Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians.

BACKGROUND: Caspase recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal recessive primary immunodeficiency conferring human susceptibility to invasive fungal disease, including spontaneous central nervous system candidiasis (sCNSc). However, clinical characterization of sCNSc is variable, hindering its recognition. Furthermore, an in-depth understanding of the bases for this susceptibility has remained elusive. OBJECTIVES: We sought to comprehensively characterize sCNSc and to dissect the mechanisms by which a hypomorphic CARD9 mutation causes susceptibility to Candida species. METHODS: We describe the clinical and radiologic findings of sCNSc caused by CARD9 deficiency in a French-Canadian cohort. We performed genetic, cellular, and molecular analyses to further decipher its pathophysiology. RESULTS: In our French-Canadian series (n = 4) sCNSc had onset in adulthood (median, 38 years) and was often misinterpreted radiologically as brain malignancies; 1 patient had additional novel features (eg, endophthalmitis and osteomyelitis). CARD9 deficiency resulted from a hypomorphic p.Y91H mutation and allelic imbalance established in this population through founder effects. We demonstrate a consistent cellular phenotype of impaired GM-CSF responses. The ability of CARD9 to complex with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is intact in our series, arguing against its involvement in susceptibility to fungi. Instead, we show that the p.Y91H mutation impairs the ability of CARD9 to complex with Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1), leading to impaired activation of nuclear factor κB and extracellular signal-regulated kinase (ERK) in monocytes and subsequent GM-CSF responses. Successful treatment of a second patient with adjunctive GM-CSF bolsters the clinical relevance of these findings. CONCLUSIONS: Hypomorphic CARD9 deficiency caused by p.Y91H results in adult-onset disease with variable penetrance and expressivity. Our findings establish the CARD9/RASGRF1/ERK/GM-CSF axis as critical to the pathophysiology of sCNSc.

Opt-out universal HCV and HIV screening in a Canadian emergency room: a cross-sectional study.

OBJECTIVES: To determine the prevalence of undiagnosed hepatitis C virus (HCV) and HIV cases in a population sample tested in the emergency room (ER) and to evaluate linkage-to-care. SETTING: Canadian university hospital. PARTICIPANTS: Adults born after 1945 who consulted at ER for any condition and on any shift were included. Patients unable to opt-out were excluded. INTERVENTIONS: ER nurse confirmed patients' eligibility and provided them with the option to opt-out. A physician met patients with a new diagnosis. Linkage-to-care was assessed 3 months postdiagnosis. Patients newly diagnosed with HCV were considered linked if they had an HCV RNA test, genotype, liver fibrosis evaluation, and if indicated, treatment prescription. Patients newly diagnosed with HIV were considered linked to care if they had an HIV serology confirmation test, viral load, CD4 cell count and started antiretroviral therapy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary objective: to determine the prevalence (overall and undiagnosed cases) of HIV and HCV among the patients who consult the ER. Secondary objectives: to determine the proportion of patients who opt-out, assess the adherence of emergency staff to the offer of testing, determine the proportion of patients linked to care at 3 months. RESULTS: Among 6350 eligible patients informed of the screening programme, 62.1% of patients were tested for at least one virus (HIV: 3905; HCV: 3910). 25% patients opted-out, 12% were not tested for organisational reasons, 0.3% (18) patients were HCV-HIV coinfected. Overall prevalence of HCV and HIV cases were 1.9% and 1.2%, respectively. Prevalence of new cases was 0.23% (95% CI 0.12% 0.45%) for HCV and 0.05% (95% CI 0.01% to 0.20%) for HIV. Among the new cases, only two HCV-infected and one HIV-infected patients were linked-to-care 3 months postdiagnosis. CONCLUSIONS: Identification of new cases of HCV and HIV through universal screening at the ER and linkage-to-care were both low. TRIAL REGISTRATION NUMBER: NCT03595527; Results.

An outbreak of surgical site infections following craniotomy procedures associated with a change in the ultrasonic surgical aspirator decontamination process.

We investigated an outbreak of surgical site infections that occurred in a tertiary care hospital in Quebec, Canada. This investigation revealed that a change in the sterilization process of the ultrasonic surgical aspirator may have caused this outbreak. It emphasizes the fact that the complex designs of surgical power tools may restrict access to cleaning and sterilization agents. Health care professionals should review manufacturers' assembly/disassembly instructions and sterilization/decontamination procedures before use of such tools.

Impact of methicillin resistant Staphylococcus aureus contact isolation units on medical care.

BACKGROUND: Patient isolation using contact precautions has gained widespread use to halt MRSA transmission, however supportive data is scarce and concerns regarding patient safety and satisfaction have been raised. At our institution, MRSA patients are isolated on a dedicated ward (cohort isolation), rather than in separate rooms. Our objectives were (1) to determine the proportion of bedside medical visits to patients on an isolation ward, (2) to quantify complications in those patients and (3) to determine if those complications are related to isolation and if they can be prevented. METHODS: This retrospective case-control study was performed on the two sites of a tertiary teaching hospital in Sherbrooke, QC, Canada. We matched MRSA patients with an admission diagnosis of heart failure or chronic obstructive pulmonary disease to similar non-isolated controls. The proportion of bedside visits was ascertained through the number of progress notes with subjective elements or with a physical examination. Complications were sought through an extensive file review, and events were analysed according to Baker's CAES causality and preventability scales. RESULTS: Overall, 111 patient pairs were analysed (35 with heart failure and 76 with COPD). Isolated patients received less bedside visits (subjective notes/1,000 patient-days: 849.6 vs. 983.3, p = 0,001). Attending physicians (454.5 vs. 451.4, p = 0,02) and residents (347.0 vs. 416.9, p = 0.01) are responsible for this discrepancy, while medical students appear to visit isolated and non-isolated patients equally (116.5 vs. 114.9, p = 0.90). Isolated patients showed a tendency towards longer stay and more preventable complications, although no difference in the total number of complications was observed. CONCLUSION: Isolated patients have less documented care that suggests less bedside visits from the medical staff, which could hamper the therapeutical relationship. Further studies are needed to explain this finding.

Emergence of and risk factors for ciprofloxacin-gentamicin-resistant Escherichia coli urinary tract infections in a region of Quebec.

BACKGROUND: An increased incidence of urinary tract infections (UTIs) caused by ciprofloxacin-gentamicin-resistant Escherichia coli (CiGREC) has been observed in a tertiary care centre in Sherbrooke, Quebec. The risk factors for such infections remained unclear. METHODS: To determine risk factors for, and outcomes of, CiGREC UTIs, a case control study was conducted. Between 2000 and 2007, 93 cases and 186 controls were identified using laboratory records of patients with greater than 10(7) colony-forming units/L of E coli in a urinary specimen. Cases had E coli with minimum inhibitory concentration to ciprofloxacin of 4 mg/L or greater and minimum inhibitory concentration to gentamicin of 8 mg/L or greater (CiGREC), and controls had E coli with any other susceptibility pattern to ciprofloxacin and gentamicin. Clinical and laboratory data were collected. Adjusted odds ratios (AOR) and their 95% CIs were calculated by logistic regression. RESULTS: The prevalence of CiGREC increased sixfold during the study period. Risk factors associated with CiGREC UTI were advanced age, male sex, urological abnormality, domicile outside Sherbrooke, living in a nursing home (AOR 11.73; 95% CI 3.70 to 37.15), use of fluoroquinolones (AOR 15.24; 95% CI 5.42 to 42.83) or aminoglycosides (AOR 6.59; 95% CI 1.22 to 35.61) within the previous month, and use of fluoroquinolones during the preceding one to 12 months (AOR 2.45; 95% CI 1.06 to 5.62). Compared with controls, cases were more likely not to receive an active antibiotic as empirical or definitive treatment, and were more likely to relapse. INTERPRETATION: In the future, it may become necessary to avoid selecting as empirical therapy of urinary tract infection an antibiotic to which the patient has been recently exposed.

Emergence of disseminated candidiasis caused by Candida krusei during treatment with caspofungin: case report and review of literature.

Current data indicate that caspofungin has in vitro activity against virtually all Candida species. However, we report herein a case of disseminated candidiasis due to Candida krusei which emerged during caspofungin treatment. Lung and brain secondary sites were then successfully treated using a combination of amphotericin B plus flucytosine, amphotericin B lipid complex, and voriconazole, sequentially. Among the total of four well documented cases of refractory invasive candidiasis during caspofungin therapy, the common risk factors appear to involve prior abdominal surgery, persistent foreign body, and anatomical sites where drug concentrations may be sub-optimal for Candida species with increased MICs. Caspofungin failure should be suspected in patients with persistent or emergent signs and symptoms of deep-seated invasive candidiasis.