Protein identification for stroke progression via Mendelian Randomization in Million Veteran Program and UK Biobank.

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke. Methods: We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (Ncases=51,929, Ncntrl=39,980) and subsequent arterial ischemic stroke (AIS) Ncases=45,120, Ncntrl=46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR). Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10-08) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10-08) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation. Conclusions: We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.

Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans.

Vaccination against SARS-CoV-2 has been effective in reducing the burden of severe disease and death from COVID-19. Third doses of mRNA-based vaccines have provided a way to address waning immunity and broaden protection against emerging SARS-CoV-2 variants. However, their comparative effectiveness for a range of COVID-19 outcomes across diverse populations is unknown. We emulated a target trial using electronic health records of US veterans who received a third dose of either BNT162b2 or mRNA-1273 vaccines between 20 October 2021 and 8 February 2022, during a period that included Delta- and Omicron-variant waves. Eligible veterans had previously completed an mRNA vaccine primary series. We matched recipients of each vaccine in a 1:1 ratio according to recorded risk factors. Each vaccine group included 65,196 persons. The excess number of events over 16 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 45.4 (95% CI: 19.4, 84.7) for documented infection, 3.7 (2.2, 14.1) for symptomatic COVID-19, 10.6 (5.1, 19.7) for COVID-19 hospitalization, 2.0 (-3.1, 6.3) for COVID-19 intensive care unit admission and 0.2 (-2.2, 4.0) for COVID-19 death. After emulating a second target trial of veterans who received a third dose between 1 January and 1 March 2022, during a period restricted to Omicron-variant predominance, the excess number of events over 9 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 63.2 (95% CI: 15.2, 100.7) for documented infection. The 16-week risks of COVID-19 outcomes were low after a third dose of mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2, particularly for documented infection.

New Frontiers in Placenta Tissue Imaging.

The placenta is a highly vascularized organ with unique structural and metabolic complexities. As the primary conduit of fetal support, the placenta mediates transport of oxygen, nutrients, and waste between maternal and fetal blood. Thus, normal placenta anatomy and physiology is absolutely required for maintenance of maternal and fetal health during pregnancy. Moreover, impaired placental health can negatively impact offspring growth trajectories as well as increase the risk of maternal cardiovascular disease later in life. Despite these crucial roles for the placenta, placental disorders, such as preeclampsia, intrauterine growth restriction (IUGR), and preterm birth, remain incompletely understood. Effective noninvasive imaging and image analysis are needed to advance the obstetrician's clinical reasoning toolkit and improve the utility of the placenta in interpreting maternal and fetal health trajectories. Current paradigms in placental imaging and image analysis aim to improve the traditional imaging techniques that may be time-consuming, costly, or invasive. In concert with conventional clinical approaches such as ultrasound (US), advanced imaging modalities can provide insightful information on the structure of placental tissues. Herein we discuss such imaging modalities, their specific applications in structural, vascular, and metabolic analysis of placental health, and emerging frontiers in image analysis research in both preclinical and clinical contexts.