Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.

BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI). METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21. RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-ß1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology. CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.

mRNA COVID-19 vaccine safety among older adults from the Canadian National Vaccine Safety Network.

This study examined short-to-medium term safety of COVID-19 vaccines among adults aged ≥65 years using the Canadian National Vaccine Safety Network active safety surveillance data. Both vaccinated and unvaccinated older adult participants recruited from seven provinces and territories were included in the analysis. Safety was assessed at 7 days after COVID-19 vaccination (dose 1, 2 and 3), and 7 months after dose 1. Multivariable logistic regression was used to examine the association between BNT162b2/mRNA-1273 COVID-19 vaccines and two short-term health events: 1) health event preventing daily activities and/or required medical consultation, 2) serious health events resulting in an emergency department visit and/or hospitalization within 7 days following each dose. We also assessed the rates of serious health events for the period between dose 1 and 2, and 7-months following dose 1. Between December 2020 and February 2022, a total of 173,038, 104,452, and 13,970 older adults completed dose 1, dose 2, and dose 3 surveys, respectively. The control survey was completed by 2,955 unvaccinated older adults. Health events occurred more frequently among recipients after dose 2 homologous mRNA-1273 (adjusted odds ratio [95 % confidence interval]: 2.91 [2.24-3.79]) and dose two heterologous (BNT162b2 followed by mRNA-1273): 1.50 [1.12-2.02] compared to unvaccinated counterparts. There was no difference in event rates after any dose of BNT162b2 and unvaccinated participants. The rates of serious health events following COVID-19 vaccination were very low (≤0.3 %) across all vaccine products and doses, and were not higher compared to unvaccinated controls, and were not associated with an emergency department visit or hospitalization within 7 days following vaccination. Reported symptoms were self-limited and rarely required medical assessment. Our findings further strengthen the current evidence that mRNA COVID-19 vaccines are safe and can be used to inform older adults about expected adverse events following COVID-19 vaccination.

Trivalent and quadrivalent seasonal influenza vaccine in adults aged 60 and older: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of influenza vaccines of any valency for adults 60 years and older. DESIGN AND SETTING: Systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs). MEDLINE, EMBASE, JBI Evidence-Based Practice (EBP) Database, PsycINFO, and Cochrane Evidence -Based Medicine database were searched from inception to 20 June 20, 2022. Two reviewers screened, abstracted, and appraised articles (Cochrane Risk of Bias (ROB) 2.0 tool) independently. We assessed certainty of findings using Confidence in Network Meta-Analysis and Grading of Recommendations, Assessment, Development and Evaluations approaches. We performed random-effects meta-analysis and network meta-analysis (NMA), and estimated odds ratios (ORs) for dichotomous outcomes and incidence rate ratios (IRRs) for count outcomes along with their corresponding 95% confidence intervals (CIs) and prediction intervals. PARTICIPANTS: Older adults (≥60 years old) receiving an influenza vaccine licensed in Canada or the USA (vs placebo, no vaccine, or any other licensed vaccine), at any dose. MAIN OUTCOME MEASURES: Laboratory-confirmed influenza (LCI) and influenza-like illness (ILI). Secondary outcomes were the number of vascular adverse events, hospitalisation for acute respiratory infection (ARI) and ILI, inpatient hospitalisation, emergency room (ER) visit for ILI, outpatient visit, and mortality, among others. RESULTS: We included 41 RCTs and 15 companion reports comprising 8 vaccine types and 206 032 participants. Vaccines may prevent LCI compared with placebo, with high-dose trivalent inactivated influenza vaccine (IIV3-HD) (NMA: 9 RCTs, 52 202 participants, OR 0.23, 95% confidence interval (CI) (0.11 to 0.51), low certainty of evidence) and recombinant influenza vaccine (RIV) (OR 0.25, 95%CI (0.08 to 0.73), low certainty of evidence) among the most efficacious vaccines. Standard dose trivalent IIV3 (IIV3-SD) may prevent ILI compared with placebo, but the result was imprecise (meta-analysis: 2 RCTs, 854 participants, OR 0.39, 95%CI (0.15 to 1.02), low certainty of evidence). Any HD was associated with prevention of ILI compared with placebo (NMA: 9 RCTs, 65 658 participants, OR 0.38, 95%CI (0.15 to 0.93)). Adjuvanted quadrivalent IIV (IIV4-Adj) may be associated with the least vascular adverse events, but the results were very uncertain (NMA: eight 8 RCTs, 57 677 participants, IRR 0.18, 95%CI (0.07 to 0.43), very low certainty of evidence). RIV on all-cause mortality may be comparable to placebo (NMA: 20 RCTs, 140 577 participants, OR 1.01, 95%CI (0.23 to 4.49), low certainty of evidence). CONCLUSIONS: This systematic review demonstrated efficacy associated with IIV3-HD and RIV vaccines in protecting older persons against LCI. RIV vaccine may reduce all-cause mortality when compared with other vaccines, but the evidence is uncertain. Differences in efficacy between influenza vaccines remain uncertain with very low to moderate certainty of evidence. PROSPERO REGISTRATION NUMBER: CRD42020177357.

Influence of Atherosclerotic Risk Factors on the Effectiveness of Therapeutic Ultrasound Cavitation for Flow Augmentation.

BACKGROUND: Shear created by inertial cavitation of microbubbles by ultrasound augments limb and myocardial perfusion and can reverse tissue ischemia. Our aim was to determine whether this therapeutic bioeffect is attenuated by atherosclerotic risk factors that are known to impair shear-mediated vasodilation and adversely affect microvascular reactivity. METHODS: In mice, lipid-stabilized decafluorobutane microbubbles (2 × 108) were administered intravenously while exposing a proximal hind limb to ultrasound (1.3 MHz, 1.3 mechanical index, pulsing interval 5 seconds) for 10 minutes. Murine strains included wild-type mice and severely hyperlipidemic mice at 15, 35, or 52 weeks of age as a model of aging and elevated cholesterol, and obese db/db mice (≈15 weeks) with severe insulin resistance. Quantitative contrast-enhanced ultrasound perfusion imaging was performed to assess microvascular perfusion in the control and ultrasound-exposed limb. An in situ electrochemical probe and in vivo biophotonic imaging were used to assess limb nitric oxide (NO) and adenosine triphosphosphate concentrations, respectively. RESULTS: Microvascular perfusion was significantly increased by several fold in the cavitation-exposed limb versus control limb for all murine strains and ages (P < .001). In wild-type and hyperlipidemic mice, hyperemia from cavitation was attenuated in the 2 older age groups (P < .01). In young mice (15 weeks), perfusion in cavitation-exposed muscle was less in both the hyperlipidemic mice and the obese db/db mice compared with corresponding wild-type mice. Using young hyperlipidemic mice as a model for flow impairment, limb NO production after cavitation was reduced but adenosine triphosphosphate production was unaltered when compared with age-matched wild-type mice. CONCLUSIONS: In mice, ultrasound cavitation of microbubbles increases limb perfusion by several fold even in the presence of traditional atherosclerotic risk factors. However, older age, hyperlipidemia, and insulin resistance modestly attenuate the degree of flow augmentation, which could impact the degree of flow response in current clinical trials in patients with critical limb ischemia.

Elevated LDL Cholesterol Increases Microvascular Endothelial VWF and Thromboinflammation After Myocardial Infarction.

BACKGROUND: In reperfused myocardial infarction, VWF (von Willebrand factor)-mediated platelet adhesion contributes to impaired microvascular reflow and possibly also to postmyocardial infarction inflammation. We hypothesized that postischemic thromboinflammatory processes are worsened by elevated LDL (low-density lipoprotein) cholesterol. METHODS: Myocardial ischemia-reperfusion or sham procedure was performed in wild-type mice and hyperlipidemic mice deficient for the LDL receptor and Apobec-1 (apolipoprotein-B mRNA editing enzyme catalytic polypeptide-1; DKO [double knockout]). DKO subgroups were treated with N-acetylcysteine, which inhibits pro-adhesive VWF multimers or with recombinant ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs-13), which enzymatically cleaves endothelial surface-associated VWF. Myocardial contrast echocardiography perfusion imaging and molecular imaging for VWF, platelet glycoprotein Ibα, and leukocyte CD18 (cluster of differentiation) were performed 30 minutes post-reperfusion. Histology, infarct sizing, and echocardiography were performed at 1.5 or 72 hours; late echocardiography was performed at day 21. RESULTS: After ischemia-reperfusion, DKO compared with wild-type mice had ≈2-fold higher (P<0.05) risk area signal for microvascular platelet adhesion, VWF, and CD18; greater impairment in microvascular reflow, and 2-fold larger infarct size. Treatment of DKO mice with N-acetylcysteine and ADAMTS13 reduced molecular imaging signal for microvascular platelet adhesion, VWF, and CD18; improved early microvascular reflow; and reduced eventual infarct size. ADAMTS13 suppressed the postmyocardial infarction neutrophil and monocyte infiltration, enhanced the time-dependent recovery of left ventricular systolic function, and prevented late left ventricular remodeling. CONCLUSIONS: In reperfused myocardial infarction, elevated LDL cholesterol promotes thromboinflammation through excess microvascular endothelial VWF and platelet adhesion, resulting in less microvascular reflow and larger infarct size. In the presence of elevated LDL cholesterol, therapies that suppress endothelial-associated VWF can promote recovery of left ventricular function and protect against remodeling.

A comparison of endovascular repair to medical management for acute vs subacute uncomplicated type B aortic dissections.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) has emerged as a viable option of treatment for uncomplicated type B aortic dissection (UTBAD) due to the potential for inducing favorable aortic remodeling. The aim of this study is to compare outcomes of UTBAD treated medically or with TEVAR in either the acute (1 to 14 days) or subacute period (2 weeks to 3 months). METHODS: Patients with UTBAD between 2007 and 2019 were identified using the TriNetX Network. The cohort was stratified by treatment type (medical management; TEVAR during the acute period; TEVAR during the subacute period). Outcomes including mortality, endovascular reintervention, and rupture were analyzed after propensity matching. RESULTS: Among 20,376 patients with UTBAD, 18,840 were medically managed (92.5%), 1099 patients were in the acute TEVAR group (5.4%), and 437 patients were in the subacute TEVAR group (2.1%). The acute TEVAR group had higher rates of 30-day and 3-year rupture (4.1% vs 1.5%; P < .001; 9.9% vs 3.6%; P < .001) and 3-year endovascular reintervention (7.6% vs 1.6%; P < .001), similar 30-day mortality (4.4% vs 2.9%; P < .068), and lower 3-year survival compared with medical management (86.6% vs 83.3%; P = .041). The subacute TEVAR group had similar rates of 30-day mortality (2.3% vs 2.3%; P = 1), 3-year survival (87.0% vs 88.8%; P = .377) and 30-day and 3-year rupture (2.3% vs 2.3%; P = 1; 4.6% vs 3.4%; P = .388), with significantly higher rates of 3-year endovascular reintervention (12.6% vs 7.8%; P = .019) compared with medical management. The acute TEVAR group had similar rates of 30-day mortality (4.2% vs 2.5%; P = .171), rupture (3.0% vs 2.5%; P = .666), significantly higher rates of 3-year rupture (8.7% vs 3.5%; P = .002), and similar rates of 3-year endovascular reintervention (12.6% vs 10.6%; P = .380) compared with the subacute TEVAR group. There was significantly higher 3-year survival (88.5% vs 84.0%; P = .039) in the subacute TEVAR group compared with the acute TEVAR group. CONCLUSIONS: Our results found lower 3-year survival in the acute TEVAR group compared with the medical management group. There was no 3-year survival benefit found in patients with UTBAD who underwent subacute TEVAR compared with medical management. This suggests the need for further studies looking at the necessity for TEVAR when compared with medical management for UTBAD as it is non-inferior to medical management. Higher rates of 3-year survival and lower rates of 3-year rupture in the subacute TEVAR group compared with the acute TEVAR group suggest superiority of subacute TEVAR. Further investigations are needed to determine the long-term benefit and optimal timing of TEVAR for acute UTBAD.

Changes in microvascular perfusion of heart and skeletal muscle in sheep around the time of birth.

NEW FINDINGS: What is the central question of this study? How does the microvascular perfusion of striated muscle change during the dynamic developmental period between the late gestation fetus and early neonate? What is the main finding and its importance? In both myocardium and skeletal muscle, perfusion of striated muscle is significantly reduced in the neonate compared to the late term fetus, but flow reserve is unchanged. The results suggest striated muscle capillary networks grow more slowly relative to the myofibres they nourish during the perinatal period. ABSTRACT: Microvascular perfusion of striated muscle is an important determinant of health throughout life. Birth is a transition with profound effects on the growth and function of striated muscle, but the regulation of microvascular perfusion around this transition is poorly understood. We used contrast-enhanced ultrasound perfusion imaging (CEUS) to study the perfusion of left ventricular myocardium and hindlimb biceps femoris, which are populations of muscle with different degrees of change in pre- to postnatal workloads and different capacities for postnatal proliferative growth. We studied separate groups of lambs in late gestation (135 days' gestational age; 92% of term) and shortly after birth (5 days' postnatal age). We used CEUS to quantify baseline perfusion, perfusion during hyperaemia induced by adenosine infusion (myocardium) or electrically stimulated unloaded exercise (skeletal muscle), flow reserve and oxygen delivery. We found heart-to-body weight ratio was greater in neonates than fetuses. Microvascular volume and overall perfusion were lower in neonates than fetuses in both muscle groups at baseline and with hyperaemia. Flux rate differed with muscle group, with myocardial flux being faster in neonates than fetuses, but skeletal muscle flux being slower. Oxygen delivery to skeletal muscle at baseline was lower in neonates than fetuses, but was not significantly different in myocardium. Flow reserve was not different between ages. Given the significant somatic growth, and the transition from hyperplastic to hypertrophic myocyte growth occurring in the perinatal period, we postulate that the primary driver of lower neonatal striated muscle perfusion is faster growth of myofibres than their associated capillary networks.

Adverse Events Following Immunization With mRNA and Viral Vector Vaccines in Individuals With Previous Severe Acute Respiratory Syndrome Coronavirus 2 Infection From the Canadian National Vaccine Safety Network.

BACKGROUND: Adults previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop short-term immunity and may have increased reactogenicity to coronavirus disease 2019 (COVID-19) vaccines. This prospective, multicenter, active-surveillance cohort study examined the short-term safety of COVID-19 vaccines in adults with a prior history of SARS-CoV-2. METHODS: Canadian adults vaccinated between 22 December 2020 and 27 November 2021 were sent an electronic questionnaire 7 days post-dose 1, dose 2, and dose 3 vaccination. The main outcome was health events occurring in the first 7 days after each vaccination that prevented daily activities, resulted in work absenteeism, or required a medical consultation, including hospitalization. RESULTS: Among 684 998 vaccinated individuals, 2.6% (18 127/684 998) reported a prior history of SARS-CoV-2 infection a median of 4 (interquartile range: 2-6) months previously. After dose 1, individuals with moderate (bedridden) to severe (hospitalized) COVID-19 who received BNT162b2, mRNA-1273, or ChAdox1-S vaccines had higher odds of a health event preventing daily activities, resulting in work absenteeism or requiring medical consultation (adjusted odds ratio [95% confidence interval]: 3.96 [3.67-4.28] for BNT162b2, 5.01 [4.57-5.50] for mRNA-1273, and 1.84 [1.54-2.20] for ChAdox1-S compared with no infection). Following dose 2 and 3, the greater risk associated with previous infection was also present but was attenuated compared with dose 1. For all doses, the association was lower or absent after mild or asymptomatic infection. CONCLUSIONS: Adults with moderate or severe previous SARS-CoV-2 infection were more likely to have a health event sufficient to impact routine activities or require medical assessment in the week following each vaccine dose.

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial.

BACKGROUND: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. OBJECTIVE: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. DESIGN: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). SETTING: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. PARTICIPANTS: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. INTERVENTION: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. MEASUREMENTS: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. RESULTS: In the intention-to-treat analysis, RT-PCR-confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR-confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. LIMITATION: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. CONCLUSION: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR-confirmed COVID-19 for medical masks when compared with HRs of RT-PCR-confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Reduced Proteolytic Cleavage of von Willebrand Factor Leads to Aortic Valve Stenosis and Load-Dependent Ventricular Remodeling.

We hypothesized that excess endothelial-associated von Willebrand factor (vWF) and secondary platelet adhesion contribute to aortic valve stenosis (AS). We studied hyperlipidemic mice lacking ADAMTS13 (LDLR -/- AD13 -/- ), which cleaves endothelial-associated vWF multimers. On echocardiography and molecular imaging, LDLR -/- AD13 -/- compared with control strains had increased aortic endothelial vWF and platelet adhesion and developed hemodynamically significant AS, arterial stiffening, high valvulo-aortic impedance, and secondary load-dependent reduction in LV systolic function. Histology revealed leaflet thickening and calcification with valve interstitial cell myofibroblastic and osteogenic transformation, and evidence for TGFß1 pathway activation. We conclude that valve leaflet endothelial vWF-platelet interactions promote AS through juxtacrine platelet signaling.

Comparative-effectiveness research of COVID-19 treatment: a rapid scoping review.

OBJECTIVES: The COVID-19 pandemic has stimulated growing research on treatment options. We aim to provide an overview of the characteristics of studies evaluating COVID-19 treatment. DESIGN: Rapid scoping review DATA SOURCES: Medline, Embase and biorxiv/medrxiv from inception to 15 May 2021. SETTING: Hospital and community care. PARTICIPANTS: COVID-19 patients of all ages. INTERVENTIONS: COVID-19 treatment. RESULTS: The literature search identified 616 relevant primary studies of which 188 were randomised controlled trials and 299 relevant evidence syntheses. The studies and evidence syntheses were conducted in 51 and 39 countries, respectively.Most studies enrolled patients admitted to acute care hospitals (84%), included on average 169 participants, with an average age of 60 years, study duration of 28 days, number of effect outcomes of four and number of harm outcomes of one. The most common primary outcome was death (32%).The included studies evaluated 214 treatment options. The most common treatments were tocilizumab (11%), hydroxychloroquine (9%) and convalescent plasma (7%). The most common therapeutic categories were non-steroidal immunosuppressants (18%), steroids (15%) and antivirals (14%). The most common therapeutic categories involving multiple drugs were antimalarials/antibiotics (16%), steroids/non-steroidal immunosuppressants (9%) and antimalarials/antivirals/antivirals (7%). The most common treatments evaluated in systematic reviews were hydroxychloroquine (11%), remdesivir (8%), tocilizumab (7%) and steroids (7%).The evaluated treatment was in favour 50% and 36% of the evaluations, according to the conclusion of the authors of primary studies and evidence syntheses, respectively. CONCLUSIONS: This rapid scoping review characterised a growing body of comparative-effectiveness primary studies and evidence syntheses. The results suggest future studies should focus on children, elderly ≥65 years of age, patients with mild symptoms, outpatient treatment, multimechanism therapies, harms and active comparators. The results also suggest that future living evidence synthesis and network meta-analysis would provide additional information for decision-makers on managing COVID-19.

Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) network cohort study.

BACKGROUND: Pregnant individuals have been receiving COVID-19 vaccines following pre-authorisation clinical trials in non-pregnant people. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. METHODS: We did an observational cohort study, set in seven Canadian provinces and territories including Ontario, Quebec, British Columbia, Alberta, Nova Scotia, Yukon, and Prince Edward Island. Eligibility criteria for vaccinated individuals were a first dose of a COVID-19 vaccine within the previous 7 days; an active email address and telephone number; ability to communicate in English or French; and residence in the aforementioned provinces or territories. Study participants were pregnant and non-pregnant females aged 15-49 years. Individuals were able to participate as controls if they were unvaccinated and fulfilled the other criteria. Data were collected primarily by self-reported survey after both vaccine doses, with telephone follow-up for those reporting any medically attended event. Participants reported significant health events (new or worsening of a health event sufficient to cause work or school absenteeism, medical consultation, or prevent daily activities) occurring within 7 days of vaccination or within the past 7 days for unvaccinated individuals. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines, adjusting for age group, previous SARS-CoV-2 infection, and trimester, as appropriate. FINDINGS: As of Nov 4, 2021, 191 360 women aged 15-49 years with known pregnancy status had completed the first vaccine dose survey and 94 937 had completed the second dose survey. 180 388 received one dose and 94 262 received a second dose of an mRNA vaccine, with 5597 pregnant participants receiving dose one and 3108 receiving dose two, and 174 765 non-pregnant participants receiving dose one and 91 131 receiving dose two. Of 6179 included unvaccinated control participants, 339 were pregnant and 5840 were not pregnant. Overall, 226 (4·0%) of 5597 vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227 (7·3%) of 3108 after dose two, compared with 11 (3·2%) of 339 pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio [aOR] 4·4 [95% CI 2·4-8·3]) compared with pregnant unvaccinated controls within the past 7 days, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0·63 [95% CI 0·55-0·72]) and dose two (aOR 0·62 [0·54-0·71]) of any mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention. INTERPRETATION: COVID-19 mRNA vaccines have a good safety profile in pregnancy. These data can be used to appropriately inform pregnant people regarding reactogenicity of COVID-19 vaccines during pregnancy, and should be considered alongside effectiveness and immunogenicity data to make appropriate recommendations about best use of COVID-19 vaccines in pregnancy. FUNDING: Canadian Institutes of Health Research, Public Health Agency of Canada.

Augmentation of Pulmonary Perfusion by Conducted Effects of a Pulmonary Artery Ultrasound Catheter.

Ultrasound (US) generated by catheters used clinically for US-facilitated thrombolysis can release shear-dependent vasodilators from endothelial and red blood cells. We hypothesized that catheter-based US in the pulmonary artery (PA) decreases downstream vascular resistance and increases pulmonary blood flow. In rhesus macaques, a U.S. Food and Drug Administration-approved multi-element US catheter was placed in a pulmonary artery. Comprehensive echocardiography was performed (i) at baseline, (ii) during hypoxemia (12% FIO2) to increase pulmonary vascular resistance (PVR) and (c) 15 min after initiating US during hypoxemia. Reduced FIO2 produced intended reductions in oxygen saturation (69 ± 3%) and PaO2 (34 ± 5 mm Hg), yet on echocardiography, hypoxemia did not create the intended model, with only modest hypoxia-related increases in PA systolic pressure (24 ± 4 to 28 ± 4 mm Hg, p = 0.05) and no significant change in PVR or multiparametric right ventricular (RV) function. Although US did not further change total PVR, on 99mTc-macroalbumin aggregate single-photon-emission computed tomography imaging, lung perfusion was significantly higher in the lung ipsilateral to the US catheter versus the contralateral control lung (133 ± 48 cpm vs. 103 ± 43 × 103 cpm, p = 0.01). We conclude that PA catheter-based US increases regional lung perfusion, most likely from vasodilators that are conducted downstream.

Tuberculosis Exposure from a Healthcare Worker to Patients in a Neonatal Intensive Care Unit (NICU).

The nosocomial spread of Mycobacterium tuberculosis from a healthcare worker with infectious pulmonary tuberculosis disease to patients remains a risk in the healthcare environment, including neonatal intensive care units. In this paper, we outlined a protocol for neonates exposed to tuberculosis in a neonatal intensive care unit that includes skin testing, chest X-ray imaging, and prophylactic isoniazid. Neonatal patients were followed up with tuberculosis skin testing at both three months corrected age and two months postexposure. To our knowledge, this is the first Canadian study to illustrate a protocol following tuberculosis exposure in a neonatal intensive care unit for exposed neonates.

Systematic Review on the Cost-Effectiveness of Seasonal Influenza Vaccines in Older Adults.

OBJECTIVES: Older adults are at high risk of influenza-related complications or hospitalization. The purpose of this systematic review is to assess the relative cost-effectiveness of all influenza vaccine options for older adults. METHODS: This systematic review identified economic evaluation studies assessing the cost-effectiveness of influenza vaccines in adults ≥65 years of age from 5 literature databases. Two reviewers independently selected, extracted, and appraised relevant studies using the JBI Critical Appraisal Checklist for Economic Evaluations and Heyland's generalizability checklist. Costs were converted to 2019 Canadian dollars and adjusted for inflation and purchasing power parity. RESULTS: A total of 27 studies were included. There were 18 comparisons of quadrivalent inactivated vaccine (QIV) versus trivalent inactivated vaccine (TIV): 5 showed QIV dominated TIV (ie, lower costs and higher health benefit), and 13 showed the results depended on willingness to pay (WTP). There were 9 comparisons of high-dose TIV (TIV-HD) versus TIV: 5 showed TIV-HD dominated TIV, and 4 showed the results depended on WTP. There were 8 comparisons of adjuvanted TIV (TIV-ADJ) versus TIV: 4 showed TIV-ADJ dominated TIV, and 4 showed the results depended on WTP. There were few pairwise comparisons among QIV, TIV-HD, and TIV-ADJ. CONCLUSIONS: The evidence suggests QIV, TIV-HD, and TIV-ADJ are cost-effective against TIV for a WTP threshold of $50 000 per quality-adjusted life-year. Future studies should include new and existing vaccine options for broad age ranges and use more robust methodologies-such as real-world evaluations or modeling studies accounting for methodological, structural, and parameter uncertainty.