The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2.

The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of spike, such as the S2 subdomain. Here, we present a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in S2, including regions outside of those commonly reported. One of the S2 mAbs, C20.119, which bound to a highly conserved epitope in the fusion peptide, was able to broadly neutralize across SARS-CoV-2 variants, SARS-CoV-1, and closely related zoonotic sarbecoviruses. The majority of the mAbs were non-neutralizing; however, many of them could mediate antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1-targeting mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Several of the mAbs with ADCC function also bound to spike trimers from other human coronaviruses (HCoVs), such as MERS-CoV and HCoV-HKU1. Our findings suggest S2 mAbs can target diverse epitopes in S2, including functional mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.

Confirmation of the Intracoronary Near-Infrared Spectroscopy Threshold of Lipid-Rich Plaques That Underlie ST-Segment-Elevation Myocardial Infarction.

OBJECTIVE: In a previous exploratory analysis, intracoronary near-infrared spectroscopy (NIRS) found the majority of culprit lesions in ST-segment-elevation myocardial infarction (STEMI) to contain a maximum lipid core burden index in 4 mm (maxLCBI4mm) of >400. This initial study was limited by a small sample size, enrollment at a single center, and post hoc selection of the maxLCBI4mm ≥400 threshold. This study was designed a priori to substantiate the ability of NIRS to discriminate STEMI culprit from nonculprit segments and to confirm the performance of the maxLCBI4mm ≥400 threshold. APPROACH AND RESULTS: At 2 centers in the United States and Sweden, 75 STEMI patients underwent intracoronary NIRS imaging after establishing thrombolysis in myocardial infarction 3 flow, but before stenting. Blinded core laboratory analysis defined the culprit segment as the 10-mm segment distal to the proximal angiographic culprit margin. The remaining vessel was divided into contiguous 10-mm nonculprit segments. The maxLCBI4mm of culprit segments (median [interquartile range]: 543 [273-756]) was 4.4-fold greater than nonculprit segments (median [interquartile range]: 123 [0-307]; P<0.001). Receiver-operating characteristic analysis demonstrated that maxLCBI4mm differentiated culprit from nonculprit segments with high accuracy (c-statistic=0.83; P<0.001). A threshold maxLCBI4mm ≥400 identified STEMI culprit segments with a sensitivity of 64% and specificity of 85%. CONCLUSIONS: This study substantiates the ability of NIRS to accurately differentiate STEMI culprit from nonculprit segments and confirms that a threshold maxLCBI4mm ≥400 is detected by NIRS in the majority of STEMI culprits.

Methylation markers for prostate cancer prognosis: a systematic review.

PURPOSE: We conducted a systematic review to summarize current evidence on the prognostic utility of DNA methylation markers in prostate cancer and ascertain knowledge gaps to inform future research. METHODS: We identified relevant studies using combined key search against PubMed database. Inclusion criteria were studies of human subjects that examined the association between DNA methylation markers and prostate cancer disease outcomes. The methodological quality of each study was systematically evaluated. Findings were qualitatively summarized. Due to heterogeneity and concerns of internal validity, no meta-analysis was performed. RESULTS: Twenty studies were reviewed; sample size ranged from 35 to 605 men in the prognostic analyses. Sixteen studies examined methylation markers in prostate cancer tissue and four examined circulating DNA methylation markers. Of all genes reviewed, paired-like homeodomain transcription factor 2 (PITX2) methylation was examined in two more rigorously designed studies and was found to be associated with biochemical recurrence. Common limitations in current literature included small sample sizes,lack of adequate adjustment for established prognostic factors, and poor reporting quality. CONCLUSION: Evidence on the prognostic utility of methylation markers in prostate cancer is inconclusive. Future research should ascertain large samples with adequate follow-up and include patients of racial/ethnic minority and those treated with modalities other than prostatectomy(e.g., using prostate cancer diagnostic biopsy as tissue source).

Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population.

BACKGROUND: The benefit of vaccinating immunocompetent patients who have had shingles has not been examined. The study assessed the association between vaccination and the incidence of herpes zoster recurrence among persons with a recent episode of clinically diagnosed herpes zoster. METHODS: This is a matched cohort study in Kaiser Permanente Southern California. Study populations were immunocompetent elderly individuals ≥ 60 years old with a recent episode of herpes zoster. Incidence of recurrent herpes zoster was compared between the vaccinated and the unvaccinated matched cohorts. RESULTS: A total of 1036 vaccinated and 5180 unvaccinated members were included. On the basis of clinically confirmed cases, the incidence of recurrent herpes zoster among persons aged <70 years was 0.99 (95% confidence interval [CI], .02-5.54) and 2.20 (95% CI, 1.10-3.93) cases per 1000 person-years in the vaccinated and unvaccinated cohorts, respectively. The adjusted hazard ratio was 0.39 (95% CI, .05-4.45) among persons aged <70 years and 1.05 (95% CI, .30-3.69) among persons aged ≥ 70 years. CONCLUSIONS: The risk of herpes zoster recurrence following a recent initial episode is fairly low among immunocompetent adults, regardless of vaccination status. Such a low risk suggests that one should evaluate the necessity of immediately vaccinating immunocompetent patients who had a recent herpes zoster episode.

Family history of zoster and risk of developing herpes zoster.

BACKGROUND: Studies have investigated a possible association between family history of HZ and the occurrence of HZ. However, the results were inconclusive and susceptible to bias. We evaluated this association in an elderly population. METHODS: The matched case-control study conducted at Kaiser Permanente Southern California in 2012-2015 included 656 incident HZ patients ≥60 whose skin lesion tested positive for varicella zoster virus by polymerase chain reaction. Half of the HZ patients were vaccinated with zoster vaccine as achieved by stratified sampling. The controls were randomly selected and 1:1 matched to the cases on sex, age (±1year), and zoster vaccination (±3 months of the case's vaccination date). Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Having any blood relative with a history of HZ was associated with a slightly increased risk of HZ (adjusted OR=1.37, 95% CI 1.05-1.79). The adjusted OR associated with having one and two categories of first-degree blood relatives with a history of HZ was 1.30 (95% CI: 0.97-1.73) and 2.53 (95% CI: 1.17-5.44), respectively. CONCLUSIONS: Our results suggested a weak association between the development of HZ and a positive family history of HZ among the elderly population.

Combined Near-Infrared Spectroscopy and Intravascular Ultrasound Imaging of Pre-Existing Coronary Artery Stents: Can Near-Infrared Spectroscopy Reliably Detect Neoatherosclerosis?

BACKGROUND: Neoatherosclerosis is an emerging phenomenon in which lipid-rich plaques (LRPs) develop within pre-existing stents. This study was undertaken to describe near-infrared spectroscopy (NIRS) and intravascular ultrasound findings in pre-existing stents and to compare NIRS findings in pre-existing stents, in which an increased lipid signal has been speculated to indicate neoatherosclerosis, and NIRS findings in a control group of freshly implanted stents, in which any lipid signal originates from fibroatheroma under the stent. METHODS AND RESULTS: At the site of LRP detected by NIRS in a cohort of pre-existing stents, intravascular ultrasound was used to determine the presence of neointimal tissue. The lipid-core burden index and maximum lipid-core burden index in 4 mm were measured within stented segments. Findings were compared between pre-existing stents and a control group of freshly implanted stents. Among 60 pre-existing stents implanted 5.5±4.0 years earlier, NIRS detected LRP in 33%. At the site of LRP, intravascular ultrasound found no neointimal tissue in 35% of cases. NIRS findings in pre-existing stents were indistinguishable from those of freshly implanted stents (lipid-core burden index: 50±72 versus 42±58; P=0.40 and maximum lipid-core burden index in 4 mm: 156±184 versus 155±203; P=0.69). CONCLUSIONS: The detection of LRP in a pre-existing stent by NIRS alone is not reliable evidence of neoatherosclerosis, as the lipid signal may originate from fibroatheroma underlying the stent. By identifying the presence or absence of neointimal tissue at the site of LRP detected by NIRS, intravascular ultrasound may provide some insight into the potential source of the lipid signal in pre-existing stents. REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01694368.

Immunomodulatory agents and risk of postpartum multiple sclerosis relapses.

OBJECTIVE: To determine whether treatment with an interferon beta or glatiramer acetate shortly after delivery reduces the otherwise increased risk of postpartum relapses of multiple sclerosis. METHODS: In a retrospective cohort of 112 women with multiple sclerosis and live births from Kaiser Permanente Southern California, complete medical and pharmacy records of the mothers and infants were reviewed. Propensity score-adjusted hazard ratios (HR) of time to first postpartum relapse were calculated. RESULTS: Of 80 women who breastfed little or not at all, 55 (69%) resumed treatment within 1 year postpartum, of whom 26 (47%) relapsed within 6 months postpartum. Resuming treatment within 2 weeks postpartum did not decrease the risk of relapse in the 2 years postpartum compared with women who resumed treatment later in the postpartum year (propensity score-adjusted HR = 1.3, 95% confidence interval = 0.5-3.4, p = 0.6). There was no difference in relapse rates between the groups in the first 6 months postpartum. However, later in the postpartum year those who resumed treatment early had fewer relapses (p = 0.08, Poisson regression). CONCLUSIONS: Among women who breastfeed little or not at all, starting treatment with interferon beta or glatiramer acetate within two weeks postpartum does not reduce the risk of postpartum relapse of multiple sclerosis but may reduce the risk of subsequent relapses in the postpartum year.

Adherence to statins and LDL-cholesterol goal attainment.

OBJECTIVES: To examine the relationship between low-density lipoprotein cholesterol (LDL-C) goal attainment and adherence to statin medications in patients with coronary artery disease (CAD). STUDY DESIGN: Cross-sectional study of CAD patients 18 years of age or older in an integrated healthcare system. METHODS: Patients dispensed 2 or more statin prescriptions between May 2009 and May 2010, were identified. Medication possession ratio (MPR) was calculated to estimate adherence. The LDL-C value closest to May 27, 2010, was used to determine goal. Adherence and LDL-C goal were defined as 80% or greater MPR and less than 100 mg/dL or less than 70 mg/dL, respectively. Electronic medical records were used to identify patient demographics and clinical information. Logistic regression was used to estimate the effect of these factors on goal attainment. RESULTS: A total of 67,100 CAD patients were identified. Overall, 85.8% had LDL-C less than 100 mg/dL, 32.4% had LDL less than 70 mg/dL, and 79.8% were adherent to their statin medication. Over 65% of patients not at LDL-C goal less than 100 mg/dL were adherent. Among patients with LDL-C less than 100 mg/dL, 17.9% were not adherent. Increasing medication adherence was associated with improved LDL-C levels. Adherence to statins, male sex, Asian and Hispanic race/ethnicity, a higher number of concurrent prescriptions, higher Charlson Comorbidity Index, and hypertension were associated with LDL-C goal attainment. CONCLUSIONS: Incorporating LDL-C levels and medication adherence at the point of care allows providers to focus interventions to address either adherence challenges or the need for medication titration in an effort to improve LDL-C goal attainment and ultimately reduce morbidity and mortality.

Epstein-Barr virus infection and expression of B-cell oncogenic markers in HIV-related diffuse large B-cell Lymphoma.

PURPOSE: Epstein-Barr virus (EBV)-mediated lymphomagenesis in the setting of HIV infection has been widely accepted. However, little is known about how EBV impacts prognosis. We investigated the hypothesis that EBV infection is associated with expression of specific B-cell oncogenic markers in HIV-related diffuse large B-cell lymphoma (DLBCL) and examined the prognostic use of detecting EBV infection. EXPERIMENTAL DESIGN: HIV-related DLBCL cases diagnosed between 1996 and 2007 within Kaiser Permanente California were identified. Immunohistochemical staining was used to analyze the expression of selected markers that are cell-cycle regulators, B-cell activators, and antiapoptotic proteins among others. EBV infection was determined by in situ hybridization of EBV RNA. Correlations between EBV and marker expression were examined using Spearman correlation coefficient. The prognostic use of EBV status was examined in multivariable Cox model adjusting for International Prognostic Index (IPI). Receiver-operating characteristics (ROC) analysis was used to evaluate improvement in model discrimination. RESULTS: Seventy HIV-related DLBCL cases were included (31% EBV±). EBV+ tumor was associated with increased expression of BLIMP1 and CD30 and reduced expression of BCL6 and LMO2. EBV+ tumor was independently associated with elevated 2-year overall mortality [HR, 3.3; 95% confidence interval (CI), 1.6-6.6]. Area under the ROC curve showed improved model discrimination when incorporating tumor EBV status with IPI in the prediction model [0.65 vs. 0.74 (IPI only)]. CONCLUSION: Our results suggest that EBV infection was associated with expression of several tumor markers that are involved in the NF-κB pathway and that detecting tumor EBV status may have prognostic use in HIV-related DLBCLs.