Ankle fracture open reduction and internal fixation in patients with cerebral palsy.

AIM: To examine patients with cerebral palsy (CP) undergoing open reduction and internal fixation (ORIF) for ankle fractures. METHOD: This was a retrospective study of adult patients undergoing ankle fracture ORIF for closed, isolated ankle fractures identified in between 2010 and 2021 in the Q1 PearlDiver M151 database. Patients with CP were identified with International Classification of Diseases (ICD)-9 and ICD-10 codes, and were matched to those without 1:10 on age, sex, and Elixhauser comorbidity index (ECI). Ninety-day adverse events were assessed with multivariable logistic regression. RESULTS: A total of 148 993 patients with isolated ankle fracture ORIF were identified, of whom 407 (0.27%) had CP. After matching, 3863 without CP were compared to 389 with CP. Patients with CP were at increased odds of: 90-day urinary tract infection (odds ratios [OR] 6.26), pneumonia (OR 3.50), minor adverse events (OR 3.46), sepsis (OR 3.30), any adverse events (OR 3.04), emergency department visits (OR 2.28), serious adverse events (OR 1.77), and prolonged length of stay more than 4 days (OR 22.44) (p < 0.001 for all). INTERPRETATION: Patients with CP undergoing ORIF for isolated, closed ankle fractures are at increased odds of several 90-day adverse events and prolonged length of stay compared to matched patients without CP. WHAT THIS PAPER ADDS: Patients with cerebral palsy (CP) undergoing ankle fracture open reduction and internal fixation (ORIF) were at increased odds of 90-day adverse events. Many of the 90-day adverse events related to previously described comorbidities associated with CP. Patients with CP undergoing ankle fracture ORIF experienced increased rates of prolonged length of stay.

Social factors associated with self-reported changes in mental health symptoms among youth in the COVID-19 pandemic: a cross-sectional survey.

BACKGROUND: Children and youth experienced marked impacts on day-to-day life in the COVID-19 pandemic that were associated with poorer familial and friend relationships, and greater mental health challenges. Few studies provide self-report data on mental health symptoms from children and youth themselves. We sought to examine the associations between social factors and child and youth self-reported symptoms of worsened mood, anxiety, and irritability during the COVID-19 pandemic. METHODS: A nationally representative cross-sectional survey was administered online to collect self-report data across 10 Canadian provinces among children (11-14 years) and youth (15-18 years), April-May 2022. Age-appropriate questions were based on The Partnership for Maternal, Newborn & Child Health and the World Health Organization of the United Nations H6 + Technical Working Group on Adolescent Health and Well-Being consensus framework and the Coronavirus Health and Impact Survey. Associations between a priori defined social factors (e.g., relationship quality) and respondent self-reported mental health were evaluated using ordinal logistic regression models adjusted for age, sex, and geographic location. RESULTS: We analyzed data from 483 (51.7%) children (11-14 years; 227, 47.0% girls) and 450 (48.3%) youth (15-18 years; 204, 45.3% girls). The parents of most children and youth had resided in Canada for over 20 years (678, 72.7%). Over one-quarter of children and youth self-identified as Black, Indigenous, or a Person of Color (134, 27.7%; 134, 29.8%, respectively). Over one-third of children and youth self-reported symptoms of worsened mood (149, 30.9%; 125, 27.8%, respectively), anxiety (181, 37.5%; 167, 37.1%, respectively), or irritability (160, 33.1%; 160, 35.6%, respectively) during, compared to pre-pandemic. In descending order of odds ratios (OR), for children and youth, worsened familial relationships (during compared to pre-pandemic) was associated with the self-reported symptoms of worsened mood (child: OR 4.22, 95%CI 2.51-6.88; youth: OR 6.65 95%CI 3.98-11.23), anxiety (child: OR 4.24, 95%CI2.69-6.75; youth: OR 5.28, 95%CI 3.17-8.86), and irritability (child: OR 2.83, 95%CI 1.76-4.56; youth: OR 6.46, 95%CI 3.88-10.90). CONCLUSIONS: Self-reported data from a nationally representative sample of children and youth suggest strong associations between social factors and mental health during the COVID-19 pandemic. Interventions targeting child and youth familial relationships may positively impact child and youth mental health.

Utilization and timing of surgical intervention for central cord syndrome in the United States.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: CCS is the most common type of incomplete spinal cord injury and can occur without or with bony injury. Surgical intervention and its timing for patients diagnosed with CCS has been controversial. The current study assessed utilization of and factors associated with operative intervention and its timing in patients diagnosed with central cord syndrome (CCS) in the absence of bony injury. METHODS: Adult patients diagnosed with CCS in the absence of vertebral fracture were queried from the national, multi-insurance, administrative 2015-2020 M151 PearlDiver database. The incidence, trends, and timing of operative intervention following CCS were assessed. Patient characteristics associated with surgical intervention and its timing were determined. RESULTS: From 2015 to 2020, 11,653 patients meeting inclusion criteria were identified, of which surgical intervention was identified for 2,003 (17.2%) and thus nonsurgical intervention for 9,650 (82.8%). The proportion of patients undergoing operative intervention evolved from 11.5% in 2015 to 19.7% in 2020 (p < 0.0001). Of those undergoing surgical intervention, the greatest increase was seen for those undergoing surgery within two days of diagnosis (5.5% in 2015 to 12.3% in 2020, p < 0.0001). On multivariable analysis, more recent year of service, region of service, younger age, and higher comorbidity burden were independent predictors of operative management (p < 0.05 for all). CONCLUSION: The majority of a large cohort of patients with first diagnosis CCS in the absence of bony injury were managed non-operatively. Operative management increased over the years of study, were performed earlier after diagnosis, and varied based on patient characteristic and geographic region.

Well-being approaches targeted to improve child and youth health post-COVID-19 pandemic: a scoping review.

BACKGROUND: Our previous work synthesized published studies on well-being interventions during COVID-19. As we move into a post-COVID-19 pandemic period there is a need to comprehensively review published strategies, approaches, and interventions to improve child and youth well-being beyond deleterious impacts experienced during COVID-19. METHODS: Seven databases were searched from inception to January 2023. Studies were included if they: (1) presented original data on an approach (i.e., approach applied) or (2) provided recommendations to inform development of a future approach (i.e., approach suggested), (3) targeted to mitigate negative impacts of COVID-19 on child and youth (≤18 year) well-being, and (4) published on or after December 2019. RESULTS: 39 studies (n = 4/39, 10.3% randomized controlled trials) from 2021 to 2023 were included. Twenty-two studies applied an approach (n = 22/39, 56.4%) whereas seventeen studies (n = 17/39, 43.6%) suggested an approach; youth aged 13-18 year (n = 27/39, 69.2%) were most frequently studied. Approach applied records most frequently adopted an experimental design (n = 11/22, 50.0%), whereas approach suggested records most frequently adopted a cross-sectional design (n = 13/22, 59.1%). The most frequently reported outcomes related to good health and optimum nutrition (n = 28/39, 71.8%), followed by connectedness (n = 22/39, 56.4%), learning, competence, education, skills, and employability (n = 18/39, 46.1%), and agency and resilience (n = 16/39, 41.0%). CONCLUSIONS: The rapid onset and unpredictability of COVID-19 precluded meaningful engagement of children and youth in strategy development despite widespread recognition that early engagement can enhance usefulness and acceptability of interventions. Published or recommended strategies were most frequently targeted to improve connectedness, belonging, and socialization among children and youth.

Corticosteroid Injections Administered Within 4 Weeks Prior to Hip Arthroscopy Are Associated With Higher Rates of Postoperative Infection.

PURPOSE: To evaluate the association between the timing of intra-articular hip corticosteroid injections and the risk of postoperative infection in patients undergoing hip arthroscopy. METHODS: The 2010-2021 PearlDiver M157 administrative claims database was queried for patients who underwent hip arthroscopy. Patients who received intra-articular corticosteroid injections within 12 weeks prior to arthroscopy were matched 1:1 to patients who did not receive such injections based on age, sex, and Elixhauser Comorbidity Index, as well as the presence of diabetes mellitus, hypertension, obesity, and tobacco use. Those with injections prior to arthroscopy were subdivided based on having received injections within 12 weeks prior to surgery. To verify that the corticosteroid injections and surgical procedures were conducted in the hip joint, Current Procedural Terminology codes were used. By use of Current Procedural Terminology and International Classification of Diseases (ninth revision and tenth revision) coding, postoperative surgical-site infection after corticosteroid injection was evaluated. The impact of the timing of preoperative corticosteroid injections on the incidence of postoperative infection was evaluated using multivariable logistic regression analysis. RESULTS: A total of 12,390 hip arthroscopy cases were identified, including 3,579 patients who received corticosteroid injections 0 to 4 weeks prior to surgery; 4,759, within 4 to 8 weeks prior to surgery; and 4,052, within 8 to 12 weeks prior to surgery. Compared with controls, patients who received corticosteroid injections within 0 to 4 weeks preoperatively had a significantly higher rate of surgical-site infection (odds ratio, 2.43; P = .0001). No significant differences in infection rates were observed at the later time intervals (4-8 weeks or 8-12 weeks). Furthermore, in comparison to controls, patients who received corticosteroid injections had a significantly higher rate of wound dehiscence (odds ratio, 1.84; P = .0007). CONCLUSIONS: Intra-articular corticosteroid injections within 4 weeks prior to hip arthroscopy were significantly associated with increased surgical-site infection rates after hip arthroscopy surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Final efficacy analysis, interim safety analysis, and immunogenicity of a single dose of recombinant novel coronavirus vaccine (adenovirus type 5 vector) in adults 18 years and older: an international, multicentre, randomised, double-blinded, placebo-controlled phase 3 trial.

BACKGROUND: The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial. METHODS: This double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial enrolled adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia. Participants were eligible for the study if they had no unstable or severe underlying medical or psychiatric conditions; had no history of a laboratory-confirmed SARS-CoV-2 infection; were not pregnant or breastfeeding; and had no previous receipt of an adenovirus-vectored, coronavirus, or SARS-CoV-2 vaccine. After informed consent was obtained, 25 mL of whole blood was withdrawn from all eligible participants who were randomised in a 1:1 ratio to receive a single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 1010 viral particle (vp)/mL Ad5-nCoV vaccine; study staff and participants were blinded to treatment allocation. All participants were contacted weekly by email, telephone, or text message to self-report any symptoms of COVID-19 illness, and laboratory testing for SARS-CoV-2 was done for all participants with any symptoms. The primary efficacy objective evaluated Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination on Jan 15, 2021. The primary safety objective evaluated the incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection. This trial is closed for enrolment and is registered with ClinicalTrials.gov (NCT04526990). FINDINGS: Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis. One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7-70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36-58]). In the primary safety analysis undertaken at the time of the efficacy analysis (36 717 participants), there was no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in both Ad5-nCoV and placebo recipients). In the extended safety cohort, 1004 (63·5%) of 1582 of Ad5-nCoV recipients and 729 (46·4%) of 1572 placebo recipients reported a solicited systemic adverse event (p<0·0001), of which headache was the most common (699 [44%] of Ad5-nCoV recipients and 481 [30·6%] of placebo recipients; p<0·0001). 971 (61·3%) of 1584 Ad5-nCoV recipients and 314 (20·0%) of 1573 placebo recipients reported an injection-site adverse event (p<0·0001), of which pain at the injection site was the most frequent; reported by 939 (59%) Ad5-nCoV recipients and 303 (19%) placebo recipients. INTERPRETATION: One dose of Ad5-nCoV is efficacious and safe in healthy adults aged 18 years and older. FUNDING: CanSino Biologics and the Beijing Institute of Biotechnology.

Antibiotic use in children hospitalised for influenza, 2010-2021: the Canadian Immunization Monitoring Program Active (IMPACT).

PURPOSE: To determine characteristics associated with inappropriate antibiotic use amongst children hospitalised for influenza. METHODS: We performed active surveillance for laboratory-confirmed influenza hospitalizations amongst children ≤ 16 years old at the 12 Canadian Immunization Monitoring Program Active hospitals, from September 2010 to August 2021. Antibiotic use was presumed appropriate if any of the following indications were met: age < 1 month, immunocompromised, hemoglobinopathy, laboratory-confirmed bacterial infection, radiographically confirmed pneumonia, admission to an intensive care unit and mechanical ventilation. Regression analyses were used to identify baseline and clinical characteristics associated with antibiotic use amongst patients without an appropriate indication. RESULTS: Amongst 8971 children, 6424 (71.6%) received any antibiotics during their hospitalisation. Amongst the 4429 children without an appropriate indication, 2366 (53.2%) received antibiotics. Antibiotic use amongst children without appropriate indication differed between study centres, ranging from 33.2% to 66.1% (interquartile range [IQR] 50.6-56.3%); it did not change significantly over time (p-value for trend = 0.28). In multivariable analyses, older age (adjusted odds ratio [aOR] 0.97, 95% confidence interval [CI] 0.96-0.99), presence of any high-risk condition (aOR 0.80, 95% CI 0.70-0.92), influenza virus type B (aOR 0.8, 95% CI 0.70-0.91) and croup (aOR 0.64, 95% CI 0.49-0.83) were associated with less, whilst fever ≥ 38.5 °C (aOR 1.82, 95% CI 1.42-2.35) and hospitalisation duration (aOR 1.12, 95% CI 1.09-1.15) were associated with more inappropriate antibiotic use. CONCLUSIONS: Over two-third of children hospitalised for influenza received antibiotics, including over half of those without an appropriate indication for antibiotic treatment. Differences amongst study centres suggest the importance of contextual determinants of antibiotic use.

Lessons learned from the experiences and perspectives of frontline healthcare workers on the COVID-19 response: a qualitative descriptive study.

BACKGROUND: During the COVID-19 pandemic, healthcare systems and healthcare workers (HCWs) faced significant demands and unique challenges. In this qualitative study, we explore the effects of the COVID-19 public health policies on British Columbia's frontline HCWs, describe what worked in the management of the pandemic, and elucidate the lessons learned that could be applied to future pandemic preparedness, recovery and response. METHODS: This qualitative descriptive study is part of a larger, national multi-case study on pandemic policy communication and uptake. Semi-structured interviews were conducted from November 2020- June 2021 with fourteen HCWs working in long-term care (LTC), acute care and public health settings. Data were inductively coded, and analyzed following a resilience framework for public health emergency preparedness, which emphasizes the essential elements of a public health system, vital to all phases of health emergency management, readiness, response and recovery. RESULTS: HCWs experienced confusion, frustration, uncertainty, anxiety, fatigue and stress, during the pandemic and detailed challenges that affected policy implementation. This included communication and coordination inconsistencies between the province and regional health authorities; lack of involvement of frontline staff in pandemic planning; inadequate training and support; inadequate personal protective equipment resource capacity and mobilization; and staffing shortages. HCWs recommended increased collaboration between frontline staff and policy makers, investment in preparing and practicing pandemic plans, and the need for training in emergency management and infection prevention and control. CONCLUSIONS: Pandemic planning, response and recovery should include inputs from actors/key stakeholders at the provincial, regional and local levels, to facilitate better coordination, communication and outcomes. Also, given the critical roles of frontline HCWs in policy implementation, they should be adequately supported and consideration must be given to how they interpret and act on policies. Bi-directional communication channels should be incorporated between policymakers and frontline HCWs to verify the appropriate adoption of policies, reflective learning, and to ensure policy limitations are being communicated and acted upon by policy makers.

Total Knee Arthroplasty: Variables Affecting 90-day Overall Reimbursement.

BACKGROUND: Total knee arthroplasty (TKA) is commonly considered to address symptomatically limiting knee osteoarthritis. With increasing utilization, understanding the variability and related drivers may help the healthcare system optimize delivery to the large numbers of patient to whom it is offered. METHODS: A total of 1,066,327 TKA patients who underwent primary TKA were isolated from a 2010 to 2021 PearlDiver national dataset. Exclusion criteria included patients less than 18 years old and traumatic, infectious, or oncologic indications. Overall, 90-day reimbursements and variables associated with the patient, surgical procedure, region, and perioperative period were abstracted. Multivariable linear regressions were performed to determine independent drivers of reimbursement. RESULTS: The 90-day postoperative reimbursements had an average (standard deviation) of $11,212.99 ($15,000.62), a median (interquartile range) of $4,472.00 ($13,101.00), and a total of $11,946,962,912. Variables independently associated with the greatest increase in overall 90-day reimbursement were related to admission (in-patient index-procedure [+$5,695.26] or hospital readmission [+$18,495.03]). Further drivers were region (Midwest +$8,826.21, West +$4,578.55, South +$3,709.40; relative to Northeast), insurance (commercial +$4,492.34, Medicaid +$1,187.65; relative to Medicare), postoperative emergency department visits (+$3,574.57), postoperative adverse events (+$1,309.35), (P < .0001 for each). CONCLUSION: The current study assessed over a million TKA patients and found large variations in reimbursement/cost. The largest increases in reimbursement were associated with admission (readmission or index procedure). This was followed by region, insurance, and other postoperative events. These results underscore the necessity to balance performing out-patient surgeries in appropriate patients versus the risk of readmissions and defined other areas for cost containment strategies.

Urgent Care Visits Sought After Primary Total Hip Arthroplasty: A Potentially Overlooked Resource.

BACKGROUND: Following total hip arthroplasty (THA), readmissions and emergency department (ED) visits have been studied. Urgent care utilization is not well-characterized and may represent an overlooked avenue to facilitate lesser acuity patient needs. METHODS: Primary THAs performed for osteoarthritis indications were identified from 2010 to April of 2021 from a large national database. The incidence and timing of 90-day postoperative ED and urgent care visits were determined. Univariable and multivariable analyses assessed factors associated with urgent care relative to ED utilization. Reasons and acuity of diagnoses for these visits were determined. For 213,189 THA patients, 90-day ED visits were identified for 37,692 (17.7%) and urgent care visits for 2,083 (1.0%). The greatest incidence of both ED and urgent care visits were in the first two postoperative weeks. RESULTS: Independent predictors of urgent care utilization relative to ED utilization were: procedures being performed in the Northeast or South, insurance plan being Commercial, women, and lesser comorbidity burden (P < .0001). Reason for visits to the ED was directly related to the surgical site for 25.6% but for urgent care were just 4.8% (P < .0001). Reasons for visits to the ED were classified as low-acuity for 57.4% and for urgent care 96.9% (P < .0001). CONCLUSION: Following THA, patients may need urgent evaluation. While many issues can be addressed through the office, urgent care visits may represent a viable and underused resource relative to the ED for a large percentage of patients who have lower acuity diagnoses.

Revaccination and Adverse Event Recurrence in Patients with Adverse Events following Immunization.

OBJECTIVES: To estimate the risk of recurrence of adverse events following immunization (AEFIs) upon revaccination and to determine among patients with suspected vaccine allergy whether allergy skin test positivity was associated with AEFI recurrence. STUDY DESIGN: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 with AEFIs who required revaccination with the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Special Immunization Clinic physicians used guidelines to inform their recommendations. Participants were followed up after revaccination to capture AEFI recurrences. Data were transferred to a central database for descriptive analysis. RESULTS: Overall, 588 participants were assessed for 627 AEFIs; 570 (91%) AEFIs occurred in children <18 years of age. AEFIs included immediate hypersensitivity (130/627; 21%), large local reactions (110/627; 18%), nonurticarial rash (51/627; 8%), seizures (26/627; 4%), and thrombocytopenia (11/627; 2%). Revaccination was recommended to 513 of 588 (87%) participants. Among participants recommended and due for revaccination during the study period, 63% (299/477) were revaccinated. AEFI recurrence was 10% (31/299) overall, 31% (15/49) for large local reactions, and 7% (5/66) for immediate hypersensitivity. No recurrence was serious. Among 92 participants with suspected vaccine allergy who underwent skin testing and were revaccinated, the negative predictive value of skin testing for AEFI recurrence was 96% (95% CI 92.5%-99.5%). CONCLUSIONS: Most individuals with AEFIs were safely revaccinated. Among those with suspected vaccine allergy, skin testing may help determine the safety of revaccination.

Identification of a Thiol-Disulfide Oxidoreductase (SdbA) Catalyzing Disulfide Bond Formation in the Superantigen SpeA in Streptococcus pyogenes.

Mechanisms of disulfide bond formation in the human pathogen Streptococcus pyogenes are currently unknown. To date, no disulfide bond-forming thiol-disulfide oxidoreductase (TDOR) has been described and at least one disulfide bonded protein is known in S. pyogenes. This protein is the superantigen SpeA, which contains 3 cysteine residues (Cys 87, Cys90, and Cys98) and has a disulfide bond formed between Cys87 and Cys98. In this study, candidate TDORs were identified from the genome sequence of S. pyogenes MGAS8232. Using mutational and biochemical approaches, one of the candidate proteins, SpyM18_2037 (named here SdbA), was shown to be the catalyst that introduces the disulfide bond in SpeA. SpeA in the culture supernatant remained reduced when sdbA was inactivated and restored to the oxidized state when a functional copy of sdbA was returned to the sdbA-knockout mutant. SdbA has a typical C46XXC49 active site motif commonly found in TDORs. Site-directed mutagenesis experiments showed that the cysteines in the CXXC motif were required for the disulfide bond in SpeA to form. Interactions between SdbA and SpeA were examined using cysteine variant proteins. The results showed that SdbAC49A formed a mixed disulfide with SpeAC87A, suggesting that the N-terminal Cys46 of SdbA and the C-terminal Cys98 of SpeA participated in the initial reaction. SpeA oxidized by SdbA displayed biological activities suggesting that SpeA was properly folded following oxidation by SdbA. In conclusion, formation of the disulfide bond in SpeA is catalyzed by SdbA and the findings represent the first report of disulfide bond formation in S. pyogenes. IMPORTANCE Here, we reported the first example of disulfide bond formation in Streptococcus pyogenes. The results showed that a thiol-disulfide oxidoreductase, named SdbA, is responsible for introducing the disulfide bond in the superantigen SpeA. The cysteine residues in the CXXC motif of SdbA are needed for catalyzing the disulfide bond in SpeA. The disulfide bond in SpeA and neighboring amino acids form a disulfide loop that is conserved among many superantigens, including those from Staphylococcus aureus. SpeA and staphylococcal enterotoxins lacking the disulfide bond are biologically inactive. Thus, the discovery of the enzyme that catalyzes the disulfide bond in SpeA is important for understanding the biochemistry of SpeA production and presents a target for mitigating the virulence of S. pyogenes.

Waning Vaccine Immunity and Vaccination Responses in Children Treated for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study.

BACKGROUND: There is no uniform guideline for postchemotherapy vaccination of children with acute lymphoblastic leukemia (ALL). We evaluated waning immunity to 14 pneumococcal serotypes, pertussis toxin (PT), tetanus toxoid (TT) and varicella, and immunogenicity of postchemotherapy diphtheria, tetanus, pertussis, hepatitis B, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) and pneumococcal vaccination among previously vaccinated children treated for ALL. METHODS: This was a multicenter trial of children with ALL enrolled 4-12 months postchemotherapy completion. Exclusion criteria included: infant ALL, relapsed ALL, and stem cell transplant recipients. Immunocompetent children were recruited as controls. Postchemotherapy participants received DTaP-IPV-Hib and 13-valent pneumococcal conjugate vaccine (PCV13) concurrently, followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) 2 months later. Serology was measured at baseline, 2 and 12 months postvaccination. Adverse events were captured via surveys. RESULTS: At enrollment, postchemotherapy participants (n = 74) were less likely than controls (n = 78) to be age-appropriately immunized with DTaP (41% vs 89%, P < .001) and PCV (59% vs 79%, P = .008). Geometric mean concentrations (GMCs) to TT, PT, PCV serotypes, and varicella were lower in postchemotherapy participants than controls after adjusting for previous vaccine doses (P < .001). Two months postvaccination, GMCs to TT, PT, and PCV serotypes increased from baseline (P < .001 for all antigens) and remained elevated at 12 months postvaccination. Antibody levels to PPV23 serotypes also increased postvaccination (P < .001). No serious adverse events were reported. CONCLUSIONS: Children treated for ALL had lower antibody levels than controls against pneumococcal serotypes, tetanus, pertussis, and varicella despite previous vaccination. Postchemotherapy vaccination with DTaP-IPV-Hib, PCV13, and PPV23 was immunogenic and well tolerated. Children with ALL would benefit from systematic revaccination postchemotherapy. CLINICAL TRIALS REGISTRATION: NCT02447718.

Randomized Trial of 2 Schedules of Meningococcal B Vaccine in Adolescents and Young Adults, Canada1.

Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17-25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%-100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.

Active surveillance of acute paediatric hospitalisations demonstrates the impact of vaccination programmes and informs vaccine policy in Canada and Australia.

Sentinel surveillance of acute hospitalisations in response to infectious disease emergencies such as the 2009 influenza A(H1N1)pdm09 pandemic is well described, but recognition of its potential to supplement routine public health surveillance and provide scalability for emergency responses has been limited. We summarise the achievements of two national paediatric hospital surveillance networks relevant to vaccine programmes and emerging infectious diseases in Canada (Canadian Immunization Monitoring Program Active; IMPACT from 1991) and Australia (Paediatric Active Enhanced Disease Surveillance; PAEDS from 2007) and discuss opportunities and challenges in applying their model to other contexts. Both networks were established to enhance capacity to measure vaccine preventable disease burden, vaccine programme impact, and safety, with their scope occasionally being increased with emerging infectious diseases' surveillance. Their active surveillance has increased data accuracy and utility for syndromic conditions (e.g. encephalitis), pathogen-specific diseases (e.g. pertussis, rotavirus, influenza), and adverse events following immunisation (e.g. febrile seizure), enabled correlation of biological specimens with clinical context and supported responses to emerging infections (e.g. pandemic influenza, parechovirus, COVID-19). The demonstrated long-term value of continuous, rather than incident-related, operation of these networks in strengthening routine surveillance, bridging research gaps, and providing scalable public health response, supports their applicability to other countries.

Immunogenicity, Lot Consistency, and Extended Safety of rVSVΔG-ZEBOV-GP Vaccine: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study in Healthy Adults.

BACKGROUND: This double-blind study assessed immunogenicity, lot consistency, and safety of recombinant vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). METHODS: Healthy adults (N = 1197) were randomized 2:2:2:2:1 to receive 1 of 3 consistency lots of rVSVΔG-ZEBOV-GP (2 × 107 plaque-forming units [pfu]), high-dose 1 × 108 pfu, or placebo. Antibody responses pre-/postvaccination (28 days, 6 months; in a subset [n = 566], months 12, 18, and 24) were measured. post hoc analysis of risk factors associated with arthritis following vaccination was performed. RESULTS: ZEBOV-GP enzyme-linked immunosorbent assay (ELISA) geometric mean titers (GMTs) increased postvaccination in all rVSVΔG-ZEBOV-GP groups by 28 days (>58-fold) and persisted through 24 months. The 3 manufacturing lots demonstrated equivalent immunogenicity at 28 days. Neutralizing antibody GMTs increased by 28 days in all rVSVΔG-ZEBOV-GP groups, peaking at 18 months with no decrease through 24 months. At 28 days, ≥94% of vaccine recipients seroresponded (ZEBOV-GP ELISA, ≥2-fold increase, titer ≥200 EU/mL), with responses persisting at 24 months in ≥91%. Female sex and a history of arthritis were identified as potential risk factors for the development of arthritis postvaccination. CONCLUSIONS: Immune responses to rVSVΔG-ZEBOV-GP persisted to 24 months. Immunogenicity and safety results support continued rVSVΔG-ZEBOV-GP development. CLINICAL TRIALS REGISTRATION: NCT02503202.

Identification of Redox Partners of the Thiol-Disulfide Oxidoreductase SdbA in Streptococcus gordonii.

We previously identified a novel thiol-disulfide oxidoreductase, SdbA, in Streptococcus gordonii that formed disulfide bonds in substrate proteins and played a role in multiple phenotypes. In this study, we used mutational, phenotypic, and biochemical approaches to identify and characterize the redox partners of SdbA. Unexpectedly, the results showed that SdbA has multiple redox partners, forming a complex oxidative protein-folding pathway. The primary redox partners of SdbA that maintain its active site in an oxidized state are a surface-exposed thioredoxin family lipoprotein called SdbB (Sgo_1171) and an integral membrane protein annotated as CcdA2. Inactivation of sdbB and ccdA2 simultaneously, but not individually, recapitulated the sdbA mutant phenotype. The sdbB-ccdA2 mutant had defects in a range of cellular processes, including autolysis, bacteriocin production, genetic competence, and extracellular DNA (eDNA) release. AtlS, the natural substrate of SdbA produced by the sdbB-ccdA2 mutant lacked activity and an intramolecular disulfide bond. The redox state of SdbA in the sdbB-ccdA2 mutant was found to be in a reduced form and was restored when sdbB and ccdA2 were knocked back into the mutant. In addition, we showed that SdbB formed a disulfide-linked complex with SdbA in the cell. Recombinant SdbB and CcdA2 exhibited oxidase activity and reoxidized reduced SdbA in vitro Collectively, our results demonstrate that S. gordonii uses multiple redox partners for oxidative protein folding.IMPORTANCEStreptococcus gordonii is a commensal bacterium of the human dental plaque. Previously, we identified an enzyme, SdbA, that forms disulfide bonds in substrate proteins and plays a role in a number of cellular processes in S. gordonii Here, we identified the redox partners of SdbA. We showed that SdbA has multiple redox partners, SdbB and CcdA2, forming a complex oxidative protein-folding pathway. This pathway is essential for autolysis, bacteriocin production, genetic competence, and extracellular DNA (eDNA) release in S. gordonii These cellular processes are considered to be important for the success of S. gordonii as a dental plaque organism. This is the first example of an oxidative protein-folding pathway in Gram-positive bacteria that consists of an enzyme that uses multiple redox partners to function.

Vaccination Against Influenza in Pregnancy: A Survey of Canadian Maternity Care Providers.

OBJECTIVE: Influenza vaccine uptake among Canadian pregnant individuals is suboptimal. Failure to incorporate vaccination into routine prenatal care and a lack of recommendations from healthcare providers are recognized as barriers to vaccination. The aim of this study was to assess Canadian maternity care providers' knowledge, attitudes, and practices regarding influenza vaccination in pregnancy. METHODS: A cross-sectional Web-based questionnaire was sent during July and August 2017 to family physicians, obstetricians-gynaecologists, midwives, pharmacists, and nurses who care for pregnant individuals. A multivariable logistic regression model was used to determine variables independently associated with providers' recommendation of the influenza vaccine in pregnancy. RESULTS: The analysis included 1061 providers. Most participants (85%) reported being vaccinated against influenza themselves, and 72% reported recommending the influenza vaccine to all of their pregnant patients during the previous influenza season. Participants' attitudes regarding influenza vaccination during pregnancy were generally positive: 64% strongly agreed that pregnant individuals are at an increased risk of complications from influenza, and 69% strongly agreed that it is safe to vaccinate pregnant individuals against influenza. The main determinants of participants' recommendations for influenza vaccination to all pregnant patients were following official recommendations on influenza vaccination, discussing vaccines with most or all pregnant individuals seen in their practice, and being vaccinated themselves during the previous influenza season. CONCLUSION: Enhancing influenza vaccine uptake in pregnancy is largely dependent on maternity care providers' recommendations. This study provides valuable insight on providers' knowledge, attitudes, and practices.

Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study.

BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. CONCLUSION: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.