A temperature-dependent virus-binding assay reveals the presence of neutralizing antibodies in human cytomegalovirus gB vaccine recipients' sera.

Human cytomegalovirus (HCMV) remains an important cause of mortality in immune-compromised transplant patients and following congenital infection. Such is the burden, an effective vaccine strategy is considered to be of the highest priority. The most successful vaccines to date have focused on generating immune responses against glycoprotein B (gB) - a protein essential for HCMV fusion and entry. We have previously reported that an important component of the humoral immune response elicited by gB/MF59 vaccination of patients awaiting transplant is the induction of non-neutralizing antibodies that target cell-associated virus with little evidence of concomitant classical neutralizing antibodies. Here we report that a modified neutralization assay that promotes prolonged binding of HCMV to the cell surface reveals the presence of neutralizing antibodies in sera taken from gB-vaccinated patients that cannot be detected using standard assays. We go on to show that this is not a general feature of gB-neutralizing antibodies, suggesting that specific antibody responses induced by vaccination could be important. Although we can find no evidence that these neutralizing antibody responses are a correlate of protection in vivo in transplant recipients their identification demonstrates the utility of the approach in identifying these responses. We hypothesize that further characterization has the potential to aid the identification of functions within gB that are important during the entry process and could potentially improve future vaccine strategies directed against gB if they prove to be effective against HCMV at higher concentrations.

Complete agenesis of corpus callosum and unilateral cortical formation anomalies detected on fetal MR imaging: a phenotype strongly associated with the male fetuses.

INTRODUCTION: In a previous study of classifying fetuses with cortical formation abnormalities (CFA) with fetal MR, we noticed a cluster of cases with unilateral CFA and complete agenesis of the corpus callosum (ACC). In this study, we provide a detailed morphological analysis of such fetuses using fetal MR to determine if there are indicators (such as the gender of the fetus) that could be used to delineate a genetic substrate of the phenotype in order to inform future studies. METHODS: We have studied 45 fetuses with the unilateral CFA/ACC phenotype and analysed through an expert consensus panel the location and fine detail of the CFA and the associated findings such as associated anomalies, head size, and sex of the fetus. RESULTS: The frontal lobe was significantly more frequently involved by CFA when compared with other lobes (p < 0.001) but no preference for the left or right hemisphere. CFA most often consisted of excessive/dysmorphic sulcation. The CFA/ACC phenotype was overwhelmingly more frequent in male fetuses (M:F 4.5:1-p < 0.0001). The most frequent associated findings were: ventriculomegaly (16/45 fetuses) and interhemispheric cysts (12/45 cases). CONCLUSIONS: This report highlights the specific phenotype of unilateral CFA/ACC that is much more common in male fetuses. This finding provides a starting point to study possible sex-linked genetic abnormalities that underpin the unilateral CFA/ACC phenotype. KEY POINTS: • We collected fetuses with unilateral cortical formation abnormality and callosal agenesis. • That distinctive neuroimaging phenotype has a strong male gender prevalence (over 80%). • This observation forms the basis of studies about outcomes and genetic substrates.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 1, experiences and recommendations for service design.

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 2, risks of adverse outcome in common anomalies.

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.

Changes in appearance of cortical formation abnormalities in the foetus detected on sequential in utero MR imaging.

OBJECTIVES: We describe 64 foetuses with cortical formation abnormalities (CFA) who had two in utero magnetic resonance (iuMR) exams, paying particular detail to those in which the original classification of CFA category changed between the two studies. The goal was to attempt to quantify the value of third-trimester follow-up studies in CFA foetuses on second-trimester iuMR imaging. METHODS: The 64 foetuses reviewed came from a CFA cohort of 374 foetuses reported in an earlier publication, which detailed a classification for foetal CFA. A consensus panel of senior paediatric neuroradiologists reviewed both studies, described any change in the category of CFA between them, and attempted to predict the possible clinical significance of any differences based on the combined clinical experience of the panel. RESULTS: In 40/64 (62%) foetuses, the CFA description was the same on both studies. In 24/64 (38%) cases, there was a category change which included three foetuses without CFA on first examination, six foetuses where the difference involved change in laterality/symmetry, and in 15 cases the re-classification involved categorical change within the same group. Brain abnormalities other than CFA were present in 30/64 (47%) foetuses on the first study and in 33/64 (52%) on the second. We predicted that prognosis would have changed on the basis of the second study in 8% of cases, all indicating worse prognosis. CONCLUSIONS: We have shown that the extra diagnostic and predicted prognostic yield justifies follow-up studies in the third trimester if a CFA is shown on the second-trimester iuMR imaging. KEY POINTS: • Sixty-four foetuses with cortical formation abnormalities had two iuMR studies, for the vast majority the baseline in the second trimester and the sequential in the third. • In three foetuses, the cortical formation abnormality (CFA) was not visible on the first study. In a further 21 foetuses, the categorical description of the CFA changed between the two studies. Prognosis changed in 8% of the cases following the second iuMR study, and in all cases, the prognosis was worse. • Multiple iuMR studies provide information about the natural history of CFA; the extra diagnostic and predicted prognostic yield justifies follow-up studies.

Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies.

Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.

Immune Correlates of Protection Against Human Cytomegalovirus Acquisition, Replication, and Disease.

Human cytomegalovirus (HCMV) is the most common infectious cause of infant birth defects and an etiology of significant morbidity and mortality in solid organ and hematopoietic stem cell transplant recipients. There is tremendous interest in developing a vaccine or immunotherapeutic to reduce the burden of HCMV-associated disease, yet after nearly a half-century of research and development in this field we remain without such an intervention. Defining immune correlates of protection is a process that enables targeted vaccine/immunotherapeutic discovery and informed evaluation of clinical performance. Outcomes in the HCMV field have previously been measured against a variety of clinical end points, including virus acquisition, systemic replication, and progression to disease. Herein we review immune correlates of protection against each of these end points in turn, showing that control of HCMV likely depends on a combination of innate immune factors, antibodies, and T-cell responses. Furthermore, protective immune responses are heterogeneous, with no single immune parameter predicting protection against all clinical outcomes and stages of HCMV infection. A detailed understanding of protective immune responses for a given clinical end point will inform immunogen selection and guide preclinical and clinical evaluation of vaccines or immunotherapeutics to prevent HCMV-mediated congenital and transplant disease.

Cytomegalovirus reactivation after bortezomib treatment for multiple myeloma and light chain amyloidosis.

OBJECTIVE: Cytomegalovirus (CMV) is an opportunistic herpesvirus, and reactivation of infection is possible in immunocompromised patients. Historically, the risk for haematology patients is restricted to those treated with an allogeneic transplant or T-cell depleting agents. Bortezomib is a highly efficacious proteasome inhibitor widely used to treat multiple myeloma and light chain (AL) amyloidosis patients. The objective of this small prospective study was to quantify the risk of CMV reactivation associated with bortezomib treatment. METHODS: Fifty-seven consecutive multiple myeloma or AL amyloidosis patients commencing bortezomib-based therapy were included. Viral copy numbers were established at baseline and then at fortnightly intervals during treatment. Pre-emptive anti-viral treatment was initiated in patients with a viral load >7500 copies/mL. RESULTS: Reactivation of CMV was detected in 39% (n = 12/31) of seropositive bortezomib treated patients compared with 0% of CMV seronegative patients. Detectable DNAemia developed during the first two cycles of treatment in 83% (n = 10/12) patients. Anti-viral treatment was initiated in 42% (n = 5/12), but no cases of active CMV disease were seen. CONCLUSION: This study suggests that there is a substantial risk of CMV reactivation in CMV-seropositive plasma cell dyscrasia patients treated with bortezomib.

Cortical formation abnormalities on foetal MR imaging: a proposed classification system trialled on 356 cases from Italian and UK centres.

OBJECTIVE: To formulate a classification system for foetal cortical formation abnormalities (CFAs) based on in utero magnetic resonance (iuMR) appearances and trial it in 356 cases. METHODS: This retrospective study included all cases of foetal CFA diagnosed between 2000 and 2017 from seven centres in Italy and UK. All of the studies were reviewed by a panel of paediatric neuroradiologists experienced in iuMR with the aid of an algorithm designed to categorise the abnormalities. RESULTS: Consensus expert review confirmed 356 foetuses with CFA and the first level of classification distinguished bilateral CFA (229/356-64%) from unilateral CFA (127/356-36%) cases with sub-classification of the bilateral cases into asymmetric (65/356-18%) and symmetric (164/356-46%) involvement. There was a statistically significant excess of foetuses with small head size, e.g. 17% of the cohort had a bi-parietal diameter < 3rd centile. There was a small but statistically significant excess of males in the cohort. Further categorisation was made on fine anatomical structure. CONCLUSIONS: It is often not possible to classify foetal CFA using the principles and nomenclature used in paediatric neuroradiology. We have created a classification system for foetal CFA based on the analysis of 356 cases and believe that this will assist future research designed to correlate ante-natal and post-natal imaging features and understand the clinical sequelae of CFA described in utero. KEY POINTS: • We describe a morphological classification system of foetal brain cortical formation abnormalities that can be used in clinical practice. • This classification system can be used in future research studies to evaluate the long-term imaging and clinical outcomes of foetal brain cortical formation abnormalities in 17- to 38-week gestational age range. • The practical value of the work is in providing a framework and language to look for imaging clues that may differentiate between different CFA in further studies.

Current state of MRI of the fetal brain in utero.

In this article we provide an overview of fetal brain development, describe the range of more common fetal neuropathology, and discuss the relevance of in utero MR (iuMR). Although ultrasonography remains the mainstay of fetal brain imaging, iuMR imaging is both feasible and safe, but presents several challenges. We discuss those challenges, the techniques employed to overcome them, and new approaches that may extend the clinical applicability of fetal iuMR. Level of Evidence: Technical Efficacy Stage. J. Magn. Reson. Imaging 2019;49:632-646.

Normative volume measurements of the fetal intra-cranial compartments using 3D volume in utero MR imaging.

PURPOSE: To describe the normal linear measurements of the skull (bi-parietal diameter and occipito-frontal diameter) and intracranial volumes (ventricular volume, brain parenchymal volume, extra-axial volume and total intra-cranial volume) in normal fetuses. MATERIALS AND METHODS: We recruited pregnant women from low-risk pregnancies whose fetuses had normal ultrasound and in utero MR studies. All volunteers had in utero MR imaging on the same 1.5T MR scanner with a protocol consisting of routine and 3D steady-state volume imaging of the fetal brain. Linear measurements of the skull were made using the volume imaging. The 3D volume imaging also was manually segmented to delineate the intracranial compartments described above to determine quantitative values for each. RESULTS: Two hundred normal fetuses were studied with gestational ages between 18 and 37 weeks. The linear skull measurements made on in utero MR imaging closely correlate with published data from ultrasonography. The intracranial volume data is presented as graphs and as tabular summaries of 3rd, 10th, 50th, 90th and 97th centiles. CONCLUSION: It is now possible to measure the volumes of the intracranial compartments in individual fetuses using ultrafast in utero MR techniques. KEY POINTS: • There are limitations in using the skull size of the fetus to comment on the state of the fetal brain. • Volumes for the intracranial compartments are presented, based on in utero MR imaging of the fetal brain between 18 and 37 weeks gestational age. • Those normative values can be used to assess fetuses with known or suspected structural brain abnormalities and may assist the differential diagnosis provided by visual assessment of routine iuMR studies.

Analysis of errors made on in utero MR studies of the foetal brain in the MERIDIAN study.

OBJECTIVES: In utero magnetic resonance (iuMR) imaging to diagnose foetal brain abnormalities has been established and is supported by meta-analyses of retrospective and prospective studies. In this paper we describe and classify the iuMR errors made in the largest diagnostic accuracy study to date (MERIDIAN). We also correlate the error rates and types with the prior experience of the reporting radiologists in order to inform how to provide a national programme with the best diagnostic accuracy achievable. METHODS: The MERIDIAN cohort of 570 foetus formed the basis of this study and included 40 cases with a confirmed diagnostic error, compared with the Outcome Reference Diagnosis. Analysis included the potential clinical effect of the error and classification of error type through an Expert Neuroradiological Panel re-reporting the study. Assessments were made regarding radiologists experience prior to MERIDIAN. RESULTS: The overall confirmed error rate for iuMR was 7·0% and it was considered that there would have been an adverse effect on prognostic information in 22/40 cases if the iuMR had informed counselling. The experienced central reporter made statistically significant fewer errors than the less experienced non-central reporters (3·8% v 11·0%) and the central reporter made fewer clinically significant errors. Furthermore, the type of cognitive errors differed between central and non-central reporters. CONCLUSIONS: Although iuMR imaging improves the diagnostic accuracy of detecting foetal brain abnormalities there remains a substantial error rate, which can have major clinical significance. We have shown that error rates are lower for more experienced reporting radiologists with fewer potential deleterious clinical implications. We discuss the implications of these findings in terms of providing a uniform national service. KEY POINTS: • Overall confirmed error rate for iuMR diagnosing foetal brain abnormalities was 7·0%. • IuMR reports had an adverse effect on counselling in 55% of error cases. • Error rates are consistently lower for more experienced radiologists. • Collaboration between radiologists, dual reporting, overseeing scan and formal training can reduce errors.

Criteria to define interruption of transmission of human cytomegalovirus from organ donor to recipient.

In this review article, we consider results suggesting that transmission of human cytomegalovirus (HCMV) from a donor of a solid organ to an immunologically naive individual can be reduced. Two randomized controlled trials have been conducted recently, one of active immunization of recipients pretransplant and another of passive immunization with monoclonal antibodies specific for HCMV given at the time of transplant. Although the available data are encouraging-providing evidence of a reduction in the incidence of HCMV viraemia-they fall short of what would be required to prove definitively that transmission has been completely prevented. Here, we reflect on these studies and propose a set of 5 criteria, which, if satisfied in the future, could be taken as proof that active and/or passive immunization against HCMV effectively interrupts transmission of virus from the donor. We suggest that these criteria are considered when designing future randomized controlled trials.

An integrated in utero MR method for assessing structural brain abnormalities and measuring intracranial volumes in fetuses with congenital heart disease: results of a prospective case-control feasibility study.

PURPOSE: To refine methods that assess structural brain abnormalities and calculate intracranial volumes in fetuses with congenital heart diseases (CHD) using in utero MR (iuMR) imaging. Our secondary objective was to assess the prevalence of brain abnormalities in this high-risk cohort and compare the brain volumes with normative values. METHODS: We performed iuMR on 16 pregnant women carrying a fetus with CHD and gestational age ≥ 28-week gestation and no brain abnormality on ultrasonography. All cases had fetal echocardiography by a pediatric cardiologist. Structural brain abnormalities on iuMR were recorded. Intracranial volumes were made from 3D FIESTA acquisitions following manual segmentation and the use of 3D Slicer software and were compared with normal fetuses. Z scores were calculated, and regression analyses were performed to look for differences between the normal and CHD fetuses. RESULTS: Successful 2D and 3D volume imaging was obtained in all 16 cases within a 30-min scan. Despite normal ultrasonography, 5/16 fetuses (31%) had structural brain abnormalities detected by iuMR (3 with ventriculomegaly, 2 with vermian hypoplasia). Brain volume, extra-axial volume, and total intracranial volume were statistically significantly reduced, while ventricular volumes were increased in the CHD cohort. CONCLUSION: We have shown that it is possible to perform detailed 2D and 3D studies using iuMR that allow thorough investigation of all intracranial compartments in fetuses with CHD in a clinically appropriate scan time. Those fetuses have a high risk of structural brain abnormalities and smaller brain volumes even when brain ultrasonography is normal.

"He looks gorgeous" - iuMR images and the transforming of foetal and parental identities.

The MERIDIAN study examined whether in-utero MRI (iuMRI) improves the accuracy of diagnosis of foetal brain abnormalities, when used as an adjunct to ultrasound anomaly scanning. A diagnostic iuMRI differs from routine ultrasound screening because of its infrequent use and scanning procedure. Nested within this trial, this sociological study explored the acceptability of iuMRI as a technology and its contribution to parental decision-making. Our sociological interpretation of the role of iuMR images in prenatal diagnosis draws on narrative interviews with women (and some partners) who underwent MRI imaging at three different centres. Overall, participants found iuMRI helpful in decision-making because it either confirmed or disconfirmed previous results, or provided additional information. Expectant couples experienced the iuMR imaging process as informative, but also as having emotive and practical value. Our paper extends the existing sociological literature on antenatal testing and visualising the foetus, by using iuMR diagnostic imaging to further explore the concept of the unborn entity. Our data suggest that alongside the iuMR images, the 'parental gaze' and accompanying commentary are used by parents to construct and transform foetal and parental identities despite ongoing uncertainties about, and shifting social contexts to their pregnancy.

Epitope-Specific Humoral Responses to Human Cytomegalovirus Glycoprotein-B Vaccine With MF59: Anti-AD2 Levels Correlate With Protection From Viremia.

The human cytomegalovirus (HCMV) virion envelope protein glycoprotein B (gB) is essential for viral entry and represents a major target for humoral responses following infection. Previously, a phase 2 placebo-controlled clinical trial conducted in solid organ transplant candidates demonstrated that vaccination with gB plus MF59 adjuvant significantly increased gB enzyme-linked immunosorbent assay (ELISA) antibody levels whose titer correlated directly with protection against posttransplant viremia. The aim of the current study was to investigate in more detail this protective humoral response in vaccinated seropositive transplant recipients. We focused on 4 key antigenic domains (AD) of gB (AD1, AD2, AD4, and AD5), measuring antibody levels in patient sera and correlating these with posttransplant HCMV viremia. Vaccination of seropositive patients significantly boosted preexisting antibody levels against the immunodominant region AD1 as well as against AD2, AD4, and AD5. A decreased incidence of viremia correlated with higher antibody levels against AD2 but not with antibody levels against the other 3 ADs. Overall, these data support the hypothesis that antibodies against AD2 are a major component of the immune protection of seropositives seen following vaccination with gB/MF59 vaccine and identify a correlate of protective immunity in allograft patients.

Use of MRI in the diagnosis of fetal brain abnormalities in utero (MERIDIAN): a multicentre, prospective cohort study.

BACKGROUND: In-utero MRI (iuMRI) has shown promise as an adjunct to ultrasound but the comparative diagnostic performance has been poorly defined. We aimed to assess whether the diagnostic accuracy and confidence of the prenatal diagnosis of fetal brain abnormalities is improved with iuMRI and assess the clinical impact and patient acceptability of iuMRI. METHODS: We did a multicentre, prospective, cohort study in the UK, at 16 fetal medicine centres, of pregnant women aged 16 years or older whose fetus had a brain abnormality detected by ultrasound at a gestational age of 18 weeks or more, had no contraindications to iuMRI, and consented to enter the study. Women carrying a fetus suspected of having a brain anomaly on ultrasound had iuMRI done within 14 days of ultrasound. The findings were reviewed by two independent panels and used to estimate diagnostic accuracy and confidence by comparison with outcome diagnoses. Changes in diagnosis, prognosis, and clinical management brought about by iuMRI and patient acceptability were assessed. FINDINGS: Participants were recruited between July 29, 2011, and Aug 31, 2014. The cohort was subdivided by gestation into the 18 weeks to less than 24 weeks fetus cohort (n=369) and into the 24 weeks or older fetus cohort (n=201). Diagnostic accuracy was improved by 23% (95% CI 18-27) in the 18 weeks to less than 24 weeks group and 29% (23-36) in the 24 weeks and older group (p<0·0001 for both groups). The overall diagnostic accuracy was 68% for ultrasound and 93% for iuMRI (difference 25%, 95% CI 21-29). Dominant diagnoses were reported with high confidence on ultrasound in 465 (82%) of 570 cases compared with 544 (95%) of 570 cases on iuMRI. IuMRI provided additional diagnostic information in 387 (49%) of 783 cases, changed prognostic information in at least 157 (20%), and led to changes in clinical management in more than one in three cases. IuMRI also had high patient acceptability with at least 95% of women saying they would have an iuMRI study if a future pregnancy were complicated by a fetal brain abnormality. INTERPRETATION: iuMRI improves diagnostic accuracy and confidence for fetal brain anomalies and leads to management changes in a high proportion of cases. This finding, along with the high patient acceptability, leads us to propose that any fetus with a suspected brain abnormality on ultrasound should have iuMRI to better inform counselling and management decisions. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Imaging Human Brain Perfusion with Inhaled Hyperpolarized 129Xe MR Imaging.

Purpose To evaluate the feasibility of directly imaging perfusion of human brain tissue by using magnetic resonance (MR) imaging with inhaled hyperpolarized xenon 129 (129Xe). Materials and Methods In vivo imaging with 129Xe was performed in three healthy participants. The combination of a high-yield spin-exchange optical pumping 129Xe polarizer, custom-built radiofrequency coils, and an optimized gradient-echo MR imaging protocol was used to achieve signal sensitivity sufficient to directly image hyperpolarized 129Xe dissolved in the human brain. Conventional T1-weighted proton (hydrogen 1 [1H]) images and perfusion images by using arterial spin labeling were obtained for comparison. Results Images of 129Xe uptake were obtained with a signal-to-noise ratio of 31 ± 9 and demonstrated structural similarities to the gray matter distribution on conventional T1-weighted 1H images and to perfusion images from arterial spin labeling. Conclusion Hyperpolarized 129Xe MR imaging is an injection-free means of imaging the perfusion of cerebral tissue. The proposed method images the uptake of inhaled xenon gas to the extravascular brain tissue compartment across the intact blood-brain barrier. This level of sensitivity is not readily available with contemporary MR imaging methods. ©RSNA, 2017.

Brain-injured Survivors of Monochorionic Twin Pregnancies Complicated by Single Intrauterine Death: MR Findings in a Multicenter Study.

Purpose To describe and classify the range of brain injuries present at prenatal, in-utero magnetic resonance (MR) imaging in co-twin survivors of monochorionic (MC) twin pregnancies complicated by single intrauterine death (SIUD). Materials and Methods This retrospective, observational study from six tertiary fetal medicine centers that perform tertiary-level prenatal in-utero MR studies reviewed cases in which prenatal in-utero MR imaging had shown a brain injury in a surviving co-twin of a twin pregnancy with a MC component complicated by SIUD. Results Forty-two surviving MC twins were described. The primary distinction of brain abnormalities was into nonfocal and focal lesions. The nonfocal lesions included periventricular leukomalacia (group 1; two fetuses), generalized encephalomalacia (group 2; nine fetuses), posterior encephalomalacia (group 3; seven fetuses), and bilateral parasagittal and perisylvian injury (group 4; three fetuses). The focal lesions included nonhemorrhagic lesions (group 5; 14 fetuses) and hemorrhagic lesions (group 6; seven fetuses). Focal brain lesions were more likely to be found in the surviving MC pregnancies complicated by twin-twin transfusion syndrome (TTTS) (odds ratio, 2.4; 95% confidence interval: 1.3, 18.5; P = .01) and in fetuses that underwent an obstetric intervention (odds ratio, 2.8; 95% confidence interval: 1.8, 23.6; P = .006). Conclusion Brain injury of the surviving co-twin after SIUD in MC pregnancies is usually of ischemic origin and spares the brainstem and cerebellum. Focal brain lesions are more frequent in pregnancies complicated by TTTS or in those where an intervention has been performed.