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In 2015, there was a large outbreak of Zika virus (ZIKV) in Brazil. Despite its relatively mild impact on healthy adults, ZIKV infection during pregnancy has been associated with severe birth defects. Currently, there is no ZIKV vaccine available, but several vaccine candidates based on the ZIKV membrane (M) and envelope (Env) structural proteins showed promising results in preclinical and clinical studies. Here, the immunogenicity and protective efficacy of a non-replicating adenoviral vector type 26 (Ad26) that encodes the ZIKV M-Env antigens (Ad26.ZIKV.M-Env) was evaluated in mice and non-human primates (NHP). Ad26.ZIKV.M-Env induced strong and durable cellular and humoral immune responses in preclinical models. Humoral responses were characterized by Env-binding and ZIKV neutralizing antibody responses while cellular responses were characterized by ZIKV reactive CD4+ and CD8+ T cells. Importantly, a single immunization with a very low dose of 4x107 vp of Ad26.ZIKV.M-Env protected mice from ZIKV challenge. In NHP, a single immunization with a typical human dose of 1x1011 vp of Ad26.ZIKV.M-Env also induced Env-binding and ZIKV neutralizing antibodies and Env and M specific cellular immune responses that associated with complete protection against viremia from ZIKV challenge as measured in plasma and other body fluids. Together these data provide the rationale to progress the Ad26.ZIKV.M-Env candidate vaccine to clinical testing.

In 2015, there was a large outbreak of Zika virus (ZIKV) in Brazil. Despite its relatively mild impact on healthy adults, ZIKV infection during pregnancy has been associated with severe birth defects. Currently, there is no ZIKV vaccine available, but several vaccine candidates based on the ZIKV membrane (M) and envelope (Env) structural proteins showed promising results in preclinical and clinical studies. Here, the immunogenicity and protective efficacy of a non-replicating adenoviral vector type 26 (Ad26) that encodes the ZIKV M-Env antigens (Ad26.ZIKV.M-Env) was evaluated in mice and non-human primates (NHP). Ad26.ZIKV.M-Env induced strong and durable cellular and humoral immune responses in preclinical models. Humoral responses were characterized by Env-binding and ZIKV neutralizing antibody responses while cellular responses were characterized by ZIKV reactive CD4.sup.+ and CD8.sup.+ T cells. Importantly, a single immunization with a very low dose of 4x10.sup.7 vp of Ad26.ZIKV.M-Env protected mice from ZIKV challenge. In NHP, a single immunization with a typical human dose of 1x10.sup.11 vp of Ad26.ZIKV.M-Env also induced Env-binding and ZIKV neutralizing antibodies and Env and M specific cellular immune responses that associated with complete protection against viremia from ZIKV challenge as measured in plasma and other body fluids. Together these data provide the rationale to progress the Ad26.ZIKV.M-Env candidate vaccine to clinical testing.

The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. We use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures at different time points during the COVID-19 pandemic in the Netherlands. Our analyses suggest that the impact of measures reducing school-based contacts depends on the remaining opportunities to reduce non-school-based contacts. If opportunities to reduce the effective reproduction number ( R e ) with non-school-based measures are exhausted or undesired and R e is still close to 1, the additional benefit of school-based measures may be considerable, particularly among older school children. As two examples, we demonstrate that keeping schools closed after the summer holidays in 2020, in the absence of other measures, would not have prevented the second pandemic wave in autumn 2020 but closing schools in November 2020 could have reduced R e below 1, with unchanged non-school-based contacts. The role of school-based contacts in the epidemiology of SARS-CoV-2 is incompletely understood. Here, the authors use an age-structured transmission model fitted to age-specific seroprevalence and hospital admission data to assess the effects of school-based measures during the COVID-19 pandemic in the Netherlands.

Households are important sites for transmission of SARS-CoV-2 and preventive measures are recommended. This study aimed to 1) investigate the impact of living with a person infected with SARS-CoV-2; 2) understand how household members implemented infection control recommendations in their home; and 3) identify the information and support needs of household members. For this observational mixed-methods study, households with a person with confirmed SARS-CoV-2 infection were recruited via drive-through testing sites of Municipal Health Services, healthcare worker screening or hospital emergency visits in the University Medical Centre Utrecht, the Netherlands and via primary care physicians, hospital emergency visits or preoperative screening in the University Hospital of Antwerp, Belgium. We recorded household characteristics, including characteristics of all household members, together with their views on prevention measures. In a subset of households one adult household member was asked to participate in an interview investigating their views on preventive measures. Survey data were analysed using descriptive statistics and interview data by rapid framework analysis. A triangulation protocol was used to integrate findings. Thirty-four households (120 household members) were included in the quantitative survey. Twenty-two households were invited to be interviewed, of which 18 completed an interview (response 81.8%). Survey data showed that almost all households implemented some preventive measures, the use of face masks being least frequently reported. Measures taken depended on what was physically possible, the perceived severity of illness of the index patient and to what extent household members were willing to limit social interaction. Respondents did not believe in the effectiveness of wearing face masks within the house, and from the interviews this was explained by media coverage of face masks, impracticality and the stigma associated with wearing masks. Interviewees reported that quarantine had a high emotional burden and wished to have more information about the exact duration of quarantine, their own COVID-19 status, symptoms and when to seek medical help. People were willing to implement prevention measures, however actual adherence depended on perceived severity of illness and the perceived risk of becoming infected. Homes are social environments and recommendations for infection prevention should account for this context. Incorporating our findings into policy making could provide households with more relevant and actionable advice.

Household transmission studies are useful to quantify SARS-CoV-2 transmission dynamics. We conducted a remote prospective household study to quantify transmission, and the effects of subject characteristics, household characteristics, and implemented infection control measures on transmission. Households with a laboratory-confirmed SARS-CoV-2 index case were enrolled < 48 h following test result. Follow-up included digitally daily symptom recording, regular nose-throat self-sampling and paired dried blood spots from all household members. Samples were tested for virus detection and SARS-CoV-2 antibodies. Secondary attack rates (SARs) and associated factors were estimated using logistic regression. In 276 households with 920 participants (276 index cases and 644 household members) daily symptom diaries and questionnaires were completed by 95%, and > 85% completed sample collection. 200 secondary SARS-CoV-2 infections were detected, yielding a household SAR of 45.7% (95% CI 39.7–51.7%) and per-person SAR of 32.6% (95% CI: 28.1-37.4%). 126 (63%) secondary cases were detected at enrollment. Mild (aRR = 0.57) and asymptomatic index cases (aRR=0.29) were less likely to transmit SARS-CoV-2, compared to index cases with an acute respiratory illness (p=0.03 for trend), and child index cases (< 12 years aRR=0.60 and 12-18 years aRR = 0.85) compared to adults (p=0.03 for trend). Infection control interventions in households had no significant effect on transmission. We found high SARs with the majority of transmissions occuring early after SARS-CoV-2 introduction into the household. This may explain the futile effect of implemented household measures. Age and symptom status of the index case influence secondary transmission. Remote, digitally-supported study designs with self-sampling are feasible for studying transmission under pandemic restrictions.

Sudden cardiac arrest (SCA) studies are often population-based, limited to sudden cardiac death, and excluding infants. To guide prevention opportunities, it is essential to be informed of pediatric SCA etiologies. Unfortunately, etiologies frequently remain unresolved. The objectives of this study were to determine paediatric SCA etiology, and to evaluate the extent of post-SCA investigations and to assess the performance of previous cardiac evaluation in detecting conditions predisposing to SCA. In a retrospective cohort (2002–2019), all children 0–18 years with out-of-hospital cardiac arrest (OHCA) referred to Erasmus MC Sophia Children's Hospital or the Amsterdam UMC (tertiary-care university hospitals), with cardiac or unresolved etiologies were eligible for inclusion. SCA etiologies, cardiac and family history and etiologic investigations in unresolved cases were assessed. The etiology of arrest could be determined in 52% of 172 cases. Predominant etiologies in children ≥ 1 year (n = 99) were primary arrhythmogenic disorders (34%), cardiomyopathies (22%) and unresolved (32%). Events in children < 1 year (n = 73) were largely unresolved (70%) or caused by cardiomyopathy (8%), congenital heart anomaly (8%) or myocarditis (7%). Of 83 children with unresolved etiology a family history was performed in 51%, an autopsy in 51% and genetic testing in 15%. Pre-existing cardiac conditions presumably causative for SCA were diagnosed in 9%, and remained unrecognized despite prior evaluation in 13%. Conclusion : SCA etiology remained unresolved in 83 of 172 cases (48%) and essential diagnostic investigations were often not performed. Over one-fifth of SCA patients underwent prior cardiac evaluation, which did not lead to recognition of a cardiac condition predisposing to SCA in all of them. The diagnostic post-SCA approach should be improved and the proposed standardized pediatric post-SCA diagnostics protocol may ensure a consistent and systematic evaluation process increasing the diagnostic yield. What is Known: • Arrests in infants remain unresolved in most cases. In children > 1 year, predominant etiologies are primary arrhythmia disorders, cardiomyopathy and myocarditis. • Studies investigating sudden cardiac arrest are often limited to sudden cardiac death (SCD) in 1 to 40 year old persons, excluding infants and successfully resuscitated children. What is New: • In patients with unresolved SCA events, the diagnostic work up was often incompletely performed. • Over one fifth of victims had prior cardiac evaluation before the arrest, with either a diagnosed cardiac condition (9%) or an unrecognized cardiac condition (13%). Graphical Abstract

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste.

ObjectivesTo develop an interactive tool that estimates what potential benefits are needed for the robot to provide value for money when compared with endoscopic or open surgical interventions.DesignA generic online interactive tool was developed to analyze the (health) effects needed to compensate for the additional costs of using a surgical robotic system from a healthcare perspective. The application of the tool is illustrated with a hypothetical new surgical robotic platform. A synthesis of evidence from different sources was used combined with interviews with surgeons.SettingFlexible tool that can be adapted to flexible settings.ParticipantsAny hospital patient group for which robotic, endoscopic or open surgical procedures may be considered as appropriate treatment alternatives (eg, urology, gynecology, and so on).InterventionRobotically assisted surgical interventions.ComparatorEndoscopic or open surgical interventions.Main outcome measuresThresholds of how much (health) effect is needed for robot-assisted surgery to provide value for money and to become cost-effective.ResultsThe utilization rate of the surgical robotic system and a reduction in complications appeared to be important aspects in determining the value for money. To become cost-effective, it was deemed important for new surgical robotic systems to have added clinical benefit and become less costly than the current system.ConclusionsThis paper and its assisting interactive tool can be used by clinicians, researchers, and policymakers to gain insight in the benefit needed to provide value for money when using a (new) surgical robotic system or, when the effects are known or can be estimated, to assess the value for money for a specific indication. For robotic surgery to provide most value for money, we recommend assessing for each indication whether the necessary effects seem achievable.

Aida Bertoli-Avella and colleagues report the identification of SMAD3 mutations in individuals with a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. The mutations cause increased aortic expression of components of the TGF-β signaling pathway. Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2–24.2 and show that the disease is caused by mutations in SMAD3 . This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission 1 , 2 , 3 . SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.