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.

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.

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.

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.

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.

Inorganic nitrate supplementation and blood flow restricted exercise tolerance in post-menopausal women.

Exercise tolerance appears to benefit most from dietary nitrate (NO3-) supplementation when muscle oxygen (O2) availability is low. Using a double-blind, randomized cross-over design, we tested the hypothesis that acute NO3- supplementation would improve blood flow restricted exercise duration in post-menopausal women, a population with reduced endogenous nitric oxide bioavailability. Thirteen women (57-76 yr) performed rhythmic isometric handgrip contractions (10% MVC, 30 per min) during progressive forearm blood flow restriction (upper arm cuff gradually inflated 20 mmHg each min) on three study visits, with 7-10 days between visits. Approximately one week following the first (familiarization) visit, participants consumed 140 ml of NO3- concentrated (9.7 mmol, 0.6 gm NO3-) or NO3-depleted beetroot juice (placebo) on separate days (≥7 days apart), with handgrip exercise beginning 100 min post-consumption. Handgrip force recordings were analyzed to determine if NO3- supplementation enhanced force development as blood flow restriction progressed. Nitrate supplementation increased plasma NO3- (16.2-fold) and NO2- (4.2-fold) and time to volitional fatigue (61.8 ± 56.5 s longer duration vs. placebo visit; p = 0.03). Nitrate supplementation increased the rate of force development as forearm muscle ischemia progressed (p = 0.023 between 50 and 75% of time to fatigue) with non-significant effects thereafter (p = 0.052). No effects of nitrate supplementation were observed for mean duration of contraction or relaxation rates (all p > 0.150). These results suggest that acute NO3- supplementation prolongs time-to-fatigue and speeds grip force development during progressive forearm muscle ischemia in postmenopausal women.

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.

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.

Association Between Hospital Outbreaks and Hand Hygiene: Insights from Electronic Monitoring.

BACKGROUND: Hand hygiene (HH) is an important patient safety measure linked to the prevention of health care-associated infection, yet how outbreaks affect HH performance has not been formally evaluated. METHODS: A controlled, interrupted time series was performed across 5 acute-care academic hospitals using group electronic monitoring. This system captures 100% of all hand sanitizer and soap dispenser activations via a wireless signal to a wireless hub; the number of activations is divided by a previously validated estimate of the number of daily HH opportunities per patient bed, multiplied by the hourly census of patients on the unit. Daily HH adherence 60 days prior and 90 days following outbreaks on inpatient units was compared to control units not in outbreaks over the same period, using a Poisson regression model adjusting for correlations within hospitals and units. Predictors of HH improvement were assessed in this multivariate model. RESULTS: In the 60 days prior to outbreaks, units destined for outbreaks had significantly lower HH adherence compared to control units (incidence rate ratio [IRR], 0.91; 95% confidence interval [CI], .90-.93; P < .0001). Following an outbreak, the HH adherence among the outbreak units increased above that of the controls (IRR, 1.04; 95% CI, 1.02-1.06; P < .0001). Greater improvements were noted for outbreaks on surgical units, for outbreaks involving antibiotic-resistant organisms and enteric pathogens, and in those outbreaks where health-care workers became ill. CONCLUSIONS: Hospital outbreaks tend to occur in units with lower HH adherence and are associated with rapid improvements in HH performance. Group electronic monitoring of HH could be used to develop novel, prospective feedback interventions designed to avert hospital outbreaks.

Household Transmission of Carbapenemase-producing Enterobacterales in Ontario, Canada.

BACKGROUND: Data on household transmission of carbapenemase-producing Enterobacterales (CPE) remain limited. We studied risk of CPE household co-colonization and transmission in Ontario, Canada. METHODS: We enrolled CPE index cases (identified via population-based surveillance from January 2015 to October 2018) and their household contacts. At months 0, 3, 6, 9, and 12, participants provided rectal and groin swabs. Swabs were cultured for CPE until September 2017, when direct polymerase chain reaction (PCR; with culture of specimens if a carbapenemase gene was detected) replaced culture. CPE risk factor data were collected by interview and combined with isolate whole-genome sequencing to determine likelihood of household transmission. Risk factors for household contact colonization were explored using a multivariable logistic regression model with generalized estimating equations. RESULTS: Ninety-five households with 177 household contacts participated. Sixteen (9%) household contacts in 16 (17%) households were CPE-colonized. Household transmission was confirmed in 3/177 (2%) cases, probable in 2/177 (1%), possible in 9/177 (5%), and unlikely in 2/177 (1%). Household contacts were more likely to be colonized if they were the index case's spouse (odds ratio [OR], 6.17; 95% confidence interval [CI], 1.05-36.35), if their index case remained CPE-colonized at household enrollment (OR, 7.00; 95% CI, 1.92-25.49), or if they had at least 1 set of specimens processed after direct PCR was introduced (OR, 6.46; 95% CI, 1.52-27.40). CONCLUSIONS: Nine percent of household contacts were CPE-colonized; 3% were a result of household transmission. Hospitals may consider admission screening for patients known to have CPE-colonized household contacts.

Spreading Addictions Care Across Oregon's Rural and Community Hospitals: Mixed-Methods Evaluation of an Interprofessional Telementoring ECHO Program.

BACKGROUND: Despite evidence of effectiveness, most US hospitals do not deliver hospital-based addictions care. ECHO (Extension for Community Healthcare Outcomes) is a telementoring model for providers across diverse geographic areas. We developed and implemented a substance use disorder (SUD) in hospital care ECHO to support statewide dissemination of best practices in hospital-based addictions care. OBJECTIVES: Assess the feasibility, acceptability, and effects of ECHO and explore lessons learned and implications for the spread of hospital-based addictions care. DESIGN: Mixed-methods study with a pre-/post-intervention design. PARTICIPANTS: Interprofessional hospital providers and administrators across Oregon. INTERVENTION: A 10-12-week ECHO that included participant case presentations and brief didactics delivered by an interprofessional faculty, including peers with lived experience in recovery. APPROACH: To assess feasibility and acceptability, we collected enrollment, attendance, and participant feedback data. To evaluate ECHO effects, we used pre-/post-ECHO assessments and performed a thematic analysis of open-ended survey responses and participant focus groups. KEY RESULTS: We recruited 143 registrants to three cohorts between January and September 2019, drawing from 32 of Oregon's 62 hospitals and one southwest Washington hospital. Ninety-six (67.1%) attended at least half of ECHO sessions. Participants were highly satisfied with ECHO. After ECHO, participants were more prepared to treat SUD; however, prescribing did not change. Participants identified substantial gains in knowledge and skills, particularly regarding the use of medications for opioid use disorder; patient-centered communication with people who use drugs; and understanding harm reduction as a valid treatment approach. ECHO built a community of practice and reduced provider isolation. Participants recognized the need for supportive hospital leadership, policies, and SUD resources to fully implement and adopt hospital-based SUD care. CONCLUSIONS: A statewide, interprofessional SUD hospital care ECHO was feasible and acceptable. Findings may be useful to health systems, states, and regions looking to expand hospital-based addictions care.

Introduction of Group Electronic Monitoring of Hand Hygiene on Inpatient Units: A Multicenter Cluster Randomized Quality Improvement Study.

BACKGROUND: The current approach to measuring hand hygiene (HH) relies on human auditors who capture <1% of HH opportunities and rapidly become recognized by staff, resulting in inflation in performance. Group electronic monitoring is a validated method of measuring HH adherence, but data demonstrating the clinical impact of this technology are lacking. METHODS: A stepped-wedge cluster randomized quality improvement study was performed on 26 inpatient medical and surgical units across 5 acute care hospitals in Ontario, Canada. The intervention involved daily HH reporting as measured by group electronic monitoring to guide unit-led improvement strategies. The primary outcome was monthly HH adherence (percentage) between baseline and intervention. Secondary outcomes included transmission of antibiotic-resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and other healthcare-associated infections. RESULTS: After adjusting for the correlation within inpatient units and hospitals, there was a significant overall improvement in HH adherence associated with the intervention (incidence rate ratio [IRR], 1.73 [95% confidence interval {CI}, 1.47-1.99]; P < .0001). Monthly HH adherence relative to the intervention increased from 29% (1 395 450/4 544 144) to 37% (598 035/1 536 643) within 1 month, followed by consecutive incremental increases up to 53% (804 108/1 515 537) by 10 months (P < .0001). There was a trend toward reduced healthcare-associated transmission of MRSA (IRR, 0.74 [95% CI, .53-1.04]; P = .08). CONCLUSIONS: The introduction of a system for group electronic monitoring led to rapid, significant improvements in HH performance within a 2-year period. This method offers significant advantages over direct observation for measurement and improvement of HH.

Morbidity in an adenosine deaminase-deficient patient during 27 years of enzyme replacement therapy.

INTRODUCTION: Adenosine deaminase (ADA) deficiency causes severe immunodeficiency that is lethal in infancy. Enzyme replacement therapy (ERT) can improve the metabolic, immune and non-immune abnormalities in patients prior to transplantation, however, its benefits over extended periods are not well characterized. We describe a 28-year-old female who received ERT for 27 years. She suffered from EBV negative B cell lymphoma of the hip at 14 years of age and Guillian-Barre Syndrome 2 years later. At 22 years of age, she experienced a gastrointestinal infection with Mycobacterium genavense. At 26 years of age, lymphoma reoccurred with multiple liver lesions followed by Mycobacterium genavense infection with dissemination to the brain. Throughout this period, ADA activity in the plasma was within the therapeutic range. Repeated evaluations demonstrated very low lymphocyte counts and impaired T cell function. CONCLUSIONS: ERT might be insufficient to maintain normal immunity over extended periods in some ADA-deficient patients.

Burkholderia cenocepacia ET12 transmission in adults with cystic fibrosis.

This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.

COVID-19 Outbreak in an Urban Hemodialysis Unit.

RATIONALE & OBJECTIVE: Hemodialysis patients are at increased risk for coronavirus disease 2019 (COVID-19) transmission due in part to difficulty maintaining physical distancing. Our hemodialysis unit experienced a COVID-19 outbreak despite following symptom-based screening guidelines. We describe the course of the COVID-19 outbreak and the infection control measures taken for mitigation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 237 maintenance hemodialysis patients and 93 hemodialysis staff at a single hemodialysis center in Toronto, Canada. EXPOSURE: Universal screening of patients and staff for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). OUTCOMES: The primary outcome was detection of SARS-CoV-2 in nasopharyngeal samples from patients and staff using reverse transcriptase-polymerase chain reaction (RT-PCR). ANALYTICAL APPROACH: Descriptive statistics were used for clinical characteristics and the primary outcome. RESULTS: 11 of 237 (4.6%) hemodialysis patients and 11 of 93 (12%) staff members had a positive RT-PCR test result for SARS-CoV-2. Among individuals testing positive, 12 of 22 (55%) were asymptomatic at time of testing and 7 of 22 (32%) were asymptomatic for the duration of follow-up. One patient was hospitalized at the time of SARS-CoV-2 infection and 4 additional patients with positive test results were subsequently hospitalized. 2 (18%) patients required admission to the intensive care unit. After 30 days' follow-up, no patients had died or required mechanical ventilation. No hemodialysis staff required hospitalization. Universal droplet and contact precautions were implemented during the outbreak. Hemodialysis staff with SARS-CoV-2 infection were placed on home quarantine regardless of symptom status. Patients with SARS-CoV-2 infection, including asymptomatic individuals, were treated with droplet and contact precautions until confirmation of negative SARS-CoV-2 RT-PCR test results. Analysis of the outbreak identified 2 index cases with subsequent nosocomial transmission within the dialysis unit and in shared shuttle buses to the hemodialysis unit. LIMITATIONS: Single-center study. CONCLUSIONS: Universal SARS-CoV-2 testing and universal droplet and contact precautions in the setting of an outbreak appeared to be effective in preventing further transmission.

Anesthetic Management of Elderly Patients With Down Syndrome: A Case Report.

In 1930, the life expectancy of patients with Down syndrome was about 10 years; today, their life expectancy is more than 60 years. With aging, there is an increased need for anesthesia and surgery. There is, however, no published information regarding the anesthetic management of older adults with Down syndrome. In this report, we described the anesthetic management of a 50-year-old woman with Down syndrome undergoing major cervical spine surgery. Components of the anesthetic that we thought would be difficult such as intravenous line placement and endotracheal intubation were accomplished without difficulty. Despite our best efforts, our patient nevertheless experienced both emergence delirium and postoperative vomiting. We advocate that physicians, advanced practice providers, and registered nurses be aware of the unique perianesthesia needs of older patients with Down syndrome.

Antimicrobial Stewardship and Intensive Care Unit Mortality: A Systematic Review.

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.

Multilocus Variable-Number Tandem-Repeat Analysis of Clostridioides difficile Clusters in Ribotype 027 Isolates and Lack of Association with Clinical Outcomes.

The epidemiology of Clostridioides difficile infection (CDI) has drastically changed since the emergence of the epidemic strain BI/NAP1/027, also known as ribotype 027 (R027). However, the relationship between the infecting C. difficile strain and clinical outcomes is still debated. We hypothesized that certain subpopulations of R027 isolates could be associated with unfavorable outcomes. We applied high-resolution multilocus variable-number tandem-repeat analysis (MLVA) to characterize C. difficile R027 isolates collected from confirmed CDI patients recruited across 10 Canadian hospitals from 2005 to 2008. PCR ribotyping was performed first to select R027 isolates that were then analyzed by MLVA (n = 450). Complicated CDI (cCDI) was defined by the occurrence of any of admission to an intensive care unit, colonic perforation, toxic megacolon, colectomy, and if CDI was the cause or contributed to death within 30 days after enrollment. Three major MLVA clusters were identified, MC-1, MC-3, and MC-10. MC-1 and MC-3 were exclusive to Quebec centers, while MC-10 was found only in Ontario. Fewer cases infected with MC-1 developed cCDI (4%) than those infected with MC-3 and MC-10 (15% and 16%, respectively), but a statistically significant difference was not reached. Our data did not identify a clear association between subpopulations of R027 and different clinical outcomes; however, the data confirmed the utility of MLVA's higher discrimination potential to better characterize CDI populations in an epidemiological analysis. For a patient with CDI, the progression toward an unfavorable outcome is a complex process that probably includes several interrelated strain and host characteristics.

Habitual cigarette smoking raises pressor responses to spontaneous bursts of muscle sympathetic nerve activity.

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.