Clinical Presentations and Outcomes of Children in Canada With Recurrent Invasive Pneumococcal Disease From the IMPACT Surveillance Network.

BACKGROUND: Invasive pneumococcal disease due to Streptococcus pneumoniae can cause mortality and severe morbidity due to sepsis, meningitis and pneumonia, particularly in young children and the elderly. Recurrent invasive pneumococcal disease is rare yet serious sequelae of invasive pneumococcal disease that is associated with the immunocompromised and leads to a high mortality rate. METHOD: This retrospective study reviewed recurrent invasive pneumococcal disease cases from the Canadian Immunization Monitoring Program, ACTive (IMPACT) between 1991 and 2019, an active network for surveillance of vaccine-preventable diseases and adverse events following immunization for children ages 0-16 years. Data were collected from 12 pediatric tertiary care hospitals across all 3 eras of public pneumococcal conjugate vaccine implementation in Canada. RESULTS: The survival rate within our cohort of 180 recurrent invasive pneumococcal disease cases was 98.3%. A decrease of 26.4% in recurrent invasive pneumococcal disease due to vaccine serotypes was observed with pneumococcal vaccine introduction. There was also a 69.0% increase in the rate of vaccination in children with preexisting medical conditions compared with their healthy peers. CONCLUSION: The decrease in recurrent invasive pneumococcal disease due to vaccine-covered serotypes has been offset by an increase of non-vaccine serotypes in this sample of Canadian children.

Should Caesarian Section Be Offered to Women With Recurrent Genital Herpes Simplex Lesions After >4 Hours of Ruptured Membranes?

BACKGROUND: Neonatal herpes simplex virus (HSV) infection and its implications have been well defined. Several methods are recommended to mitigate the risk of maternal transmission of HSV to the neonate, including CS, suppressive antiviral therapy for the mother, and prophylaxis for the infant. The utility of CS in women who present with a duration of rupture of membranes greater than 4 hours remains a question. CASE: We present a case of a woman who presented following 10 hours of rupture of membranes with HSV genital lesions, suspected to be the result of untreated recurrent infection. A CS was done. CONCLUSION: Extensive studies for the presence of HSV by PCR of the placenta and infant failed to detect the virus.

The National Advisory Committee on Infection Prevention and Control (NAC-IPC).

This paper describes the work of the National Advisory Committee on Infection Prevention and Control (NAC-IPC), previously Infection Prevention and Control Expert Working Group, a longstanding external advisory body that provides subject matter expertise and advice to the Public Health Agency of Canada (PHAC) on the prevention and control of infectious diseases in Canadian health care settings. Originally established by Health Canada as the Infection Control Guidelines Steering Committee in 1992, this advisory board has been providing expert advice on infection prevention and control (IPC) guideline development for over 25 years. The NAC-IPC provides advice to inform the development of comprehensive or concise guidelines, quick reference guides and interim guidelines (usually for emerging pathogens), working closely with PHAC's national Healthcare-Associated Infections (HAIs) surveillance programs for Canadian health care facilities. PHAC's HAI-IPC professionals conduct the necessary literature research, data extraction, evidence synthesis, evidence grading (where applicable) and scientific writing for the guidelines. Due to the paucity of clinical trials and high quality observational studies to inform recommendations for emerging pathogens, expert opinion is critical for interpreting available evidence. .

Meta-analysis of transcutaneous electrical nerve stimulation for relief of spinal pain.

We conducted a systematic review and meta-analysis analysing the existing data on transcutaneous electrical nerve stimulation (TENS) or interferential current (IFC) for chronic low back pain (CLBP) and/or neck pain (CNP) taking into account intensity and timing of stimulation, examining pain, function and disability. Seven electronic databases were searched for TENS or IFC treatment in non-specific CLBP or CNP. Four reviewers independently selected randomized controlled trials (RCTs) of TENS or IFC intervention in adult individuals with non-specific CLBP or CNP. Primary outcomes were for self-reported pain intensity and back-specific disability. Two reviewers performed quality assessment, and two reviewers extracted data using a standardized form. Nine RCTs were selected (eight CLBP; one CNP), and seven studies with complete data sets were included for meta-analysis (655 participants). For CLBP, meta-analysis shows TENS/IFC intervention, independent of time of assessment, was significantly different from placebo/control (p < 0.02). TENS/IFC intervention was better than placebo/control, during therapy (p = 0.02), but not immediately after therapy (p = 0.08), or 1-3 months after therapy (p = 0.99). Analysis for adequate stimulation parameters was not significantly different, and there was no effect on disability. This systematic review provides inconclusive evidence of TENS benefits in low back pain patients because the quality of the studies was low, and adequate parameters and timing of assessment were not uniformly used or reported. Without additional high-quality clinical trials using sufficient sample sizes and adequate parameters and outcome assessments, the outcomes of this review are likely to remain unchanged. SIGNIFICANCE: These data highlight the need for additional high-quality RCTs to examine the effects of TENS in CLBP. Trials should consider intensity of stimulation, timing of outcome assessment and assessment of pain, disability and function.

Mycobacterium chimaera infections in post-operative patients exposed to heater-cooler devices: An overview.

A multi-country outbreak of Mycobacterium chimaera infection associated with contaminated heater-cooler devices (HCDs) has been reported, with more than 70 cases in Europe and the United States and two cases in Canada to date. The epidemiological and microbiological characteristics of this outbreak provide evidence for common-source transmission of M. chimaera from the exhaust air of intrinsically contaminated HCDs to patients during cardiac surgery. To date, all reported cases have been associated with Stöckert 3T HCDs manufactured at one plant by LivaNova prior to September 2014. Implantation of prosthetic material increases the risk of infection. Infections usually present as prosthetic valve endocarditis, vascular graft infection or disseminated infection. Reported mortality rates have varied, but were often over 40%. Several measures are recommended to facilitate case-finding and mitigate risk of exposure. The feasibility of some risk mitigation measures and their effectiveness in reducing the risk of exposure are yet to be determined. Until HCDs are redesigned in a manner that prevents water contamination and aerosolization, separating the HCD exhaust air from the operating room air during surgery may be the most effective risk mitigation strategy. However, possible unintended consequences of this approach should be considered. This overview summarizes findings from peer-reviewed and other relevant national documents on key features of the outbreak, including the source, identified risk factors for infection, signs and symptoms of infection, burden of disease, risk mitigation measures, management challenges and knowledge gaps.

Complete sequences of a novel blaNDM-1-harbouring plasmid from Providencia rettgeri and an FII-type plasmid from Klebsiella pneumoniae identified in Canada.

OBJECTIVES: Emergence of plasmids harbouring bla(NDM-1) is a major public health concern due to their association with multidrug resistance and their potential mobility. METHODS: PCR was used to detect bla(NDM-1) from clinical isolates of Providencia rettgeri (PR) and Klebsiella pneumoniae (KP). Antimicrobial susceptibilities were determined using Vitek 2. The complete DNA sequence of two bla(NDM-1) plasmids (pPrY2001 and pKp11-42) was obtained using a 454-Genome Sequencer FLX. Contig assembly and gap closures were confirmed by PCR-based sequencing. Comparative analysis was done using BLASTn and BLASTp algorithms. RESULTS: Both clinical isolates were resistant to all ß-lactams, carbapenems, aminoglycosides, ciprofloxacin and trimethoprim/sulfamethoxazole, and susceptible to tigecycline. Plasmid pPrY2001 (113 295 bp) was isolated from PR. It did not show significant homology to any known plasmid backbone and contained a truncated repA and novel repB. Two bla(NDM-1)-harbouring plasmids from Acinetobacter lwoffii (JQ001791 and JQ060896) shared 100% similarity to a 15 kb region that contained bla(NDM-1). pPrY2001 also contained a type II toxin/antitoxin system. pKp11-42 (146 695 bp) was isolated from KP. It contained multiple repA genes. The plasmid backbone had the highest homology to the IncFIIk plasmid type (51% coverage, 100% nucleotide identity). The bla(NDM-1) region was unique in that it was flanked upstream by IS3000 and downstream by a novel transposon designated Tn6229. pKp11-42 also contained a number of mutagenesis and plasmid stability proteins. CONCLUSIONS: pPrY2001 differed from all known plasmids due to its novel backbone and repB. pKp11-42 was similar to IncFIIk plasmids and contained a number of genes that aid in plasmid persistence.

Carbapenem-resistant Gram-negative bacilli in Canada 2009-10: results from the Canadian Nosocomial Infection Surveillance Program (CNISP).

OBJECTIVES: To investigate the occurrence and molecular mechanisms associated with carbapenemases in carbapenem-resistant Gram-negative isolates from Canadian cases. METHODS: Twenty hospital sites across Canada submitted isolates for a 1 year period starting 1 September 2009. All Enterobacteriaceae with MICs ≥ 2 mg/L and Acinetobacter baumannii and Pseudomonas aeruginosa with MICs ≥ 16 mg/L of carbapenems were submitted to the National Microbiology Laboratory (NML) where carbapenem MICs were confirmed by Etest and isolates were characterized by PCR for carbapenemase genes, antimicrobial susceptibilities, PFGE and plasmid isolation. RESULTS: A total of 444 isolates (298 P. aeruginosa, 134 Enterobacteriaceae and 12 A. baumannii) were submitted to the NML of which 274 (61.7%; 206 P. aeruginosa, 59 Enterobacteriaceae and 9 A. baumannii) met the inclusion criteria as determined by Etest. Carbapenemase genes were identified in 30 isolates: bla(GES-5) (n = 3; P. aeruginosa), bla(KPC-3) (n = 7; Enterobacteriaceae), bla(NDM-1) (n = 2; Enterobacteriaceae), bla(VIM-2) and bla(VIM-4) (n = 8; P. aeruginosa) bla(SME-2) (n = 1; Enterobacteriaceae) and bla(OXA-23) (n = m9; A. baumannii). PFGE identified a cluster in each of Enterobacteriaceae, P. aeruginosa and A. baumannii corresponding to isolates harbouring carbapenemase genes. Three KPC plasmid patterns (IncN and FllA) were identified where indistinguishable plasmid patterns were identified in unrelated clinical isolates. CONCLUSIONS: Carbapenemases were rare at the time of this study. Dissemination of carbapenemases was due to both dominant clones and common plasmid backbones.

Screening for sexually transmitted infection pathogens in semen samples.

The transmission of sexually transmitted infection (STI) pathogens from an infected donor to the recipient of a semen donation in assisted conception may result not only in acute infection but also in long-term reproductive complications or adverse outcomes of pregnancy, including infection of the offspring. Screening for bacterial STI pathogens, Chlamydia trachomatis and Neisseria gonorrhoeae is strongly recommended because these pathogens can cause serious reproductive complications in the recipients of semen donations and infection in their offspring. Screening for these pathogens should be performed using the most sensitive methods, such as nucleic acid amplified tests. False-negative results due to inhibitory substances in the semen sample should be monitored using amplification controls. Where specimen transport is not a problem and culture facilities are available, N gonorrhoeae can also be detected by culture. Laboratories performing screening should subscribe to proficiency programs and have strict quality controls. Although Trichomonas vaginalis, group B streptococcus and genital mycoplasmas have been associated with adverse outcomes of pregnancy, the frequent finding of these organisms in healthy individuals brings into question the validity of mandatory inclusion of these organisms in the screening panel. Although viral STI pathogens and Treponema pallidum - the causative agent of syphilis - may be detected in semen, their presence may be more sensitively detected through antibody testing of the donor. Screening donors for HIV, hepatitis B and syphilis by serology is uniformly recommended in all of the guidelines, but the value of screening either donors or semen samples for cytomegalovirus, herpes simplex viruses and human papilloma viruses is less clear.

High resolution sequence-based DPB1 typing identified two novel DPB1 alleles, DPB1*9401 and DPB1*9501, from a Kenyan population.

Two novel DPB1 alleles, DPB1*9401 and DPB1*9501, were identified from a Kenyan population during sequence-based HLA-DPB1 typing. Molecular cloning and sequencing of multiple clones confirmed that one of the new DPB1 alleles is identical to DPB1*0402 at exon 2 except for a single nucleotide substitution (CGG -->TGG), changing codon 70 from Arg to Trp. The new allele has been named DPB1*9401. This is the first report of polymorphism at codon 70 of HLA-DPB1 alleles. New codon combinations have been identified in another novel DPB1 allele named DPB1*9501. The extensive diversity at DPB1 locus of this East African population is being revealed by high resolution sequence-based DPB1 typing.

HLA-A and HLA-B in Kenya, Africa: allele frequencies and identification of HLA-B*1567 and HLA-B*4426.

HLA-A and HLA-B alleles of a population from Kenya, Africa were examined by sequencing exon 2 and exon 3 DNA and typing using a Taxonomy-based Sequence-analysis (TBSA) method. Extensive diversities were observed at both HLA-A and HLA-B loci in this population. Forty-one HLA-A alleles were identified from 159 unrelated individuals. The most frequently observed alleles were A*6802 (11.64%), A*02011/09 (9.75%), A*7401/02 (9.43%), A*3001 (7.86%), A*3002 (7.23%) and A*3601 (6.6%). Forty-nine HLA-B alleles were identified in 161 unrelated individuals, including two novel alleles, B*1567 and B*4426. The most frequently observed HLA-B alleles were B*5301 (9.01%), B*5801 (8.38%), B*4201 (7.76%), B*1503 (7.14%), B*1801 (6.21%), and B*5802 (5.90%). The most frequently observed HLA-A-B haplotypes were A*3601-B*5301 (3.55%) and A*3001-B*4201 (3.19%), followed by A*7401/02-B*5801 (2.84%), A*7401/02-B*5802 (2.84%) and A*02011/09-B*1503 (2.13%). Linkage disequilibrium and chi2 analysis showed the association of these HLA-A-B haplotypes at the antigen level to be significant. The frequencies of HLA-A and HLA-B alleles from the Kenyan population were compared with that of a population from Cameroon. The difference in allele and haplotype frequency distributions partly reflected the different ethnic composition of these two African populations.

Human leucocyte antigen supertypes and immune susceptibility to HIV-1, implications for vaccine design.

T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22-0.81, P=0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03-0.54, P=0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed 'supertopes'), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

Lymphocyte subsets in human immunodeficiency virus type 1-infected and uninfected children in Nairobi.

BACKGROUND: Reference lymphocyte subset values for African children are lacking. This study documents these values as well as their alterations associated with perinatal and postnatal HIV-1 transmission and with protection from HIV-1 infection. METHODS: Lymphocyte subsets were determined for HIV-1-seronegative nonpregnant women and their children (controls) and for uninfected, perinatally infected and postnatally infected children born to HIV-1-seropositive mothers in Nairobi, Kenya. The mean, median and 5th and 95th percentile values for CD4+ and CD8+ lymphocyte counts and percentages were determined and compared at the age ranges birth to 3 months, 4 months to 1 year, yearly from 1 to 5 years and from 6 to 10 years of age. RESULTS: Among control children counts differed from published values of other populations. In all age ranges, whereas the absolute values were significantly higher than adult values, the percentages were significantly lower. Children perinatally infected with HIV-1 had clearly distinguishable differences in lymphocyte subset percentages by 3 months of age, when the median CD4+ percentage was 27.9% (5th to 95th percentile, 25.7 to 30.1%) for infected vs. 35.9% (33.3 to 38.7%) for uninfected and 39.9% (37.8 to 42.2%) for control children, P < 0.001; whereas the median CD8+ percentage was 37.0% (33.1 to 41.0%) for infected vs. 27.5% (24.2 to 30.8%) for uninfected and 27.5% (24.2 to 30.8%) for control children, P = 0.001. Differences between uninfected and control children disappeared after 1 year of age. CONCLUSIONS: Normal lymphocyte subset values among African children differ from those in other populations. Significant differences are detectable by 3 months of age in CD4+ and CD8+ lymphocyte percentages among perinatally infected infants, which may be useful as an adjunct in diagnosis. Transient differences observed among HIV-1-exposed but uninfected infants could reflect a successful immune response to HIV-1 challenge.

The HLA A2/6802 supertype is associated with reduced risk of perinatal human immunodeficiency virus type 1 transmission.

Certain HLAs may, in part, account for differences in human immunodeficiency virus type 1 (HIV-1) susceptibility by presenting conserved immunogenic epitopes for T cell recognition. The HLA supertype A2/6802 is associated with decreased susceptibility to HIV-1 among sex workers. The alleles in this supertype present the same HIV-1 peptide epitopes for T cell recognition in some cases. This study sought to determine whether the HLA A2/6802 supertype influenced HIV-1 transmission in a prospective cohort of HIV-1-infected mothers and children in Kenya. Decreased perinatal HIV-1 infection risk was strongly associated with possession of a functional cluster of related HLA alleles, called the A2/6802 supertype (odds ratio, 0.12; 95% confidence interval, 0.03-0.54; P=.006). This effect was independent of the protective effect of maternal-child HLA discordance. These data provide further evidence that HLA supertypes are associated with differential susceptibility to HIV-1 transmission.

Sociodemographic characteristics, care, feeding practices, and growth of cohorts of children born to HIV-1 seropositive and seronegative mothers in Nairobi, Kenya.

UNLABELLED: OBJECTIVES To compare sociodemographic profiles, child care, child feeding practices and growth indices of children born to HIV-1 seropositive and seronegative mothers. METHODS: A cohort study of 234 children (seropositive and seronegative) born to HIV-1 seropositive mothers and 139 children born to seronegative mothers in Pumwani Maternity Hospital which serves a low-income population in Nairobi, Kenya from December 1991 and January 1994. RESULTS: With few exceptions, at the time of their birth children in all three cohorts had parents with similar characteristics, lived in similar housing in similar geographical areas, had their mothers as their primary care givers, had similar feeding practices and similar growth status and patterns. However, the HIV-1 seropositive mothers were slightly younger (23.8 years vs. 25.0 years, P < 0.01), if married they were less likely to be their husband's first wife (79% vs. 91%, P = 0.02) and more likely to have a one-room house (75% vs. 63%, P = 0.04). All three cohorts had mean Z-scores in length-for-age and in weight-for-height within the normal range (>/= 2.0 Z-scores) from birth to 21 months with the exception of the length-for-age of the seropositive children at the 18-month visit. In all cohorts length-for-age became more compromised than weight-for-length, dropping to about -1.45 Z-score by 21 months; in contrast, weight-for-length dropped to about -0.5 Z-score by this age. The only statistically significant differences in growth indices among the three cohorts were between the two cohorts of seronegative children: those with seronegative mothers were less compromised in length-for-age at 1.5 months (mean Z-score = -0.19 vs. -0.48, P < 0.05) and more compromised in weight-for-length at 6 months (mean Z-score = 0.10 vs. 0.45, P < 0.05) and at 18 months (mean Z-score = -0.73 vs. -0.16, P < 0.05). 27-34% were exclusively breastfed at 1.5 months; 52-61% consumed solid foods in addition to breast milk by 2.5 months. CONCLUSIONS: Low-income HIV-1 seropositive- and seronegative-born children were from families with similar characteristics and similar housing environments. Similar growth patterns in the cohorts suggest that the challenging environment and the choice of weaning foods had an impact on all three cohorts. The aggressive care given the children with HIV-1 seropositive mothers and their children may have reduced the progression and impact of HIV-1 disease on the growth of the seropositive children. Further research is needed to corroborate our findings to be certain that our results are not affected by loss to follow-up bias: we lost the same proportion in all three cohorts but cannot verify that the children we lost had the same growth patterns as those who remained in the study.

Development of protegrins for the treatment and prevention of oral mucositis: structure-activity relationships of synthetic protegrin analogues.

Protegrin antimicrobial peptides possess activity against gram-positive and gram-negative bacteria and yeasts. An extensive structure-activity relationship (SAR) study was conducted on several hundred protegrin analogues to gain understanding of the relationship between the primary and secondary structure of the protegrins and their antimicrobial activities, and to identify a protegrin analogue for clinical development. Native sequence protegrins are cationic, amphiphilic peptides that are characterized by the presence of a beta-sheet structure that is maintained by two disulfide bridges. The presence of the beta-sheet is key to the stability of the protegrin structure; linearized analogues or analogues that have amino acid substitutions that eliminate hydrogen bonding across the beta-sheet have reduced activity, especially in the presence of physiological concentrations of NaCl. Also, maintaining amphiphilicity of the beta-sheet is key; analogues with substitutions of polar amino acids in the hydrophobic face have reduced activity. Analogues with reduced positive charge tend to be less active, an observation that is more marked for gram-negative than gram-positive bacteria, and may implicate binding to lipopolysaccharide as a key mechanistic step in the killing of gram-negative bacteria. A very large number of amino acid substitutions are tolerated by the protegrin structure, implying that overall structural features such as amphiphilicity, charge, and shape are more important to activity than the presence of specific amino acids. This lack of importance of specific stereochemistry is supported by the fact that completely D-amino acid substituted protegrins are fully potent. Based on the SAR studies, and on the microbiological data from an animal model, one protegrin analogue, IB-367, was selected for clinical development as a topical agent to prevent the oral mucositis associated with cancer therapy.