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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. 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. 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. 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. Canadian Institutes of Health Research, Public Health Agency of Canada.

Abstract Background Antimicrobial stewardship programs (ASPs) using audit and feedback in the intensive care unit (ICU) setting can reduce harms related to inappropriate antibiotic use. However, inappropriate discontinuation or narrowing of antibiotic treatment could increase infection-related mortality in this population. Individual ASP studies are underpowered to detect differences in mortality. Methods We conducted a systematic review and meta-analysis of audit and feedback in the ICU setting, using mortality as our outcome. Results Of 2447 citations, 11 studies met our inclusion criteria. Although a variety of study designs were used to assess reductions in antibiotic use, mortality was analyzed using an uncontrolled before-after study design in all studies. Five studies directed audit and feedback to all or most ICU patients receiving antibiotics and measured overall ICU mortality. In the meta-analysis of these studies, the pooled relative risk of ICU mortality was 1.03 (95% confidence interval, .93–1.14). A second meta-analysis of 3 smaller studies that evaluated mortality only in patients directly assessed by the ASP found a pooled relative risk of ICU mortality of 1.06 (95% confidence interval, .80 to 1.4). Three studies were not appropriate for meta-analysis, but their results were consistent with our overall findings. Conclusions Our systematic review did not identify a change in mortality associated with antimicrobial stewardship using audit and feedback in the ICU setting. These results increase our confidence that audit and feedback can be safely implemented in this setting. Future studies should report standardized estimates of mortality and use more robust study designs to assess mortality, when feasible. Our systematic review of antimicrobial stewardship programs using audit and feedback in the ICU setting found no change in mortality rates with implementation of the intervention and increases our confidence in the safety of antimicrobial stewardship, even in high-risk settings.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5–5.1, p  = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 –0.94, n  = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 –0.79, n  = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07–3.36; p  = 0.027, n  = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction. Platelet hyperreactivity is associated with cardiovascular events in patients with PAD. Here the authors derive and validate a circulating platelet genetic signature to discriminate platelet hyperreactivity and cardiovascular risk.

Background The objective of this review was to examine the current guidelines for infection prevention and control (IPAC) of coronavirus disease-19 (COVID-19) or other coronaviruses in adults 60 years or older living in long-term care facilities (LTCF). Methods EMBASE, MEDLINE, Cochrane library, pre-print servers, clinical trial registries, and relevant grey literature sources were searched until July 31, 2020, using database searching and an automated method called Continuous Active Learning® (CAL®). All search results were processed using CAL® to identify the most likely relevant citations that were then screened by a single human reviewer. Full-text screening, data abstraction, and quality appraisal were completed by a single reviewer and verified by a second. Results Nine clinical practice guidelines (CPGs) were included. The most common recommendation in the CPGs was establishing surveillance and monitoring systems followed by mandating the use of PPE; physically distancing or cohorting residents; environmental cleaning and disinfection; promoting hand and respiratory hygiene among residents, staff, and visitors; and providing sick leave compensation for staff. Conclusions Current evidence suggests robust surveillance and monitoring along with support for IPAC initiatives are key to preventing the spread of COVID-19 in LTCF. However, there are significant gaps in the current recommendations especially with regard to the movement of staff between LTCF and their role as possible transmission vectors. Systematic review registration PROSPERO CRD42020181993

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-β1 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.

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. 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.

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Younger women rely on altering cardiac output (Q̇ $\\dot{Q}$ ) to regulate blood pressure (BP). In contrast, older women rely more on altering vascular tone. However, evidence suggests that the ability to alter systemic vascular conductance (SVC) is diminished in older women. In the present study, cardioselective β‐blockade was utilized to diminish the relative contribution of Q̇ $\\dot{Q}$to BP regulation and thereby evaluate age‐related vascular limitations in women at rest and during large muscle dynamic exercise. Younger (n = 13, mean age 26.0 years) and older (n = 14, mean age 61.8 years) healthy women performed submaximal bouts of semi‐recumbent cycling exercise at varying intensities while receiving an intravenous infusion of esmolol, a β1‐antagonist, or saline control in a repeated‐measures crossover design. Q̇ $\\dot{Q}$was attenuated during esmolol infusion, with greater reductions during exercise (moderate, –1.0 (95% CI, –1.6 to –0.5) L/min, P < 0.001; heavy, –2.0 (95% CI, –2.6 to –1.5) L/min, P < 0.001) than seated rest (–0.5 (95% CI, –1.1 to 0.0) L/min, P = 0.048), and this reduction was not significantly different between age groups (P = 0.122). Older women exhibited a greater attenuation in mean arterial pressure (MAP) during esmolol (–7 (95% CI, –9 to –4) mmHg, P < 0.001) relative to younger women (–2 (95% CI, –5 to 0) mmHg, P = 0.071). These changes coincided with a greater reduction of SVC in the younger women during esmolol (–15 (95% CI, –20 to –10) mL/min/mmHg, P < 0.001) compared to older women (–3 (95% CI, –9 to 2) mL/min/mmHg, P = 0.242). Together, these findings provide evidence that older, postmenopausal women have a diminished ability to adjust SVC in order to regulate MAP. What is the central question of this study? Will older women have a greater reduction in mean arterial pressure during cardioselective β‐blockade compared to younger women? And will older women exhibit a smaller reduction in systemic vascular conductance in response to cardioselective β‐blockade relative to younger women? What is the main finding and its importance? Cardioselective β‐blockade revealed a limitation in the systemic vasoconstrictor capacity of older women to maintain blood pressure both at rest and during dynamic exercise. These findings may have significant clinical implications, particularly during hypotensive stressors such as heat stress, hypovolemia and orthostatic hypotension.

Background: The demand for COVID-19 vaccines has diminished as the pandemic lingers. Understanding vaccine hesitancy among essential workers is important in reducing the impact of future pandemics by providing effective immunization programs delivered expeditiously. Method: Two surveys exploring COVID-19 vaccine acceptance in 2021 and 2022 were conducted in cohorts of health care providers (HCP) and education workers participating in prospective studies of COVID-19 illnesses and vaccine uptake. Demographic factors and opinions about vaccines (monovalent and bivalent) and public health measures were collected in these self-reported surveys. Modified multivariable Poisson regression was used to determine factors associated with hesitancy. Results: In 2021, 3 % of 2061 HCP and 6 % of 3417 education workers reported hesitancy (p < 0.001). In December 2022, 21 % of 868 HCP and 24 % of 1457 education workers reported being hesitant to receive a bivalent vaccine (p = 0.09). Hesitance to be vaccinated with the monovalent vaccines was associated with earlier date of survey completion, later receipt of first COVID-19 vaccine dose, no influenza vaccination, and less worry about becoming ill with COVID-19. Factors associated with hesitance to be vaccinated with a bivalent vaccine that were common to both cohorts were receipt of two or fewer previous COVID-19 doses and lower certainty that the vaccines were safe and effective. Conclusion: Education workers were somewhat more likely than HCP to report being hesitant to receive COVID-19 vaccines but reasons for hesitancy were similar. Hesitancy was associated with non-receipt of previous vaccines (i.e., previous behaviour), less concern about being infected with SARS-CoV-2, and concerns about the safety and effectiveness of vaccines for both cohorts. Maintaining inter-pandemic trust in vaccines, ensuring rapid data generation during pandemics regarding vaccine safety and effectiveness, and effective and transparent communication about these data are all needed to support pandemic vaccination programs. •3 % of health care providers and 6 % of education workers reported hesitancy about receiving their first COVID-19 vaccines.•21 % of health care providers and 24 % of education workers were hesitant about receiving a bivalent COVID-19 vaccine.•Factors associated with COVID-19 vaccine hesitancy were similar for health care and education workers and for monovalent and bivalent vaccines.

Background Antimicrobial decision making in intensive care units (ICUs) is challenging. Unnecessary antimicrobials contribute to the development of resistant pathogens, Clostridium difficile infection and drug related adverse events. However, inadequate antimicrobial therapy is associated with mortality in critically ill patients. Antimicrobial stewardship programs are increasingly being implemented to improve antimicrobial prescribing, but the optimal approach in the ICU setting is unknown. We assessed the impact of an audit and feedback antimicrobial stewardship intervention on antimicrobial use, antimicrobial costs, clinical outcomes and microbiologic outcomes in two ICUs with different patient populations. Methods The audit and feedback intervention was implemented in a trauma and neurosurgery ICU (TNICU) and a medical surgical ICU (MSICU) at a 465-bed teaching hospital in Toronto, Canada. ICU patients were reviewed Monday to Friday by a physician and pharmacist with infectious diseases training. Recommendations related to appropriate antimicrobial use were presented to ICU teams during a dedicated daily meeting. A controlled interrupted time series analysis was used to compare outcomes in the 12 months before and after the intervention. Cardiovascular and coronary care ICUs served as control units. Results Mean total monthly antimicrobial use in defined daily doses (DDD) per 1000 patient days was reduced 28 % in the TNICU (1433 vs. 1037) but increased 14 % in the MSICU (1705 vs. 1936). In the time series analysis, total monthly antimicrobial use in the TNICU decreased by 375 DDD per 1000 patient days (p < 0.0009) immediately following the intervention, followed by a non-significant downward trend in use of −9 DDD per 1000 patient days ( p  = 0.56). No significant changes in antimicrobial use were identified in the MSICU. Antimicrobial use temporarily increased in one control unit and remained unchanged in the other. There were no changes in mortality, length of stay, readmission rate, incidence of C. difficile infection or resistance patterns of E. coli and P. aeruginosa in either intervention unit. Conclusions Audit and feedback antimicrobial stewardship programs can lead to significant reductions in total antimicrobial use in the ICU setting. However, this effect may be context-dependent and further work is needed to determine the ingredients necessary for success.