Investigation of a Lomentospora prolificans case cluster with whole genome sequencing

Lomentospora prolificans has caused outbreaks in immunocompromised patients. We performed whole genome sequencing (WGS) on 4 L. prolificans isolates from infections occurring during an 8-month period in the haematology unit at Hospital 1., and 2 isolates from unrelated infections at Hospital 2., showing a high number of mutational differences (>10,000 single nucleotide polymorphisms) between L. prolificans isolates from Hospital 1. Novel typing of isolates by WGS did not demonstrate a single causative strain

Determining Mortality Rates Attributable to Clostridium difficile Infection

To determine accuracy of measures of deaths attributable to Clostridium difficile infection, we compared 3 measures for 2007–2008 in Ontario, Canada: death certificate; death within 30 days of infection; and panel review. Data on death within 30 days were more feasible than panel review and more accurate than death certificate data

An inactivating caspase 11 passenger mutation originating from the 129 murine strain in mice targeted for c-IAP1

A recent study revealed that ES (embryonic stem) cell lines derived from the 129 murine strain carry an inactivating mutation within the caspase 11 gene (Casp4) locus [Kayagaki, Warming, Lamkanfi, Vande Walle, Louie, Dong, Newton, Qu, Liu, Heldens, Zhang, Lee, Roose-Girma and Dixit (2011) Nature 479, 117–121]. Thus, if 129 ES cells are used to target genes closely linked to caspase 11, the resulting mice might also carry the caspase 11 deficiency as a passenger mutation. In the present study, we examined the genetic loci of mice targeted for the closely linked c-IAP (cellular inhibitor of apoptosis) genes, which were generated in 129 ES cells, and found that, despite extensive backcrossing into a C57BL/6 background, c-IAP1−/− animals are also deficient in caspase 11. Consequently, data obtained from these mice should be re-evaluated in this new context

The association between indwelling urinary catheter use in the elderly and urinary tract infection in acute care

BACKGROUND: The use of indwelling urinary catheters (IUCs) is thought to be the most significant risk factor for developing nosocomial urinary tract infections (UTIs). However, it is unclear how many elderly patients have preexisting bacteriuria prior to IUC placement. The purpose of this study was to determine 1) the frequency and appropriateness of IUC use in the Emergency Department (ED) in elderly patients admitted to our acute care hospital, 2) the percentage of elderly patients with an IUC who were discharged from the hospital with a diagnosis of UTI, 3) the percentage of patients with IUCs who were diagnosed and treated for UTI in the ED or who had admission bacteriuria ≥10(5 )organisms/ml indicating preexisting UTI, and 4) the percentage of patients with no indication of UTI on admission who had inappropriately placed IUCs and subsequently were diagnosed with a UTI. METHODS: Retrospective chart review. Chi square used to test significance of differences in proportions. RESULTS: Seventy three percent of patients who received an IUC in the ED were elderly (≥65 years old). During the study period, 277 elderly patients received an IUC prior to admission. Of these, 77 (28%) were diagnosed with UTI during their hospitalization. Fifty three (69%) of those diagnosed with a UTI by discharge either had the UTI diagnosed in the ED or had bacteriuria ≥10(5 )organisms/ml prior to IUC placement. Of the 24 elderly patients who developed a catheter-associated UTI (i.e., 9% of the elderly population who received an IUC), 11 of the IUCs were placed inappropriately. Thus, 4% of elderly patients with no indication of UTI on admission who received an inappropriate IUC in the ED had a primary or secondary diagnosis of UTI by discharge. The overall rate of nosocomial UTI due to an inappropriately placed IUC was the same in males and females. CONCLUSION: This study indicates that the strong association between IUC use and UTI may be partly explained by the high prevalence of preexisting UTI prior to IUC placement. Further prospective studies are needed to clarify the true risk vs benefit ratio for IUC use in acutely ill elderly patients

Urethral catheters: can we reduce use?

<p>Abstract</p> <p>Background</p> <p>Indwelling urinary catheters are the main cause of healthcare-associated urinary tract infections. It can be expected that reduction of the use of urinary catheters will lead to decreased numbers of urinary tract infection.</p> <p>Methods</p> <p>The efficacy of an intervention programme to improve adherence to recommendations to reduce the use of urethral catheters was studied in a before-after comparison in ten Dutch hospitals. The programme detected barriers and facilitators and each individual facility was supported with developing their own intervention strategy. Outcome was evaluated by the prevalence of catheters, alternatives such as diapers, numbers of urinary tract infections, the percentage of correct indications and the duration of catheterization. The costs of the implementation as well as the catheterization were evaluated.</p> <p>Results</p> <p>Of a population of 16,495 hospitalized patients 3335 patients of whom 2943 were evaluable for the study, had a urethral catheter. The prevalence of urethral catheters decreased insignificantly in neurology (OR 0.93; 95% CI 0.77 - 1.13) and internal medicine wards (OR 0.97; 95% CI 0.83 - 1.13), decreased significantly in surgical wards (OR 0.84; 95% CI 0.75 - 0.96), but increased significantly in intensive care (IC) and coronary care (CC) units (OR 1.48; 95% CI 1.01 - 2.17). The use of alternatives was limited and remained so after the intervention. Duration of catheterization decreased insignificantly in IC/CC units (ratio after/before 0.95; 95% CI 0.78 - 1.16) and neurology (ratio 0.97; 95% CI 0.80 - 1.18) and significantly in internal medicine (ratio 0.81; 95% CI 0.69 - 0.96) and surgery wards (ratio 0.80; 95% CI 0.71 - 0.90). The percentage of correct indications on the day of inclusion increased from 50 to 67% (p < 0.0001). The prevalence of urinary tract infections in catheterized patients did not change. The mean cost saved per 100 patients was € 537.</p> <p>Conclusion</p> <p>Targeted implementation of recommendations from an existing guideline can lead to better adherence and cost savings. Especially, hospitals which use a lot of urethral catheters or where catheterization is prolonged, can expect important improvements.</p

Clinical effectiveness of rapid tests for methicillin resistant Staphylococcus aureus (MRSA) in hospitalized patients: a systematic review

<p>Abstract</p> <p>Background</p> <p>Methicillin resistant <it>Staphylococcus aureus </it>(MRSA) are often resistant to multiple classes of antibiotics. The research objectives of this systematic review were to evaluate the clinical effectiveness of polymerase chain reaction (PCR) versus chromogenic agar for MRSA screening, and PCR versus no screening for several clinical outcomes, including MRSA colonization and infection rates.</p> <p>Methods</p> <p>An electronic literature search was conducted on studies evaluating polymerase chain reaction techniques and methicillin (also spelled meticillin) resistant <it>Staphylococcus aureus </it>that were published from 1993 onwards using Medline, Medline In-Process & Other Non-Indexed Citations, BIOSIS Previews, and EMBASE. Due to the presence of heterogeneity in the selected studies, the clinical findings of individual studies were described.</p> <p>Results</p> <p>Nine studies that compared screening for MRSA using PCR versus screening using chromogenic agar in a hospital setting, and two studies that compared screening using PCR with no or targeted screening were identified. Some studies found lower MRSA colonization and acquisition, infection, and transmission rates in screening with PCR versus screening with chromogenic agar, and the turnaround time for screening test results was lower for PCR. One study reported a lower number of unnecessary isolation days with screening using PCR versus screening with chromogenic agar, but the proportion of patients isolated was similar between both groups. The turnaround time for test results and number of isolation days were lower for PCR versus chromogenic agar for MRSA screening.</p> <p>Conclusions</p> <p>The use of PCR for MRSA screening demonstrated a lower turnaround time and number of isolation days compared with chromogenic agar. Given the mixed quality and number of studies (11 studies), gaps remain in the published literature and the evidence remains insufficient. In addition to screening, factors such as the number of contacts between healthcare workers and patients, number of patients attended by one healthcare worker per day, probability of colonization among healthcare workers, and MRSA status of hospital shared equipment and hospital environment must be considered to control the transmission of MRSA in a hospital setting.</p

Application of a stochastic modeling to evaluate tuberculosis onset in patients treated with tumor necrosis factor inhibitors

In this manuscript we apply stochastic modeling to investigate the risk of reactivation of latent mycobacterial infections in patients undergoing treatment with tumor necrosis factor inhibitors. First, we review the perspective proposed by one of the authors in a previous work and which consists in predicting the occurrence of reactivation of latent tuberculosis infection or newly acquired tuberculosis during treatment; this is based on variational procedures on a simple set of parameters (e.g. rate of reactivation of a latent infection). Then, we develop a full analytical study of this approach through a Markov chain analysis and we find an exact solution for the temporal evolution of the number of cases of tuberculosis infection (re)activation. The analytical solution is compared with Monte Carlo simulations and with experimental data, showing overall excellent agreement. The generality of this theoretical framework allows to investigate also the case of non-tuberculous mycobacteria infections; in particular, we show that reactivation in that context plays a minor role. This may suggest that, while the screening for tuberculous is necessary prior to initiating biologics, when considering non-tuberculous mycobacteria only a watchful monitoring during the treatment is recommended. The framework outlined in this paper is quite general and could be extremely promising in further researches on drug-related adverse events.Comment: 26 pages, 7 figure

Molecular determinants of Smac mimetic induced degradation of cIAP1 and cIAP2

The inhibitors of apoptosis (IAP) proteins cIAP1 and cIAP2 have recently emerged as key ubiquitin-E3 ligases regulating innate immunity and cell survival. Much of our knowledge of these IAPs stems from studies using pharmacological inhibitors of IAPs, dubbed Smac mimetics (SMs). Although SMs stimulate auto-ubiquitylation and degradation of cIAPs, little is known about the molecular determinants through which SMs activate the E3 activities of cIAPs. In this study, we find that SM-induced rapid degradation of cIAPs requires binding to tumour necrosis factor (TNF) receptor-associated factor 2 (TRAF2). Moreover, our data reveal an unexpected difference between cIAP1 and cIAP2. Although SM-induced degradation of cIAP1 does not require cIAP2, degradation of cIAP2 critically depends on the presence of cIAP1. In addition, degradation of cIAP2 also requires the ability of the cIAP2 RING finger to dimerise and to bind to E2s. This has important implications because SM-mediated degradation of cIAP1 causes non-canonical activation of NF-κB, which results in the induction of cIAP2 gene expression. In the absence of cIAP1, de novo synthesised cIAP2 is resistant to the SM and suppresses TNFα killing. Furthermore, the cIAP2-MALT1 oncogene, which lacks cIAP2's RING, is resistant to SM treatment. The identification of mechanisms through which cancer cells resist SM treatment will help to improve combination therapies aimed at enhancing treatment response

Non-Canonical NF-κB Activation and Abnormal B Cell Accumulation in Mice Expressing Ubiquitin Protein Ligase-Inactive c-IAP2

Loss of c-IAP2 ubiquitin ligase activity, which occurs in the lymphoma-causing c-IAP2/MALT1 fusion protein, activates non-canonical NF-κB signaling and results in B cell abnormalities characteristic of MALT lymphoma

Towards better guidance on caseload thresholds to promote positive tuberculosis treatment outcomes:a cohort study

BACKGROUND: In low-incidence countries, clinical experience of tuberculosis is becoming more limited, with potential consequences for patient outcomes. In 2007, the Department of Health released a guidance 'toolkit' recommending that tuberculosis patients in England should not be solely managed by clinicians who see fewer than 10 cases per year. This caseload threshold was established to try to improve treatment outcomes and reduce transmission, but was not evidence based. We aimed to assess the association between clinician or hospital caseload and treatment outcomes, as well as the relative suitability of making recommendations using each caseload parameter. METHODS: Demographic and clinical data for tuberculosis cases in England notified to Public Health England's Enhanced Tuberculosis Surveillance system between 2003 and 2012 were extracted. Mean clinician and hospital caseload over the past 3 years were calculated and treatment outcomes grouped into good/neutral and unfavourable. Caseloads over time and their relationship with outcomes were described and analysed using random effects logistic regression, adjusted for clustering. RESULTS: In a fully adjusted multivariable model (34,707 cases)there was very strong evidence that management of tuberculosis by clinicians with fewer than 10 cases per year was associated with greater odds of an unfavourable outcome compared to clinicians who managed greater numbers of cases (cluster-specific odds ratio, 1.14; 95 % confidence interval, 1.05-1.25; P = 0.002). The relationship between hospital caseload and treatment outcomes was more complex and modified by a patient's place of birth and ethnicity. The clinician caseload association held after adjustment for hospital caseload and when the clinician caseload threshold was reduced down to one. CONCLUSIONS: Despite the relative ease of making recommendations at the hospital level and the greater reliability of recorded hospital versus named clinician, our results suggest that clinician caseload thresholds are more suitable for clinical guidance. The current recommended clinician caseload threshold is functional. Sensitivity analyses reducing the threshold indicated that clinical experience is pertinent even at very low average caseloads, which is encouraging for low burden settings