Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming.

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

Ultrasound-guided lymph node fine-needle aspiration for evaluating post-vaccination germinal center responses in humans.

The lymph node (LN) is a critical biological site for immune maturation after vaccination as it includes several cell populations critical for priming the antibody response. Here, we present a protocol for sampling the LN and isolating cell populations to evaluate immunogens targeting germline cells. We describe steps for media and tube preparation and sample collection using an ultrasound-guided LN fine-needle aspiration procedure. This protocol is safe, quick, low-cost, and less invasive than excisional biopsy. For complete details on the use and execution of this protocol, please refer to Leggat et al. (2022).1.

A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses.

The engineered outer domain germline targeting version 8 (eOD-GT8) 60-mer nanoparticle was designed to prime VRC01-class HIV-specific B cells that would need to be matured, through additional heterologous immunizations, into B cells that are able to produce broadly neutralizing antibodies. CD4 T cell help will be critical for the development of such high-affinity neutralizing antibody responses. Thus, we assessed the induction and epitope specificities of the vaccine-specific T cells from the IAVI G001 phase 1 clinical trial that tested immunization with eOD-GT8 60-mer adjuvanted with AS01B. Robust polyfunctional CD4 T cells specific for eOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were induced after two vaccinations with either the 20- or 100-microgram dose. Antigen-specific CD4 T helper responses to eOD-GT8 and LumSyn were observed in 84 and 93% of vaccine recipients, respectively. CD4 helper T cell epitope "hotspots" preferentially targeted across participants were identified within both the eOD-GT8 and LumSyn proteins. CD4 T cell responses specific to one of these three LumSyn epitope hotspots were observed in 85% of vaccine recipients. Last, we found that induction of vaccine-specific peripheral CD4 T cells correlated with expansion of eOD-GT8-specific memory B cells. Our findings demonstrate strong human CD4 T cell responses to an HIV vaccine candidate priming immunogen and identify immunodominant CD4 T cell epitopes that might improve human immune responses either to heterologous boost immunogens after this prime vaccination or to other human vaccine immunogens.

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming.

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials. One-Sentence Summary: Human genetic variation can modulate the strength of vaccine-induced broadly neutralizing antibody precursor B cell responses.

Vaccination induces HIV broadly neutralizing antibody precursors in humans.

Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.

Ectopic pregnancy: a resident's guide to imaging findings and diagnostic pitfalls.

Ectopic pregnancy (EP) is a term used to describe any pregnancy which does not implant into the uterine cavity. There are several types of EPs: tubal, interstitial, ovarian, abdominal, heterotopic, cervical, and cesarean scar. Ectopic pregnancies can acutely rupture and are the number one cause of maternal death in the first trimester of pregnancy. Therefore, prompt recognition and accurate localization have significant clinical implications on patient outcome. Unfortunately, EPs have many mimickers, which can make the diagnosis challenging in certain cases. In this review, we aim to describe and illustrate sonographic findings of each type of EP, as well as present mimickers and various imaging pitfalls. We will clarify how to avoid potential misdiagnoses that could adversely affect patient outcomes. Lastly, we will briefly address management of each type of EP and discuss potential complications.

The Rare, the Odd, and the Atypical: A Pictorial Essay of Testicular and Paratesticular Diseases.

ABSTRACT: Understanding a variety of scrotal diseases is essential to developing an accurate differential diagnosis and is critical in providing optimal patient care. Ultrasound is the imaging modality of choice when evaluating for scrotal pathology, with the major purpose of locating such pathology to either the testis, or epididymis, or other intrascrotal structures, as well as characterizing lesions as solid or cystic. It is generally assumed that most solid intratesticular masses are more likely malignant, whereas most extratesticular ones are benign, although some exceptions to that rule exist. This pictorial essay will focus on rare and less commonly encountered benign and malignant testicular and paratesticular pathologies, which may pose a diagnostic dilemma for interpreting radiologists and treating physicians. Knowledge of their imaging characteristics will help narrow the differential diagnosis and assist in proper patient management and care.

Imaging of Infertility, Part 1: Hysterosalpingograms to Magnetic Resonance Imaging.

Infertility, or subfertility, is the inability to achieve a clinical pregnancy after a 1-year period of regular unprotected sexual intercourse in women younger than 35 and after 6 months in women older than 35. Although initial assessment involves a multitude of factors, including a detailed medical history, physical examination, semen analysis, and hormonal evaluation, diagnostic imaging of the female partner often plays an important role in establishing the etiology for infertility. This article provides an overview of the multimodality imaging assessment of female infertility and details the developmental and acquired pelvic abnormalities in which diagnostic imaging aids in evaluation.

Imaging of Infertility, Part 2: Hysterosalpingograms to Magnetic Resonance Imaging.

Infertility, or subfertility, is the inability to achieve a clinical pregnancy after a 1-year period of regular unprotected sexual intercourse in women younger than 35 and after 6 months in women older than 35. Although initial assessment involves a multitude of factors, including a detailed medical history, physical examination, semen analysis, and hormonal evaluation, diagnostic imaging of the female partner often plays an important role in establishing the etiology for infertility. This article provides an overview of the multimodality imaging assessment of female infertility and details the developmental and acquired pelvic abnormalities in which diagnostic imaging aids in evaluation.

Imaging of Benign Adnexal Disease.

This article provides an overview of the imaging evaluation of benign ovarian and adnexal masses in premenopausal and postmenopausal women and lesions discovered during pregnancy. Current imaging techniques are discussed, including pitfalls and differential diagnosis when necessary, as well as management. It also reviews the now well-established American College of Radiology (ACR)/Society of Radiologists in Ultrasound consensus guidelines and covers the more recently introduced Ovarian-Adnexal Reporting and Data System by the ACR and the recently published ADNEx Scoring System.

Prevalence of Low-Attenuation Homogeneous Papillary Renal Cell Carcinoma Mimicking Renal Cysts on CT.

OBJECTIVE: The objective of our study was to determine the attenuation range of homogeneous papillary renal cell carcinomas (RCCs) on contrast-enhanced CT. MATERIALS AND METHODS: This retrospective study was performed at two institutions from January 1, 2007, to January 1, 2017. Multiphasic CT studies with and without IV contrast material of 114 patients with pathologically proven papillary RCCs were independently reviewed by two sets of two abdominal radiologists. Seventy-two cases were excluded because of subjective lesion heterogeneity, leaving 42 homogeneous RCCs. Three ROIs were placed on all lesions for all CT phases, and the mean attenuations were calculated. RESULTS: Mean lesion size was 2.8 cm (range, 1.2-11.0 cm). The attenuation range for each CT phase was as follows: unenhanced, 14.7-50.7 HU; corticomedullary, 32.2-99.5 HU; portal venous, 40.8-95.1 HU; nephrographic, 17.9-90.8 HU; and excretory, 18.0-73.0 HU. Two of 114 (1.8%; 95% CI, 0.2-6.5%) RCCs were homogeneous and less than 30 HU on the portal venous or nephrographic phase. One of these RCCs was a solid hypoenhancing mass, and the other was a homogeneous cystic RCC. Of the cases with an unenhanced phase, three of 107 (2.8%; 95% CI, 0.6-8.8%) were both homogeneous and were less than 20 HU in attenuation. CONCLUSION: Papillary RCCs are rarely both subjectively homogeneous and less than 20 HU at unenhanced CT and less than 30 HU at portal venous or nephrographic phase CT.

Comparing Dose-Length Product-Based and Monte Carlo Simulation Organ-Based Calculations of Effective Dose in 16- and 64-MDCT Examinations Using Automatic Tube Current Modulation.

OBJECTIVE: The purpose of this study is to compare dose-length product (DLP)-based calculation of effective dose (EDDLP) with Monte Carlo simulation organ-based calculation of effective dose (EDMCO) in 16- and 64-MDCT examinations, with the use of clinical examinations with automatic tube current modulation. MATERIALS AND METHODS: Dose data were obtained from 50 consecutive unenhanced head CT examinations, unenhanced chest CT examinations, and unenhanced and contrast-enhanced abdominopelvic CT examinations performed using 16- and 64-MDCT scanners, as well as from 50 pulmonary CT angiography (CTA) examinations performed using a 64-MDCT scanner and 31 pulmonary CTA examinations performed using a 16-MDCT scanner. The EDMCO and the mean patient effective diameter were calculated using commercially available software. The EDDLP was also calculated. Both the mean difference and percentage difference between EDDLP and EDMCO were calculated, and they were statistically compared according to patient sex, type of examination performed, and type of scanner used. RESULTS: EDDLP significantly underestimated the EDMCO by 0.3 mSv (19%) for men who underwent unenhanced head CT, 0.5 mSv (29%) for women who underwent unenhanced head CT, 0.9-1.4 mSv (9-13%) for men who underwent chest CT, and 4.7-4.8 mSv (39%) for women who underwent chest CT (p < 0.001). The EDDLP overestimated the EDMCO by 1.9-2.0 mSv (12-14%) for men who underwent abdominopelvic CT (p < 0.001), with no significant difference noted for women who underwent abdominopelvic CT's. No significant difference was noted in the percentage difference in ED between the 16- and 64-MDCT scanners (p ≥ 0.13). CONCLUSION: EDDLP underestimates EDMCO, the reference standard for dose calculation, by 19-39% in unenhanced head CT examinations and, among women, in chest CT examinations. EDDLP deviates from EDMCO by less than 15% for chest CT examinations of men and for abdominopelvic CT. These differences can be attributed to variable patient body habitus, automatic tube current modulation, and sex-neutral k-coefficients, and they should be considered when calculating ED, particularly in women.

ACR Appropriateness Criteria® Multiple Gestations.

Women with twin or higher-order pregnancies will typically have more ultrasound examinations than women with a singleton pregnancy. Most women will have at minimum a first trimester scan, a nuchal translucency evaluation scan, fetal anatomy scan at 18 to 22 weeks, and one or more scans in the third trimester to evaluate growth. Multiple gestations are at higher risk for preterm delivery, congenital anomalies, fetal growth restriction, placenta previa, vasa previa, and velamentous cord insertion. Chorionicity and amnionicity should be determined as early as possible when a twin pregnancy is identified to permit triage of the monochorionic group into a closer surveillance model. Screening for congenital heart disease is warranted in monochorionic twins because they have an increased rate of congenital cardiac anomalies. In addition, monochorionic twins have a higher risk of developing cardiac abnormalities in later gestation related to right ventricular outflow obstruction, in particular the subgroups with twin-twin transfusion syndrome or selective intrauterine growth restriction. Monochorionic twins have unique complications including twin-to-twin transfusion syndrome, twin embolization syndrome, and acardius, or twin-reversed arterial perfusion sequence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

CT of suspected thoracic acute aortic injury in the emergency department: is routine abdominopelvic imaging worth the additional collective radiation dose?

This study aimed to determine the incidence of non-traumatic acute aortic injury (AAI) extending from the chest into the abdomen or pelvis in emergency department (ED) patients with acute aortic syndrome (AAS), to estimate the effective dose of the abdominopelvic portion of these CT exams, and to compare the number needed to screen (NNS) with the collective population radiation dose of imaging those stations. All patients (n = 238) presenting to the ED with AAS between March 2014 and June 2015 who were imaged per CT AAI protocol (noncontrast and contrast-enhanced CT angiography of the chest, abdomen, and pelvis) were retrospectively identified in this IRB-approved HIPAA-compliant study. The Stanford classification for positive cases of AAI was further subclassified based on chest, abdominal, or pelvic involvement. The dose length product (DLP) of each exam was used to estimate the dose of the abdominal and pelvic stations and the collective effective dose for the population. There were five cases of aortic dissection (AD) and two of intramural hematoma (IMH), with an AAI incidence of 2.9/100. Three cases of AAI were confined to the chest. Two cases of AAI were confined to the chest and abdomen, and two cases involved the chest, abdomen, and pelvis. There was only one case of AAI involving the ascending aorta that extended into the abdomen or pelvis. The number needed to screen to identify (a) AAI extending from the chest into the abdomen or pelvis was 59.5 and (b) Stanford A AAI extending into the abdomen or pelvis was 238. The estimated mean effective dose for the abdominopelvic stations were unenhanced abdomen 2.3 mSv, unenhanced pelvis 3.3 mSv, abdominal CTA 2.5 mSv, and pelvic CTA 3.6 mSv. The collective effective doses to the abdomen and pelvis with unenhanced CT and CTA in 59.5 patients and 238 patients were 761.6 and 3046.4 mSv, respectively. While the estimated mean effective dose for imaging of the abdominopelvic stations are low, the collective effective dose should also be considered. It may be beneficial to modify or omit routine unenhanced CT and/or CTA of the abdomen/pelvis in this patient population in the absence of abdominal symptoms, and image the abdomen and pelvis in positive thoracic cases only.

ACR Appropriateness Criteria Assessment of Fetal Well-Being.

Although there is limited evidence that antepartum testing decreases the risk for fetal death in low-risk pregnancies, women with high-risk factors for stillbirth should undergo antenatal fetal surveillance. The strongest evidence supporting antepartum testing pertains to pregnancies complicated by intrauterine fetal growth restriction secondary to uteroplacental insufficiency. The main ultrasound-based modalities to determine fetal health are the biophysical profile, modified biophysical profile, and duplex Doppler velocimetry. In patients at risk for cardiovascular compromise, fetal echocardiography may also be indicated to ensure fetal well-being. Although no single antenatal test has been shown to be superior, all have high negative predictive values. Weekly or twice-weekly fetal testing has become the standard practice in high-risk pregnancies. The timing for the initiation of assessments of fetal well-being should be tailored on the basis of the risk for stillbirth and the likelihood of survival with intervention. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Imaging Pregnant and Lactating Patients.

As use of imaging in the evaluation of pregnant and lactating patients continues to increase, misperceptions of radiation and safety risks have proliferated, which has led to often unwarranted concerns among patients and clinicians. When radiologic examinations are appropriately used, the benefits derived from the information gained usually outweigh the risks. This review describes appropriateness and safety issues, estimated doses for imaging examinations that use iodizing radiation (ie, radiography, computed tomography, nuclear scintigraphy, and fluoroscopically guided interventional radiology), radiation risks to the mother and conceptus during various stages of pregnancy, and use of iodinated or gadolinium-based contrast agents and radiotracers in pregnant and lactating women. Maternal radiation risk must be weighed with the potential consequences of missing a life-threatening diagnosis such as pulmonary embolus. Fetal risks (ie, spontaneous abortion, teratogenesis, or carcinogenesis) vary with gestational age and imaging modality and should be considered in the context of the potential benefit of medically necessary diagnostic imaging. When feasible and medically indicated, modalities that do not use ionizing radiation (eg, magnetic resonance imaging) are preferred in pregnant and lactating patients. Radiologists should strive to minimize risks of radiation to the mother and fetus, counsel patients effectively, and promote a realistic understanding of risks related to imaging during pregnancy and lactation.

ACR appropriateness Criteria® infertility.

Appropriate imaging for women undergoing infertility workup depends upon the clinician's suspicion for potential causes of infertility. Transvaginal US is the preferred modality to assess the ovaries for features of polycystic ovary syndrome (PCOS), the leading cause of anovulatory infertility. For women who have a history or clinical suspicion of endometriosis, which affects at least one third of women with infertility, both MRI and pelvic US can provide valuable information. If tubal occlusion is suspected, whether due to endometriosis, previous pelvic inflammatory disease, or other cause, hysterosalpingogram (HSG) is the preferred method of evaluation. To assess for anatomic causes of recurrent pregnancy loss (RPL) such as Müllerian anomalies, synechiae, and leiomyomas, saline infusion sonohysterography, MRI and 3-D US are most appropriate. Up to 10% of women suffering recurrent pregnancy loss have a congenital Müllerian anomaly. When assessment of the pituitary gland is indicated, MRI is the imaging exam of choice.The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

ACR Appropriateness Criteria pelvic floor dysfunction.

Pelvic floor dysfunction is a common and potentially complex condition. Imaging can complement physical examination by revealing clinically occult abnormalities and clarifying the nature of the pelvic floor defects present. Imaging can add value in preoperative management for patients with a complex clinical presentation, and in postoperative management of patients suspected to have recurrent pelvic floor dysfunction or a surgical complication. Imaging findings are only clinically relevant if the patient is symptomatic. Several imaging modalities have a potential role in evaluating patients; the choice of modality depends on the patient's symptoms, the clinical information desired, and the usefulness of the test. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions; they are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals, and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.