Invasive and Non-invasive Clinical Haemophilus influenzae Type A Isolates Activate Differentiated HL-60 Cells In Vitro.

Background: The effective elimination of encapsulated bacteria like Haemophilus influenzae type a (Hia) relies on immune mechanisms such as complement-mediated opsonophagocytosis by neutrophils in coordination with opsonization by anti-capsular antibodies. This study evaluated if Hia could activate the immune response through neutrophils and if these responses differed between encapsulated versus unencapsulated or invasive versus non-invasive strains. Methods: HL-60-derived neutrophil-like cells (dHL-60), differentiated with 1.25% dimethyl sulfoxide over 9 days, were used in an opsonophagocytosis assay and in vitro infection model to measure Hia's susceptibility to killing and dHL-60 surface molecule expression, respectively. The impact of strain-specific features on the immune response was investigated using clinical isolates of a dominant North American sequence type (ST)-23, including Hia 11-139 (encapsulated, invasive), 14-61 (encapsulated, non-invasive), 13-0074 (unencapsulated, invasive), as well as a representative ST-4 isolate (Hia 13-240, encapsulated, invasive), and a nontypeable strain (NTHi 375, unencapsulated, non-invasive). Results: Unencapsulated and non-invasive Hi strains were more susceptible to killing by the innate immune response while the ST-23 invasive strain, Hia 11-139 required serum antibodies for destruction. Flow cytometry analysis showed increased expression of co-stimulatory molecule ICAM-1 and Fc receptors (CD89, CD64) but decreased expression of the Fc receptor CD16, revealing potential mechanisms of neutrophil-mediated defense against Hia that extend to both non-invasive and invasive strains. Conclusions: Hia clinical isolates with diverse pathogenicity illustrated contrasting susceptibility to killing by immune mechanisms while maintaining the same capacity to activate neutrophil-like cells, further underscoring the need for additional studies on Hia's pathogenesis.

Carriage of Haemophilus influenzae serotype A in children: Canadian Immunization Research Network (CIRN) study.

Background: Haemophilus influenzae serotype a (Hia) has recently emerged as an important cause of invasive disease, mainly affecting young Indigenous children. Carriage of H. influenzae is a pre-requisite for invasive disease and reservoir for transmission. To better understand the epidemiology of invasive Hia disease, we initiated a multicentre study of H. influenzae nasopharyngeal carriage among Canadian children. Methods: With prior parental consent, we collected nasotracheal tubes used during general anaesthesia in healthy children following routine dental surgery in a regional hospital of northwestern Ontario and a dental clinic in central Saskatchewan. In northwestern Ontario, all children were Indigenous (median age 48.0 months, 45.8% female); in Saskatchewan, children were from various ethnic groups (62% Indigenous, median age 56.3 months, 43.4% female). Detection of H. influenzae and serotyping were performed using molecular-genetic methods. Results: A total of 438 nasopharyngeal specimens, 286 in northwestern Ontario and 152 in Saskatchewan were analyzed. Hia was identified in 26 (9.1%) and 8 (5.3%) specimens, respectively. In Saskatchewan, seven out of eight children with Hia carriage were Indigenous. Conclusions: The carriage rates of Hia in healthy children in northwestern Ontario and Saskatchewan are comparable to H. influenzae serotype b (Hib) carriage among Alaska Indigenous children in the pre-Hib-vaccine era. To prevent invasive Hia disease, paediatric conjugate Hia vaccines under development have the potential to reduce carriage of Hia, and thus decrease the risk of transmission and disease among susceptible populations. Addressing the social determinants of health may further eliminate conditions favouring Hia transmission in Indigenous communities.

Historique: L'Haemophilus influenzae de sérotype a (Hia) a récemment émergé comme une cause importante de maladie invasive, particulièrement chez les jeunes enfants autochtones. Il faut être porteur de l'H. influenzae pour contracter une maladie invasive et devenir un réservoir de transmission. Pour mieux comprendre l'épidémiologie de l'infection invasive à Hia, les chercheurs ont lancé une étude multicentrique sur le portage nasopharyngé de l'H. influenzae chez les enfants canadiens. Méthodologie: Après avoir obtenu le consentement des parents, les chercheurs ont recueilli les sondes nasotrachéales utilisées pendant l'anesthésie générale chez des enfants en santé après une chirurgie dentaire courante dans un hôpital régional du nord-ouest de l'Ontario et une clinique dentaire du centre de la Saskatchewan. Dans le nord-ouest de l'Ontario, tous les enfants étaient autochtones (âge médian de 48,0 mois, 45,8 % de filles); en Saskatchewan, les enfants provenaient de divers groupes ethniques (62 % d'Autochtones, âge médian de 56,3 mois, 43,4 % de femmes). La détection de l'H. influenzae et le sérotypage ont été effectués au moyen de méthodes de génétique moléculaire. Résultats: Au total, les chercheurs ont analysé 438 échantillons nasopharyngés, soit 286 du nord-ouest de l'Ontario et 152 de la Saskatchewan. L'Hia a été décelé dans 26 (9,1 %) et huit (5,3 %) échantillons, respectivement. En Saskatchewan, sept des huit enfants porteurs de l'Hia étaient autochtones. Conclusions: Le taux de portage de l'Hia chez les enfants en santé du nord-ouest de l'Ontario et de la Saskatchewan était comparable à celui du portage de l'H. influenzae du sérotype b (Hib) chez les enfants autochtones de l'Alaska avant le déploiement des vaccins contre le Hib. Pour éviter l'infection invasive à Hia, les vaccins pédiatriques conjugués contre l'Hia en cours de développement peuvent réduire le portage de l'Hia, et donc le risque de transmission et de maladie dans les populations susceptibles. Le fait d'aborder les déterminants sociaux de la santé pourrait contribuer à éliminer les conditions favorables à la transmission à Hia dans les communautés autochtones.

Biocompatibility and proteomic profiling of DMSA-coated iron nanocubes in a human glioblastoma cell line.

Background: Superparamagnetic iron core iron oxide shell nanocubes have previously shown superior performance in magnetic resonance imaging T2 contrast enhancement compared with spherical nanoparticles. Methods: Iron core iron oxide shell nanocubes were synthesized, stabilized with dimercaptosuccinic acid (DMSA-NC) and physicochemically characterized. MRI contrast enhancement and biocompatibility were assessed in vitro. Results: DMSA-NC showed a transverse relaxivity of 122.59 mM-1·s-1 Fe. Treatment with DMSA-NC did not induce cytotoxicity or oxidative stress in U-251 cells, and electron microscopy demonstrated DMSA-NC localization within endosomes and lysosomes in cells following internalization. Global proteomics revealed dysregulation of iron storage, transport, transcription and mRNA processing proteins. Conclusion: DMSA-NC is a promising T2 MRI contrast agent which, in this preliminary investigation, demonstrates favorable biocompatibility with an astrocyte cell model.

MRI is a powerful tool used in the diagnosis of cancer, strokes and other injuries. An MRI scan can be improved with the use of iron oxide nanoparticles, which enhance the contrast of the image. In this study we have developed cube-shaped iron nanoparticles (nanocubes), which have been previously shown to be more effective at inducing contrast. We demonstrated that iron-based nanocubes do not damage or induce stress in cells and work effectively as an MRI contrast agent. We further analyzed how the nanocubes may affect cell functioning by investigating changes to protein levels in the cells. The results of this study are promising steps towards using iron-based nanocubes as a tool to improve the clarity of MRI scans for medical imaging and diagnosis. Future work must determine whether these nanocubes work effectively and safely in an animal model, which is a critical step in progressing to their use in clinical settings.

Tdap vaccine in pregnancy and immunogenicity of pertussis and pneumococcal vaccines in children: What is the impact of different immunization schedules?

BACKGROUND: In 2019, the 3 + 1 schedule for children's vaccination (2-4-6-18 months old) was changed for a reduced 2 + 1 schedule (2-4-12 months old) in Quebec, Canada. We compared the post-booster anti-pertussis and anti-pneumococcus IgG antibody concentrations among children of Tdap-vaccinated and unvaccinated mothers for different vaccine schedules and vaccine formulations. METHODS: We conducted an observational cohort study. An invitation letter to potential participants was provided during a routine vaccination visit. Children's blood samples were analyzed post-booster at 13 (2 + 1 schedule) or 19 (3 + 1 schedule) months of age for antibodies against pertussis antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)) and pneumococcal antigens (serotypes 4, 18C, 19A, and 19F). IgG concentrations among children of Tdap-vaccinated and unvaccinated mothers for each vaccination schedule were compared using geometric mean concentrations (GMCs) and GMC ratios (GMRs), adjusting for potentially immune-response-influencing factors (aGMR). Serotype-specific pneumococcal seroprotection rates were also compared. RESULTS: A total of 360 children were included for pertussis analysis and 248 for pneumococcal analysis. For the 2 + 1 schedule, 13-month-old children of Tdap-vaccinated mothers had lower GMCs against PT, FHA, and PRN, with aGMR (95 %CI) of 0.77 (0.65-0.90), 0.66 (0.55-0.79), 0.72 (0.52-0.99), respectively. For the 3 + 1 schedule, at 19 months old, the interference appeared to be attenuated (higher aGMR values). GMCs against PT were slightly higher in the 3 + 1 than the 2 + 1 schedule: 126.5 IU/ml vs 91.6 IU/ml; aGMR = 1.27. GMCs against PT, FHA and PRN were slightly higher among children who received Infanrix hexa® compared to those who received Pediacel® at 12 months old. For pneumococcal antibodies, at 13 months old, there was no strong evidence of immune interference in children of Tdap-vaccinated mothers. CONCLUSION: Infant vaccination schedule may influence immune interference associated with maternal Tdap vaccination. More studies are needed to assess the clinical impact of this interference on children's protection.

Evaluation of Dimercaptosuccinic Acid-Coated Iron Nanoparticles Immunotargeted to Amyloid Beta as MRI Contrast Agents for the Diagnosis of Alzheimer's Disease.

Nanoparticle-based magnetic contrast agents have opened the potential for magnetic resonance imaging (MRI) to be used for early non-invasive diagnosis of Alzheimer's disease (AD). Accumulation of amyloid pathology in the brain has shown association with cognitive decline and tauopathy; hence, it is an effective biomarker for the early detection of AD. The aim of this study was to develop a biocompatible magnetic nanoparticle targeted to amyloid beta (Aß) plaques to increase the sensitivity of T2-weighted MRI for imaging of amyloid pathology in AD. We presented novel iron core-iron oxide nanoparticles stabilized with a dimercaptosuccinic acid coating and functionalized with an anti-Aß antibody. Nanoparticle biocompatibility and cellular internalization were evaluated in vitro in U-251 glioblastoma cells using cellular assays, proteomics, and transmission electron microscopy. Iron nanoparticles demonstrated no significant in vitro cytotoxicity, and electron microscopy results showed their movement through the endocytic cycle within the cell over a 24 h period. In addition, immunostaining and bio-layer interferometry confirmed the targeted nanoparticle's binding affinity to amyloid species. The iron nanoparticles demonstrated favourable MRI contrast enhancement; however, the addition of the antibody resulted in a reduction in the relaxivity of the particles. The present work shows promising preliminary results in the development of a targeted non-invasive method of early AD diagnosis using contrast-enhanced MRI.

Epidemiology of invasive Haemophilus influenzae disease in northwestern Ontario: comparison of invasive and noninvasive H. influenzae clinical isolates.

In the post-Haemophilus influenzae type b (Hib) vaccine era, invasive H. influenzae type a (Hia) disease emerged in North American Indigenous populations. The role of Hia in noninvasive disease is uncertain; it is unknown whether noninvasive Hia infections are prevalent in populations with a high incidence of invasive disease, and whether invasive and noninvasive Hia isolates have different characteristics. We analyzed all invasive and noninvasive clinical H. influenzae isolates collected in a northwestern Ontario hospital serving 82% Indigenous population over 5.5 years. Serotyping, clonal analysis, and antimicrobial sensitivity testing were conducted on 233 noninvasive and 20 invasive isolates. Among noninvasive isolates, 91% were nontypeable (NTHi) and 3% were Hia; Hia was the most frequent invasive isolate (60%). Incidence rates of invasive H. influenzae disease (12.5/100 000/year) greatly exceeded average provincial data, with the highest found in <6-year-old children (63.9/100 000/year); the proportion of Hia among invasive isolates was seven times larger than in Ontario. No difference in clonal characteristics between invasive and noninvasive Hia isolates was found. Antibiotic resistance was more common among NTHi than among encapsulated isolates, without differences between invasive and noninvasive isolates. Considering the significance of Hia in Indigenous populations, pediatric immunization against Hia will be useful to prevent serious infections in young Indigenous children.

A Pediatric Investigators Collaborative Network on Infections in Children (PICNIC) multi-centre Canadian descriptive analysis of Haemophilus influenzae bacteremia in children: Emerging serotypes.

Background: There has been dramatic reduction in Haemophilus influenzae serotype b (Hib) since introduction of Hib vaccines, but children still experience serious invasive Haemophilus influenzae (Hi) disease caused by various serotype and non-typeable bacteria. The object of this study was to describe the serotype distribution and clinical spectrum of Hi bacteremia in children admitted to Canadian hospitals. Methods: All children with Hi bacteremia admitted 2013 through 2017 to 10 centres across Canada were included. Demographic, clinical, treatment and outcome data were collected. Results: Haemophilus influenzae bacteremia occurred in 118 children of median age 12 months (inter-quartile range: 7-48 months). Forty-three (36%) isolates were non-typeable (NTHi) and 8 were not typed. Of the 67 typeable (THi), Hia (H. influenzae serotype a) (n=36, 54%), Hif (serotype f) (n=19, 26%) and Hib (serotype b) (n=9, 13%) dominated. The THi was more likely than NTHi bacteremia to present as meningitis (p<0.001), particularly serotype a (p=0.04) and less likely to present as pneumonia (p<0.001). Complicated disease (defined as intensive care unit admission, need for surgery, long-term sequelae or death) occurred in 31 (26%) cases and were more likely to have meningitis (p<0.001) than were those with uncomplicated disease. Conclusion: In the era of efficacious conjugate Hib vaccines, NTHi, Hia and Hif have emerged as the leading causes of invasive Hi in Canadian children, with Hia being most likely to result in meningitis and complicated disease. A vaccine for all NTHi and THi would be ideal, but knowledge of the current disease burden from circulating strains will inform prioritization of vaccine targets.

Opsonophagocytic activity against Streptococcus pneumoniae in Indigenous and non-Indigenous patients with severe chronic kidney disease immunized with 13-valent pneumococcal conjugate vaccine.

Adults with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive pneumococcal immunization. Some studies suggest that previous immunization with 23-valent pneumococcal polysaccharide vaccine (PPV23) may decrease the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV13). Via quantitation of serum IgG, IgM, and IgA specific to 7 pneumococcal serotypes (3, 6B, 9V, 14, 19A, 19F, 23F), we recently found that the response to PCV13 in previously PPV23 immunized patients with severe CKD was inferior compared to PPV23 naïve patients. As a follow-up of the previous study, we assessed the titers of opsonizing antibodies specific to 13 vaccine serotypes in sera collected as per the original clinical trial protocol. Opsonophagocytic activity (OPA) titers were determined in 57 previously PPV23-immunized (Group 1) and 72 PPV23-naïve (Group 2) patients pre- and post-PCV13 immunization (days 28 and 365). Pre-immunization, the geometrical mean titers (GMT) for 3/13 serotype-specific antibodies were significantly higher in Group 1 than in Group 2. PCV13 induced a significant GMT rise in both groups; an increase in 5/13 serotype-specific GMTs in Group 1 and 12/13 GMTs in Group 2 was present at one year post-immunization. Fold increase in GMTs by day 28 ranged between 2.4 (serotype 1) and 24.6 (serotype 6A) in Group 1, and between 4.3 (serotype 3) and 67.0 (serotype 6A) in Group 2. The fold increase was significantly larger in Group 2 than in Group 1 for serotypes 1, 4, 7F, and 18C. Patients of Indigenous ethnic background had significantly higher GMT for serotypes 6B and 23F at baseline, and for serotypes 5, 6B, 14, 18C, 19A, 19F, and 23F at Day 28 post-immunization, compared to the non-Indigenous counterpart. Conclusions: Patients with severe CKD developed functionally active pneumococcal antibodies post-PCV13 immunization. Previously administered PPV23 had a negative impact on several serotype-specific OPA responses to PCV13 that lasted for at least one year post-immunization. ClinicalTrials.gov ID: NCT02370069.

Naturally acquired antibody against Haemophilus influenzae type a in pediatric saliva.

We developed a salivary assay for the detection of naturally acquired IgA antibody against Haemophilus influenzae type a (Hia) capsular polysaccharide in healthy Indigenous children from Northwestern Ontario, Canada. Hia-specific IgA antibody was detected in the saliva of 93% of Indigenous children aged 2-7 years.

Naturally acquired antibodies against 7 Streptococcus pneumoniae serotypes in Indigenous and non-Indigenous adults.

Despite the use of pneumococcal conjugate vaccines for pediatric immunization, North American Indigenous populations continue to experience high burden of pneumococcal infections. Naturally acquired antibodies, which can protect unvaccinated adults against pneumococcal infections, have not previously been studied in Canadian Indigenous people. We analysed concentrations of natural serum IgG, IgM and IgA antibodies specific to 7 serotype-specific capsular polysaccharides (3, 6B, 9V, 14, 19A, 19F and 23F) in 141 healthy individuals (age between 18 and 80 years), including Indigenous adults living in 2 geographical different areas of Ontario, Canada, and non-Indigenous residing in northwestern Ontario. Regardless of the geographical area, concentrations of IgG specific to serotypes 6B, 9V, and 14, IgM specific to 9V, and all serotype-specific IgA were significantly higher in Indigenous study participants as compared to non-Indigenous. The differences are likely attributed to an increased exposure of Indigenous individuals to Streptococcus pneumoniae and/or cross-reactive antigens of other microorganisms or plants present in the environment. Although in non-Indigenous adults concentrations of IgM specific to 9V, 19A, 19F, and 23F significantly decreased with age, this was not observed in Indigenous individuals suggesting that Indigenous people may experience continuous exposure to pneumococci and cross-reactive antigens over the life span. Women had generally higher concentrations of natural IgG and IgM concentrations than men, with more striking differences found in Indigenous adults, potentially associated with larger exposure of women to young children, the major reservoir of pneumococci in communities. Our data suggest that increased rates of pneumococcal infections among Indigenous people are unlikely related to deficiency of naturally acquired antibodies, at least those specific to 7 common serotypes. Determining serological correlates of protection for adults will be essential to identify the groups in need of adult pneumococcal immunizations that may prevent excessive burden of the disease among North American Indigenous people.

Seroprevalence of IgG and IgM antibodies to Haemophilus influenzae type a in Canadian children.

BACKGROUND: Over the last 2 decades, Haemophilus influenzae type a (Hia) has emerged as a significant cause of invasive disease in some geographic regions and populations. Recognition of the importance of Hia in the etiology of serious disease, particularly in young children, prompted the development of a new protein-capsular polysaccharide conjugate vaccine, similar in design to a vaccine against H. influenzae type b. At present, understanding of Hia immunology is incomplete; the immunological correlate of protection against invasive disease is unknown. METHODS: Our objective was to study Hia antibody in children of various ages residing in a Canadian province with low incidence rates of invasive disease. The enzyme-linked immunosorbent assays were performed to quantify plasma IgG and IgM specific to Hia capsular polysaccharide in 133 children (3 months to 16 years). RESULTS: Both anti-Hia IgG and IgM concentrations increased with age and were significantly higher in older children; a positive correlation between age and concentrations of Hia antibody was found. IgM antibody concentrations were significantly higher than IgG, with mean IgM concentrations over 10 times larger than IgG across all age groups. CONCLUSIONS: The steady rise of naturally acquired, Hia-specific IgG and IgM concentrations in a pediatric population with low incidence rates of invasive Hia disease suggests the exposure to some cross-reactive environmental antigens as a major source of the antibody. However, the carriage rates of Hia in the region are unknown and further seroepidemiological studies are warranted. Although natural antibody may protect certain population groups against invasive disease, immunization of younger children will be essential to prevent serious infections if Hia continues to spread across North America.

Quantum dots as a theranostic approach in Alzheimer's disease: a systematic review.

Aim: Quantum dots (QDs) are nanoparticles that have an emerging application as theranostic agents in several neurodegenerative diseases. The advantage of QDs as nanomedicine is due to their unique optical properties that provide high sensitivity, stability and selectivity at a nanoscale range. Objective: To offer renewed insight into current QD research and elucidate its promising application in Alzheimer's disease (AD) diagnosis and therapy. Methods: A comprehensive literature search was conducted in PubMed and Google Scholar databases that included the following search terms: 'quantum dots', 'blood-brain barrier', 'cytotoxicity', 'toxicity' and 'Alzheimer's disease'; PRISMA guidelines were adhered to. Results: Thirty-four publications were selected to evaluate the ability of QDs to cross the blood-brain barrier, potential toxicity and current AD diagnostic and therapeutic applications. Conclusion: QD's unique optical properties and versatility to conjugate to various biomolecules, while maintaining a nanoscale size, render them a promising theranostic tool in AD.

Plasma lipidome is dysregulated in Alzheimer's disease and is associated with disease risk genes.

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer's disease. This study explores a battery of plasma lipids that can differentiate Alzheimer's disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75-97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aß42. This suggests that oligomeric Aß42 plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.

Immunogenicity and safety of the 13-valent pneumococcal conjugate vaccine in 23-valent pneumococcal polysaccharide vaccine-naïve and previously immunized adult patients with severe chronic kidney disease.

Individuals with chronic kidney disease (CKD) are at high risk of pneumococcal infections and recommended to receive the 23-valent pneumococcal polysaccharide vaccine (PPV23). Although the 13-valent pneumococcal conjugate vaccine (PCV13) has been found to have higher immunogenicity compared to PPV23 in adults with some immunocompromising conditions, previous PPV23 immunization may decrease the immunogenicity of PCV13. We assessed immunogenicity and safety of PCV13 in 74 PPV23-naïve and 58 previously PPV23-immunized (>1 year ago) patients with severe (stage 4-5) CKD. Serum IgG, IgM, and IgA specific to seven serotypes, i.e. 3, 6B, 9V, 14, 19A, 19F, 23F were quantified pre- and 4 weeks and one year post-immunization. Baseline concentrations for most serotype-specific IgG and IgM, and serotype 3-specific IgA were higher in previously PPV23-immunized compared to PPV23-naïve patients. Immunization with PCV13 significantly increased almost all serotype-specific IgG, all IgA and some IgM; an increase in some serotype-specific IgG and IgM lasted for one year. Fold increases in antibody concentrations and the proportion of individuals with >2-fold increase post-immunization were generally larger in PPV23-naïve than previously immunized patients for most serotype-specific IgG and some IgA. The data show that in patients with CKD who received previous PPV23 immunization over one year ago, the antibody response to PCV13 was inferior compared to pneumococcal vaccine naïve study participants. In both groups, the lowest response to PCV13 was found for serotype 3. Patients of Indigenous ethnic background demonstrated a superior immune response to PCV13 compared to the non-Indigenous counterpart that could partially be related to Indigenous study participants' younger age. Although we found that previous PPV23 immunization could contribute to the more frequent occurrence of systemic adverse events post PCV13 immunization, those did not exceed the mild to moderate range.

Amphiphilic desmuramyl peptides for the rational design of new vaccine adjuvants: Synthesis, in vitro modulation of inflammatory response and molecular docking studies.

Nucleotide-binding oligomerization domain 2 (NOD2) is cytosolic surveillance receptor of the innate immune system capable of recognizing the bacterial and viral infections. Muramyl dipeptide (MDP) is the minimal immunoreactive unit of murein. NOD2 perceives MDP as pathogen-associated molecular pattern, thereby triggering an immune response with undesirable side-effects. Beneficial properties of MDP, such as pro-inflammatory characteristics for the rational design of new vaccine adjuvants, can be harnessed by strategically re-designing the molecule. In this work, a new class of amphiphilic desmuramylpeptides (DMPs) were synthesized by replacing the carbohydrate moiety (muramic acid) of the parent molecule with hydrophilic arenes. A lipophilic chain was also introduced at the C-terminus of dipeptide moiety (alanine-isoglutamine), while conserving its L-D configuration. These novel DMPs were found to set off the release of higher levels of tumour necrosis factor alpha (TNF-α) than Murabutide, which is a well-known NOD2 agonist. Molecular docking studies indicate that all these DMPs bind well to NOD2 receptor with similar dock scores (binding energy) through a number of hydrogen bonding and hydrophobic/π interactions with several crucial residues of the receptor. More studies are needed to further assess their immunomodulatory therapeutic potential, as well as the possible involvement of NOD2 activation.

Nanoparticles as contrast agents for the diagnosis of Alzheimer's disease: a systematic review.

Nanoparticle (NP)-based magnetic contrast agents have opened the potential for MRI to be used for early diagnosis of Alzheimer's disease (AD). This article aims to review the current progress of research in this field. A comprehensive literature search was performed based on PubMed, Medline, EMBASE, PsychINFO and Scopus databases using the following terms: 'Alzheimer's disease' AND 'nanoparticles' AND 'Magnetic Resonance Imaging.' 33 studies were included that described the development and utility of various NPs for AD imaging, including their coating, functionalization, MRI relaxivity, toxicity and bioavailability. NPs show immense promise for neuroimaging, due to superior relaxivity and biocompatibility compared with currently available imaging agents. Consistent reporting is imperative for further progress in this field.

Zero valent iron core-iron oxide shell nanoparticles as small magnetic particle imaging tracers.

Nanoparticle tracers with small sizes and large magnetization are critical for biomedical imaging and especially for magnetic particle imaging (MPI). Small size is important for accessing future intracellular and neurological in vivo applications Here, we show <15 nm nanoparticles made of zero valent iron cores, iron oxide shells and coated with a strongly binding brush co-polymer are effective MPI tracers. The small nanoparticle cores create a hydrodynamic diameter that is half of the state-of-the-art iron oxide tracers while the strongly magnetic zero valent iron maintains similar MPI signal magnitude and resolution.

Whole genome sequencing to study the phylogenetic structure of serotype a Haemophilus influenzae recovered from patients in Canada.

This study examined the phylogenetic structure of serotype a Haemophilus influenzae (Hia) isolates recovered from patients in Canada. Hia isolates from 490 separate patients and an American Type Culture Collection (ATCC) strain were analyzed by multilocus sequence typing (MLST), with 18 different sequence types (STs) identified. Most (85.7%) Hia patient isolates were typed as ST-23 and another 12.7% belonged to 14 different STs with 6, 5, or 4 MLST gene loci related to ST-23 (ST-23 complex). Core genome single-nucleotide variation phylogeny (SNVPhyl) on whole genome sequence (WGS) data of 121 Hia patient isolates representing all identified STs and the ATCC strain revealed 2 phylogenetic populations, with all the ST-23 complex isolates within 1 population. The other phylogenetic population contained only the ATCC strain and 3 patient isolates. Concatenated hitABC sequences retrieved from WGS data and analyzed by MEGA (Molecular Evolutionary Genetic Analysis) alignment confirmed the phylogeny obtained by SNVPhyl. The sodC gene was found only in isolates in the minor phylogenetic population. The 2 phylogenetic populations of the Canadian Hia isolates are similar to the 2 clonal divisions described for serotype b H. influenzae. Combining MLST, core SNVPhyl, and hitABC gene sequence alignment showed that most (99.4%) Canadian Hia patient isolates belonged to 1 major phylogenetic population.

The effect of pneumococcal immunization on total and antigen-specific B cells in patients with severe chronic kidney disease.

BACKGROUND: While the 23-valent pneumococcal polysaccharide vaccine (PPV23) is routinely used in Canada and some other countries to prevent pneumococcal infection in adults with chronic kidney disease (CKD), patients develop a suboptimal antibody response to PPV23 due to their immune dysfunction. The 13-valent pneumococcal conjugate vaccine (PCV13) has superior immunogenicity in some categories of immunocompromised adults; however, its effect on the immune response in CKD patients has only been addressed by two recent studies with conflicting results. The effect of PPV23 or PCV13 on B cells in these patients has not been previously studied. We studied the absolute numbers and proportions of B cells and subpopulations in two groups of adult patients with severe CKD pre- and 7 days post-immunization with PCV13: pneumococcal vaccine naïve and previously immunized with PPV23 (over one year ago). RESULTS: PPV23 immunized patients had significantly lower proportions and absolute numbers of class switched memory (CD19 + CD27 + IgM-), as well as lower absolute numbers of IgM memory (CD19 + CD27 + IgM+) and class switched B cells (CD19 + CD27-IgM-) compared to PPV23 naïve patients. Following PCV13 immunization, the differences in absolute numbers of B-cell subpopulations between groups remained significant. The PPV23 immunized group had higher proportions of CD5- B cells along with lower proportions and absolute numbers of CD5+ B cells compared to PPV23 naïve patients both pre- and post-immunization with PCV13. However, previous PPV23 immunization did not have a noticeable effect on the numbers of total IgG or serotype 6B and 14 specific antibody-secreting cells detected 7 days post-immunization with PCV13. Nevertheless, fold increase in anti-serotype 14 IgG concentrations 28 days post-PCV13 was greater in PPV23 naïve than in previously immunized patients. CONCLUSIONS: The results suggest that immunization with PPV23 may result in long-term changes in B-cell subpopulations such as increased prevalence of CD5- B cells and decreased prevalence of class switched memory B cells in the peripheral blood. Because previous immunization with PPV23 in patients with CKD is associated with a significant decrease in the total class switched memory B cells in response to subsequent immunization with PCV13, this may reduce PCV13 immunogenicity in the setting of PPV23 followed by PCV13. TRIAL REGISTRATION: Registered February 24, 2015 at ClinicalTrials.gov (NCT02370069).