Investigating the Influence of High-Speed Gantry Rotation in Cardiac CT on Motion Artifacts in Aortic Stenosis Patients Not Premedicated with β-Blockers: The FAST-CCT Randomized Trial Protocol.

Coronary CT angiography (CCTA) is increasingly used as a non-invasive tool to assess coronary artery disease (CAD). However, CCTA is subject to motion artifacts, potentially limiting its clinical utility. Despite faster (0.35 and 0.28 s/rot) gantry rotation times, low (60-65 bpm) heartbeat is recommended, and the use of β-blockers is often needed. Technological advancements have resulted in the development of faster rotation speeds (0.23 s/rot). However, their added value in patients not premedicated with β-blockers remains unclear. This prospective single-center, two-arm, randomized, controlled trial aims to assess the influence of fast rotation on coronary motion artifacts, diagnostic accuracy of CCTA for CAD, and patient safety. We will randomize a total of 142 patients aged ≥ 50 scheduled for an aortic stenosis work-up to receive CCTA with either a fast (0.23) or standard (0.28 s/rot) gantry speed. rate of CCTAs with coronary motion artifacts hindering interpretation. assessable coronary segments rate, diagnostic accuracy against invasive coronary angiography (ICA), motion artifact magnitude per segment, contrast-to-noise ratio (CNR), and patient ionizing radiation dose. The local ethics committee has approved the protocol. Potential significance: FAST-CCT may improve motion artifact reduction and diagnosis quality, thus eliminating the need for rate control and β-blocker administration. gov identifier: NCT05709652

Age-Dependent Maturation of Toll-Like Receptor-Mediated Cytokine Responses in Gambian Infants

The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health

The Tuberculin Skin Test (TST) Is Affected by Recent BCG Vaccination but Not by Exposure to Non-Tuberculosis Mycobacteria (NTM) during Early Life

The tuberculin skin test (TST) is widely used in TB clinics to aid Mycobacterium tuberculosis (M.tb) diagnosis, but the definition and the significance of a positive test in very young children is still unclear. This study compared the TST in Gambian children at 4½ months of age who either received BCG vaccination at birth (Group 1) or were BCG naïve (Group 2) in order to examine the role of BCG vaccination and/or exposure to environmental mycobacteria in TST reactivity at this age. Nearly half of the BCG vaccinated children had a positive TST (≥5 mm) whereas all the BCG naïve children were non-reactive, confirming that recent BCG vaccination affects TST reactivity. The BCG naïve children demonstrated in vitro PPD responses in peripheral blood in the absence of TST reactivity, supporting exposure to and priming by environmental mycobacterial antigens. Group 2 were then vaccinated at 4½ months of age and a repeat TST was performed at 20–28 months of age. Positive reactivity (≥5 mm) was evident in 11.1% and 12.5% infants from Group 1 and Group 2 respectively suggesting that the timing of BCG vaccination had little effect by this age. We further assessed for immune correlates in peripheral blood at 4½ months of age. Mycobacterial specific IFNγ responses were greater in TST responders than in non-responders, although the size of induration did not correlate with IFNγ. However the IFNγ: IL-10 ratio positively correlated with TST induration suggesting that the relationship between PPD induced IFNγ and IL-10 in the peripheral blood may be important in controlling TST reactivity. Collectively these data provide further insights into how the TST is regulated in early life, and how a positive response might be interpreted

Plasmodium Protease ROM1 Is Important for Proper Formation of the Parasitophorous Vacuole

Apicomplexans are obligate intracellular parasites that invade host cells by an active process leading to the formation of a non-fusogenic parasitophorous vacuole (PV) where the parasite replicates within the host cell. The rhomboid family of proteases cleaves substrates within their transmembrane domains and has been implicated in the invasion process. Although its exact function is unknown, Plasmodium ROM1 is hypothesized to play a role during invasion based on its microneme localization and its ability to cleave essential invasion adhesins. Using the rodent malaria model, Plasmodium yoelii, we carried out detailed quantitative analysis of pyrom1 deficient parasites during the Plasmodium lifecycle. Pyrom1(-) parasites are attenuated during erythrocytic and hepatic stages but progress normally through the mosquito vector with normal counts of oocyst and salivary gland sporozoites. Pyrom1 steady state mRNA levels are upregulated 20-fold in salivary gland sporozoites compared to blood stages. We show that pyrom1(-) sporozoites are capable of gliding motility and traversing host cells normally. Wildtype and pyrom1(-) sporozoites do not differ in the rate of entry into Hepa1–6 hepatocytes. Within the first twelve hours of hepatic development, however, only 50% pyrom1(-) parasites have developed into exoerythrocytic forms. Immunofluorescence microscopy using the PVM marker UIS4 and transmission electron microscopy reveal that the PV of a significant fraction of pyrom1(-) parasites are morphologically aberrant shortly after invasion. We propose a novel function for PyROM1 as a protease that promotes proper PV modification to allow parasite development and replication in a suitable environment within the mammalian host

Risk factors for the spread of vaccine-derived type 2 polioviruses after global withdrawal of trivalent oral poliovirus vaccine and the effects of outbreak responses with monovalent vaccine: a retrospective analysis of surveillance data for 51 countries in Africa

BACKGROUND: Expanding outbreaks of circulating vaccine-derived type 2 poliovirus (cVDPV2) across Africa after the global withdrawal of trivalent oral poliovirus vaccine (OPV) in 2016 are delaying global polio eradication. We aimed to assess the effect of outbreak response campaigns with monovalent type 2 OPV (mOPV2) and the addition of inactivated poliovirus vaccine (IPV) to routine immunisation. METHODS: We used vaccination history data from children under 5 years old with non-polio acute flaccid paralysis from a routine surveillance database (the Polio Information System) and setting-specific OPV immunogenicity data from the literature to estimate OPV-induced and IPV-induced population immunity against type 2 poliomyelitis between Jan 1, 2015, and June 30, 2020, for 51 countries in Africa. We investigated risk factors for reported cVDPV2 poliomyelitis including population immunity, outbreak response activities, and correlates of poliovirus transmission using logistic regression. We used the model to estimate cVDPV2 risk for each 6-month period between Jan 1, 2016, and June 30, 2020, with different numbers of mOPV2 campaigns and compared the timing and location of actual mOPV2 campaigns and the number of mOPV2 campaigns required to reduce cVDPV2 risk to low levels. FINDINGS: Type 2 OPV immunity among children under 5 years declined from a median of 87% (IQR 81-93) in January-June, 2016 to 14% (9-37) in January-June, 2020. Type 2 immunity from IPV among children under 5 years increased from 3% (<1-6%) in January-June, 2016 to 35% (24-47) in January-June, 2020. The probability of cVDPV2 poliomyelitis among children under 5 years was negatively correlated with OPV-induced and IPV-induced immunity and mOPV2 campaigns (adjusted odds ratio: OPV 0·68 [95% CrI 0·60-0·76], IPV 0·82 [0·68-0·99] per 10% absolute increase in estimated population immunity, mOPV2 0·30 [0·20-0·44] per campaign). Vaccination campaigns in response to cVDPV2 outbreaks have been smaller and slower than our model shows would be necessary to reduce risk to low levels, covering only 11% of children under 5 years who are predicted to be at risk within 6 months and only 56% within 12 months. INTERPRETATION: Our findings suggest that as mucosal immunity declines, larger or faster responses with vaccination campaigns using type 2-containing OPV will be required to stop cVDPV2 transmission. IPV-induced immunity also has an important role in reducing the burden of cVDPV2 poliomyelitis in Africa. FUNDING: Bill & Melinda Gates Foundation, Medical Research Council Centre for Global Infectious Disease Analysis, and WHO. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Effects of antenatal and postnatal environments on CD4 T-cell responses to Mycobacterium bovis BCG in healthy infants in the Gambia.

The Mycobacterium bovis BCG vaccine has a poor record of efficacy in low-income tropical settings. Against this background, we evaluated the immune response of infants to mycobacterial antigens over the 2 years following BCG vaccination at birth by measuring the gamma interferon (IFN-gamma), interleukin-2 (IL-2), and CD154 responses of CD4 T cells. Similar numbers of cells expressed IFN-gamma in infants, 4- to 5-year-old children, and adults, while CD154 was not expressed at comparable levels until the second year of infancy. The IL-2 response remained relatively low in infants, children, and adults but correlated negatively with mother's body mass index and was highest among infants born to Mandinka mothers. Similarly, infants born in the wet season had a stronger CD154 response than those born in the dry season throughout the 2 years of the study. We conclude that the prenatal and perinatal environments have a lasting effect on the response of infants to the BCG vaccine

Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses. CONCLUSIONS: The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV