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Modern sequencing instruments bring unprecedented opportunity to study within-host viral evolution in conjunction with viral transmissions between hosts. However, no computational simulators are available to assist the characterization of within-host dynamics. This limits our ability to interpret epidemiological predictions incorporating within-host evolution and to validate computational inference tools. To fill this need we developed Apollo, a GPU-accelerated, out-of-core tool for within-host simulation of viral evolution and infection dynamics across population, tissue, and cellular levels. Apollo is scalable to hundreds of millions of viral genomes and can handle complex demographic and population genetic models. Apollo can replicate real within-host viral evolution; accurately recapturing observed viral sequences from HIV and SARS-CoV-2 cohorts derived from initial population-genetic configurations. For practical applications, using Apollo-simulated viral genomes and transmission networks, we validated and uncovered the limitations of a widely used viral transmission inference tool. Apollo is a GPU-accelerated simulator of within-host viral evolution, spanning host populations, tissues, and cells. It scales to millions of viral genomes and supports complex demographic and population genetic models.

Background Rapid/point-of-care respiratory virus nucleic acid tests (NAT) may improve oseltamivir, antibiotic, diagnostic test, and hospital bed utilization. Previous randomized controlled trials (RCT) on this topic have not used standard procedures of an accredited healthcare and laboratory system. Methods We conducted a parallel RCT at two hospitals [paediatric = Alberta Children’s Hospital (ACH); primarily adult = Peter Lougheed Centre (PLC)]. Patients with a respiratory viral testing order were randomized to testing at either a central accredited laboratory (standard arm) or with a rapid polymerase chain reaction test at an on-site accredited laboratory followed by standard testing [rapid on-site test (ROST) arm] based on day of specimen receipt at the laboratory. Patients and clinicians were blinded to assignment. The primary outcome for ACH was inpatient length of stay (LOS) and for PLC was the proportion of inpatients prescribed oseltamivir. Results 706 patient encounters were included at ACH; 322 assigned to ROST (181 inpatients) and 384 to the standard arm (194 inpatients). 422 patient encounters were included at PLC; 200 assigned to ROST (157 inpatients) and 222 to the standard arm (175 inpatients). The rate of oseltamivir prescription and number of doses given was reduced in PLC inpatients negative for influenza in the ROST arm compared to standard arm [mean 14.9% (95% CI 9.87–21.9) vs. 27.5% (21.0–35.2), p = 0.0135; mean 2.85 doses (SEM 2.39–3.32) vs. 4.17 doses (3.85–4.49) p = 0.022, respectively]. ROST also significantly reduced oseltamivir use at ACH, reduced chest radiographs (ACH), and laboratory test ordering (PLC), but not antibiotic prescriptions. ROST also reduced the median turnaround time by > 24 h (ACH and PLC). The LOS at ACH was not significantly different between the ROST and standard arms [median 4.05 days (SEM 1.79–18.2) vs 4.89 days (2.07–22.9), p = 0.062, respectively]. No adverse events were reported. Conclusions In a RCT representing implementation of ROST in an accredited laboratory system, we found that a ROST improved oseltamivir utilization and is the first RCT to show reduced ancillary testing in both paediatric and adult populations. A larger study is required to assess reduction in paediatric LOS as ACH was underpowered. These findings help justify the implementation of rapid on-site respiratory virus testing for inpatients. Trial registration ISRCTN, number 10110119, Retrospectively Registered, 01/12/2021.

Background.Routine infant vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) began in the Calgary Health Region (Alberta, Canada) in 2002. We measured the impact of this vaccine program on invasive pneumococcal disease (IPD). Methods.Prospective, population-based surveillance of all cases of IPD (with culture specimens obtained from sterile sites) was conducted from January 1998 through December 2007. Demographic and clinical data were collected. All viable isolates were saved and serotyped. Results.There were 1182 IPD cases over the 10-year period. Comparison of the vaccine period (2003–2007) with the prevaccine period (1998–2001) revealed that the incidence of IPD due to PCV7 serotypes decreased significantly by 86%, 59%, 38%, and 78% in the 6-23-month, 2-4-year, 16-64-year, and 65-84-year age groups, respectively. The total number of IPD cases decreased by 77%, 45%, and 34% in the 6-23-month, 2-4-year, and 65-84-year age groups, respectively. The incidence of IPD due to non-PCV7 serotypes increased by 183%, and the total incidence of IPD increased by 73% among adults aged 16-64 years; however, this increase was primarily attributed to a large outbreak of serotype 5 IPD among homeless adults during the period 2005–2007. There were 5 cases of IPD due to PCV7 serotypes among vaccinated children in the vaccine period. Conclusions.Since the introduction of PCV7 vaccine, there has been a profound decrease in the total number of cases of IPD among children and in cases due to PCV7 serotypes among subjects of all ages in Calgary, indicating a strong direct effect and herd effect of the vaccine. The serotypes that now cause IPD have changed significantly. The magnitude and impact of replacement IPD caused by non-PCV7 serotypes is not yet known.

Background The first Canadian outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) was identified in 2004 in Calgary, Alberta. Using a novel model of MRSA population-based surveillance, sociodemographic risk associations, yearly geospatial dissemination and prevalence of CA-MRSA infections over an 11 year period was identified in an urban healthcare jurisdiction of Calgary. Methods Positive MRSA case records, patient demographics and laboratory data were obtained from a centralized Laboratory Information System of Calgary Laboratory Services in Calgary, Alberta, Canada between 2004 and 2014. Public census data was obtained from Statistics Canada, which was used to match with laboratory data and mapped using Geographic Information Systems. Results During the study period, 52.5% of positive MRSA infections in Calgary were CA-MRSA cases. The majority were CMRSA10 (USA300) clones (94.1%; n  = 4255), while the remaining case ( n  = 266) were CMRSA7 (USA400) clones. Period prevalence of CMRSA10 increased from 3.6 cases/100000 population in 2004, to 41.3 cases/100000 population in 2014. Geospatial analysis demonstrated wide dissemination of CMRSA10 annually in the city. Those who are English speaking (RR = 0.05, p  <  0.0001), identify as visible minority Chinese (RR = 0.09, p  = 0.0023) or visible minority South Asian (RR = 0.25, p  = 0.015), and have a high median household income (RR = 0.27, p  <  0.0001) have a significantly decreased relative risk of CMRSA10 infections. Conclusions CMRSA10 prevalence increased between 2004 and 2007, followed by a stabilization of cases by 2014. Certain sociodemographic factors were protective from CMRSA10 infections. The model of MRSA population-surveillance and geomap outbreak events can be used to track the epidemiology of MRSA in any jurisdiction.

Haemophilus influenzae is a Gram-negative pathobiont, frequently recovered from the airways of persons with cystic fibrosis (pwCF). Previous studies of H. influenzae infection dynamics and transmission in CF predominantly used molecular methods, lacking resolution. In this retrospective cohort study, representative yearly H. influenzae isolates from all pwCF attending the Calgary Adult CF Clinic with H. influenzae positive sputum cultures between 2002 and 2016 were typed by pulsed-field gel electrophoresis. Isolates with shared pulsotypes common to ≥ 2 pwCF were sequenced by Illumina MiSeq. Phylogenetic and pangenomic analyses were used to assess genetic relatedness within shared pulsotypes, and epidemiological investigations were performed to assess potential for healthcare associated transmission. H. influenzae infection was observed to be common (33% of patients followed) and dynamic in pwCF. Most infected pwCF exhibited serial infections with new pulsotypes (75% of pwCF with ≥ 2 positive cultures), with up to four distinct pulsotypes identified from individual patients. Prolonged infection by a single pulsotype was only rarely observed. Intra-patient genetic diversity was observed at the single-nucleotide polymorphism and gene content levels. Seven shared pulsotypes encompassing 39% of pwCF with H. influenzae infection were identified, but there was no evidence, within our sampling scheme, of direct patient-to-patient infection transmission.

Background Haemophilus influenzae is prevalent within the airways of persons with cystic fibrosis (pwCF). H. influenzae is often associated with pulmonary exacerbations (PEx) in pediatric cohorts, but in adults, studies have yielded conflicting reports around the impact(s) on clinical outcomes such as lung function decline. Accordingly, we sought to discern the prevalence, natural history, and clinical impact of H. influenzae in adult pwCF. Methods This single-centre retrospective cohort study reviewed all adult pwCF with H. influenzae sputum cultures between 2002 and 2016. From this cohort, persistently infected subjects (defined as: ≥2 samples with the same pulsotype and > 50% sputum culture-positive for H. influenzae in each year) were matched (1:2) to controls without H. influenzae . Demographic and clinical status (baseline health or during periods of PEx) were obtained at each visit that H. influenzae was cultured. Yearly biobank isolates were typed using pulsed-field gel electrophoresis (PFGE) to assess relatedness. Results Over the study period, 30% ( n  = 70/240) of pwCF were culture positive for H. influenzae , of which 38 (54%) were culture-positive on multiple occasions and 12 (17%) had persistent infection. One hundred and thirty-seven isolates underwent PFGE, with 94 unique pulsotypes identified. Two (1.5%) were serotype f with the rest non-typeable (98.5%). H. influenzae isolation was associated with an increased risk of PEx (RR = 1.61 [1.14–2.27], p  = 0.006), however, this association was lost when we excluded those who irregularly produced sputum (i.e. only during a PEx). Annual lung function decline did not differ across cohorts. Conclusions Isolation of H. influenzae was common amongst adult pwCF but often transient. H. influenzae infection was not associated with acute PEx or chronic lung function decline.

Background Aeromonas hydrophila is a water-dwelling, gram-negative rod-shaped bacterium, associated with diarrheal illness and, less commonly, necrotizing skin and soft tissue infections, especially among immunocompromised patients. Necrotizing fasciitis is associated with a high mortality rate, especially when caused by Aeromonas spp . Our patient was infected with an extremely aggressive form of multidrug-resistant Aeromonas spp . that produced both an extended-spectrum β-lactamase and an Amp C enzyme. Aeromonads are being recognized as important emerging pathogens because of their inherent antibiotic resistance profiles compounded by other virulence factors. These difficult-to-treat organisms can have significant implications in both clinical and public health settings. Case presentation A 37-year-old Caucasian male with immunosuppression due to aplastic anemia being treated with cyclosporine, presented to hospital with relapsed disease. While in hospital, he subsequently developed overwhelming sepsis secondary to bilateral lower extremity necrotizing fasciitis. The necrotizing fasciitis was caused by a multidrug-resistant strain of A. hydrophila. Despite broad-spectrum antibiotics and aggressive surgical debridement, he succumbed to this severe invasive infection. Conclusions Necrotizing fasciitis caused by Aeromonas spp . is a rare infection that may have a poor clinical outcome, particularly if the diagnosis is delayed and/or the organism is highly virulent and multidrug resistant. Enhanced education of clinicians and microbiologists is required to prevent unnecessary complications and improve survival.

Background Bloodstream infections (BSI) have been traditionally classified as either community acquired (CA) or hospital acquired (HA) in origin. However, a third category of healthcare-associated (HCA) community onset disease has been increasingly recognized. The objective of this study was to compare and contrast characteristics of HCA-BSI with CA-BSI and HA-BSI. Methods All first episodes of BSI occurring among adults admitted to hospitals in a large health region in Canada during 2000-2007 were identified from regional databases. Cases were classified using a series of validated algorithms into one of HA-BSI, HCA-BSI, or CA-BSI and compared on a number of epidemiologic, microbiologic, and outcome characteristics. Results A total of 7,712 patients were included; 2,132 (28%) had HA-BSI, 2,492 (32%) HCA-BSI, and 3,088 (40%) had CA-BSI. Patients with CA-BSI were significantly younger and less likely to have co-morbid medical illnesses than patients with HCA-BSI or HA-BSI (p < 0.001). The proportion of cases in males was higher for HA-BSI (60%; p < 0.001 vs. others) as compared to HCA-BSI or CA-BSI (52% and 54%; p = 0.13). The proportion of cases that had a poly-microbial etiology was significantly lower for CA-BSI (5.5%; p < 0.001) compared to both HA and HCA (8.6 vs. 8.3%). The median length of stay following BSI diagnosis 15 days for HA, 9 days for HCA, and 8 days for CA (p < 0.001). Overall the most common species causing bloodstream infection were Escherichia coli, Staphylococcus aureus , and Streptococcus pneumoniae . The distribution and relative rank of importance of these species varied according to classification of acquisition. Twenty eight day all cause case-fatality rates were 26%, 19%, and 10% for HA-BSI, HCA-BSI, and CA-BSI, respectively (p < 0.001). Conclusion Healthcare-associated community onset infections are distinctly different from CA and HA infections based on a number of epidemiologic, microbiologic, and outcome characteristics. This study adds further support for the classification of community onset BSI into separate CA and HCA categories.

Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur.

Human immunodeficiency virus type 1 (HIV-1) infects and destroys cells of the immune system leading to an overt immune deficiency known as HIV acquired immunodeficiency syndrome (HIV/AIDS). The gut associated lymphoid tissue is one of the major lymphoid tissues targeted by HIV-1, and is considered a reservoir for HIV-1 replication and of major importance in CD4+ T-cell depletion. In addition to immunodeficiency, HIV-1 infection also directly causes gastrointestinal (GI) dysfunction, also known as HIV enteropathy. This enteropathy can manifest itself as many pathological changes in the GI tract. The objective of this study was to determine the association of gut HIV-1 infection markers with long-term survival in a cohort of men who have sex with men (MSM) enrolled pre-HAART (Highly Active Antiretroviral Therapy). We examined survival over 15-years in a cohort of 42 HIV-infected cases: In addition to CD4+ T cell counts and HIV-1 plasma viral load, multiple gut compartment (duodenum and colon) biopsies were taken by endoscopy every 6 months during the initial 3-year period. HIV-1 was cultured from tissues and phenotyped and viral loads in the gut tissues were determined. Moreover, the tissues were subjected to an extensive assessment of enteroendocrine cell distribution and pathology. The collected data was used for survival analyses, which showed that patients with higher gut tissue viral load levels had a significantly worse survival prognosis. Moreover, lower numbers of serotonin (duodenum) and somatostatin (duodenum and colon) immunoreactive cell counts in the gut tissues of patients was associated with significant lower survival prognosis. Our study, suggested that HIV-1 pathogenesis and survival prognosis is associated with altered enteroendocrine cell numbers, which could point to a potential role for enteroendocrine function in HIV infection and pathogenesis.