholestatic morphology in a patient taking self-initiated large quantities of extended-release niacin. Despite medical management and support, the patient unfortunately expired on day 16 of hospitalization. Given ease of access and unclear long-term benefit in hyperlipidemia, the current case serves to raise awareness of niacin’s potential hepatotoxicity through highlighting a severe outcome. Although mode of liver injury remains unknown, the use of extended-release niacin formulations and prolonged high-dose supplementation is associated with enhanced hepatotoxicity. Careful review and counseling of commonly available supplements remains an important task of both hospital and primary care physicians.

Purpose of review The purpose of this review is to outline the temporal bone management of external and middle ear carcinoma. The review will outline the current evidence involved in deciding which surgical approach to take, as well as new advances in auditory rehabilitation and immunotherapy. Recent findings Traditional surgical approaches include lateral temporal bone resection, subtotal temporal bone resection and total temporal bone resection. They can also involve parotidectomy and neck dissection depending on extension of disease into these areas. Options for auditory rehabilitation include osseointegrated hearing aids, transcutaneous bone-conduction implants, and active middle ear implants. Recent advances in immunotherapy have included the use of anti-PD-1 monoclonal antibodies. Summary The mainstay of management of temporal bone disease involves surgical resection. Early-stage tumours classified according to the Pittsburgh staging tool can often be treated with lateral temporal bone resection, whereas late-stage tumours might need subtotal or total temporal bone resection. Parotidectomy and neck dissection might also be indicated if there is a risk of occult regional disease. Recent advances in immunotherapy have been promising, particularly around anti-PD-1 inhibitors. However, larger clinical trials will be required to test the extent of efficacy, particularly around combination use with surgery.

Purpose of review The purpose of this review is to provide a comprehensive anatomical appraisal of the neurosurgical anatomy exposed through the endonasal and paranasal sinuses routes, focusing on the most common expanded endonasal approaches (EEAs) as well as recent advances in this surgical field. Recent findings The EEAs are redefining the management of skull base pathology. Neurovascular structures previously considered a limitation, can be now approached through these surgical corridors. Advances in this field include the development of new surgical techniques and routes that allow better visualization and access to pathologies located in the ventral skull base. Understanding the surgical anatomy related to EEAs is essential not only for neurosurgeons but also for rhinologists. Summary Knowledge of the surgical anatomy of the most common EEAs that utilize paranasal sinuses as a surgical corridor enables more effective management of complex skull base pathologies. Comprehensive anatomical knowledge of these corridors and the surrounding neurovascular structures is crucial to maximize benefits of EEAs and improve outcomes.

AbstractBackgroundThrough whole‐exome sequencing of 60 formalin‐fixed paraffin‐embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non‐European populations are lacking.MethodsIn this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH.ResultsTwo hundred and two nonbenign, ClinVar‐annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co‐occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co‐occurring interactions. Two hundred and seventy‐nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11‐595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair.ConclusionsNGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.