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

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity

Influenza Vaccination of Healthcare Workers: Critical Analysis of the Evidence for Patient Benefit Underpinning Policies of Enforcement

Background: Four cluster randomized controlled trials (cRCTs) conducted in long-term care facilities (LTCFs) have reported reductions in patient risk through increased healthcare worker (HCW) influenza vaccination. This evidence has led to expansive policies of enforcement that include all staff of acute care hospitals and other healthcare settings beyond LTCFs. We critique and quantify the cRCT evidence for indirect patient benefit underpinning policies of mandatory HCW influenza vaccination. Methods: Plausibility of the four cRCT findings attributing indirect patient benefits to HCW influenza vaccination was assessed by comparing percentage reductions in patient risk reported by the cRCTs to predicted values. Plausibly predicted values were derived according to the basic mathematical principle of dilution, taking into account HCW influenza vaccine coverage and the specificity of patient outcomes for influenza. Accordingly, predicted values were calculated as a function of relevant compound probabilities including vaccine efficacy (ranging 40–60% in HCWs and favourably assuming the same indirect protection conferred through them to patients) × change in proportionate HCW influenza vaccine coverage (as reported by each cRCT) × percentage of a given patient outcome (e.g. influenza-like illness (ILI) or all-cause mortality) plausibly due to influenza virus. The number needed to vaccinate (NNV) for HCWs to indirectly prevent patient death was recalibrated based on real patient data of hospital-acquired influenza, with adjustment for potential under-detection (5.2-fold), and using favourable assumptions of HCW-attributable risk (ranging 60–80%). Results: In attributing patient benefit to increased HCW influenza vaccine coverage, each cRCT was found to violate the basic mathematical principle of dilution by reporting greater percentage reductions with less influenza-specific patient outcomes (i.e., all-cause mortality > ILI > laboratory-confirmed influenza) and/or patient mortality reductions exceeding even favourably-derived predicted values by at least 6- to 15-fold. If extrapolated to all LTCF and hospital staff in the United States, the prior cRCT-claimed NNV of 8 would implausibly mean >200,000 and >675,000 patient deaths, respectively, could be prevented annually by HCW influenza vaccination, inconceivably exceeding total US population mortality estimates due to seasonal influenza each year, or during the 1918 pandemic, respectively. More realistic recalibration based on actual patient data instead shows that at least 6000 to 32,000 hospital workers would need to be vaccinated before a single patient death could potentially be averted. Conclusions: The four cRCTs underpinning policies of enforced HCW influenza vaccination attribute implausibly large reductions in patient risk to HCW vaccination, casting serious doubts on their validity. The impression that unvaccinated HCWs place their patients at great influenza peril is exaggerated. Instead, the HCW-attributable risk and vaccine-preventable fraction both remain unknown and the NNV to achieve patient benefit still requires better understanding. Although current scientific data are inadequate to support the ethical implementation of enforced HCW influenza vaccination, they do not refute approaches to support voluntary vaccination or other more broadly protective practices, such as staying home or masking when acutely illFunding support in the form of wages for Dr. Gaston De Serres was provided foremost by the Quebec Public Health Institute (Institut national de sante´ publique du Que´bec), Que´bec, Canada and in part by the Ontario Nurses’ Associatio

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

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

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

Risk Factors for Colonization with Extended-Spectrum β-Lactamase–producing Bacteria and Intensive Care Unit Admission

Coexisting conditions and previous antimicrobial drug exposure predict colonization

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

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