Reduced IFNλ4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes

Hepatitis C virus (HCV) infections are the major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. Both spontaneous and treatment-induced clearance of HCV depend on genetic variation within the interferon-lambda locus, but until now no clear causal relationship has been established. Here we demonstrate that an amino-acid substitution in the IFNλ4 protein changing a proline at position 70 to a serine (P70S) substantially alters its antiviral activity. Patients harbouring the impaired IFNλ4-S70 variant display lower interferon-stimulated gene (ISG) expression levels, better treatment response rates and better spontaneous clearance rates, compared with patients coding for the fully active IFNλ4-P70 variant. Altogether, these data provide evidence supporting a role for the active IFNλ4 protein as the driver of high hepatic ISG expression as well as the cause of poor HCV clearance.

Invasive mould infections: a multi-disciplinary update.

Systemic fungal infections remain a significant cause of mortality in neutropenic and immunocompromised patients, despite advances in their diagnosis and treatment. The incidence of such infections is rising due to the use of intensive chemotherapy regimens in patients with solid tumours or haematological cancers, the increasing numbers of allogeneic haematopoietic stem cell and solid organ transplants, and the use of potent immunosuppressive therapy in patients with autoimmune disorders. In addition, the epidemiology of systemic fungal infections is changing, with atypical species such as Aspergillus terreus and zygomycetes becoming more common. Treatment has traditionally focused on empirical therapy, but targeted pre-emptive therapy in high-risk patients and prophylactic antifungal treatment are increasingly being adopted. New treatments, including lipid formulations of amphotericin B, second-generation broad-spectrum azoles, and echinocandins, offer effective antifungal activity with improved tolerability compared with older agents; the potential impact of these treatments is reflected in their inclusion in current treatment and prophylaxis guidelines. New treatment strategies, such as aerosolized lipid formulations of amphotericin B, may also reduce the burden of mortality associated with systemic fungal infections. The challenge is to identify ways of coupling potentially effective treatments with early and reliable identification of patients at highest risk of infection.

A Prospective Multicenter SPOG 2003 FN Study of Microbiologically Defined Infections in Pediatric Cancer Patients with Fever and Neutropenia.

BACKGROUND: Fever and neutropenia (FN) often complicate anticancer treatment and can be caused by potentially fatal infections. Knowledge of pathogen distribution is paramount for optimal patient management. METHODS: Microbiologically defined infections (MDI) in pediatric cancer patients presenting with FN by nonmyeloablative chemotherapy enrolled in a prospective multi-center study were analyzed. Effectiveness of empiric antibiotic therapy in FN episodes with bacteremia was assessed taking into consideration recently published treatment guidelines for pediatric patients with FN. RESULTS: MDI were identified in a minority (22%) of pediatric cancer patients with FN. In patients with, compared to without MDI, fever (median, 5 [IQR 3-8] vs. 2 [IQR1-3] days, p < 0.001) and hospitalization (10 [6-14] vs. 5 [3-8] days, p < 0.001) lasted longer, transfer to the intensive care unit was more likely (13 of 95 [14%] vs. 7 of 346 [2.0%], p < 0.001), and antibiotics were given longer (10 [7-14] vs. 5 [4-7], p < 0.001). Empiric antibiotic therapy in FN episodes with bacteremia was highly effective if not only intrinsic and reported antimicrobial susceptibilities were considered but the purposeful omission of coverage for coagulase negative staphylococci and enterococci was also taken into account (81% [95%CI 68 - 90] vs. 96.6% [95%CI 87 - 99.4], p = 0.004) CONCLUSIONS: MDI were identified in a minority of FN episodes but they significantly affected management and the clinical course of pediatric cancer patients. Compliance with published guidelines was associated with effectiveness of empiric antibiotic therapy in FN episodes with bacteremia.

Strategic behaviours in healthcare : evidence from primary care and pharmaceutical markets

We analyse the strategic behaviours of agents in a market through the appropriate¬ness of their skills to the market. If agents' skills are well adapted to market and they can reach their target, they will not need to adopt strategic behaviours. The agents will behave as selfish individuals. However, if their skills are not well adapted and they cannot attain their target alone, they will adopt strategic behaviours to reach their objectives. These behaviours will have a different impact on the utilities of other agents, depending on the skills and the objectives of the agent. If these agents need other agents to reach their objectives, they will behave as altruistic individuals who internalise the utilities of other agents in reaching their objectives and will adopt cooperative behaviours. However, if these agents fear that other agents could prevent them from reaching their target because they can foresee that the skills of other agents are better adapted than their own skills, the agents will then behave as predator individuals and will adopt destructive behaviours to attain their objective. It is in the interests of these agents to manipulate information to increase disorder and dissimulate their lack of skills. They will reproduce the strategies of animals that modify their appearance to escape predators or simulate being bait to attract their prey. These agents will seek to induce chaos into the behaviours of other agents to amplify the impact of their strategies. The appropriateness of skills to the market allows an understanding of the emer-gence of networks and associated strategies. The members of a networks are inputs who are excluded when their costs are higher than their benefits. A network simul-taneously allows cooperation and selfish, predatory behaviours among its members. A network may adopt informational strategies when seeking to become the leader in a market or when it cannot survive. The creation of networks and the manipulation of information are two overlapping evolutionary strategies, with the first strategy favouring the second. In our model, an agent does not behave like a firm that aims only to maximise the profits of the firm but rather as a member of a network who adopts strategic behaviours as a function of the interests of this network. If his skills are well adapted to the market and he can innovate, he will not invest in erroneous input; in contrast, if his skills are not adapted, the agent will invest in the erroneous input of information into the market in order to survive. Therefore, when any informational asymmetries between the agents and their principals characterise the market, the price cannot be the main element that allows equilibrium to be reached in the market; instead, the appropriateness of skills to the market enables equilibrium. We will now apply these hypotheses to explain the strategic behaviours of physicians and pharmaceutical companies.

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality.

OBJECTIVES: Although infectious disease (ID) consultation has been associated with lower mortality in Staphylococcus aureus bloodstream infections, it is still not mandatory in many centers. This study aimed at assessing the impact of ID consultation on diagnostic and therapeutic management of methicillin-resistant S. aureus (MRSA) bacteremia. METHODS: Retrospective cohort study of all patients with MRSA bacteremia from 2001 to 2010. ID consultations were obtained on request between 2001 and 2006 and became mandatory since 2007. RESULTS: 156 episodes of MRSA bacteremia were included, mostly from central venous catheter (32%) and skin and soft tissue (19%) infections. ID consultation coverage was 58% between 2001 and 2006 and 91% between 2007 and 2010. ID consultation was associated with more echocardiography (59% vs. 26%, p < 0.01), vancomycin trough level measurements (99% vs. 77%, p < 0.01), follow-up blood cultures (71% vs. 50%, p = 0.05), deep-seated infections (43% vs. 16%, p < 0.01), more frequent infection source control (83% vs. 57%, p = 0.03), a longer duration of MRSA-active therapy (median and IQR: 17 days, 13-30, vs. 12, 3-14, p < 0.01) and a 20% reduction in 7-day, 30-day and in-hospital mortality. CONCLUSIONS: ID consultation was associated with a better management of patients with MRSA bacteremia and a reduced mortality.

Invasive Candida infections in the ICU

Invasive candidiasis, including candidemia and deep-seated Candida infections, is a severe opportunistic infection with an overall mortality in ICU patients comparable to that of severe sepsis/septic shock. With an incidence ranging from 5 to 10 cases per 1000 ICU admissions, invasive candidiasis represents 510% of all ICU-acquired infections. Although a high proportion of critically ill patients is colonised with Candida spp., only 540% develop an invasive infection. The occurrence of this complication is difficult to predict and an early diagnosis remains a major challenge. Indeed, blood cultures are positive in a minority of cases and often late in the course of infection. New non-culture based laboratory techniques may contribute to early diagnosis and management of invasive candidiasis. Recent data suggest that prediction rules based on risk factors, clinical and microbiological parameters or monitoring of Candida colonisation may efficiently identify critically ill patients at high risk of invasive candidiasis who may benefit of preventive or pre-emptive antifungal therapy. In many cancer centres, exposure to azoles antifungals has been associated with an epidemiological shift from Candida albicans to non-albicans Candida species with reduced antifungal susceptibility or intrinsic resistance. This trend has not been observed in recent surveys on candidemia in non-immunocompromised ICU patients. Prophylaxis, pre-emptive or empirical antifungal treatment are possible approaches for prevention or early management of invasive candidiasis. However, the selection of high-risk patients remains critical for an efficient management aimed at reducing the number needed to treat and thus avoiding unnecessary treatments associated with the emergence of resistance, drug toxicity and costs.

Low-dose cidofovir for the treatment of polyomavirus-associated nephropathy: two case reports and review of the literature.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials. METHODS: Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (> or = 10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN. RESULTS: No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports. CONCLUSIONS: In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.

Polymorphic mutations associated with the emergence of the multinucleoside/tide resistance mutations 69 insertion and Q151M.

BACKGROUND: We hypothesized that polymorphic mutations exist that are associated with the emergence of the multinucleoside resistance mutations (MNR), 69 insertion and Q151M. METHODS: The Swiss HIV Cohort Study was screened, and the frequencies of polymorphic mutations in HIV-1 (subtype B) were compared between patients detected with the 69 insertion (n = 17), Q151M (n = 29), ≥2 thymidine analogue mutations (TAM) 1 (n = 400) or ≥2 TAM 2 (n = 249). Logistic regressions adjusted for the antiretroviral treatment history were performed to analyze the association of the polymorphic mutations with MNR. RESULTS: The 69 insertion and TAM 1 were strongly associated and occurred in 94.1% (16 of 17) together. The 69 insertion seemed to emerge as a consequence of the TAM 1 pathway (median years until detection: 6.8 compared with 4.4 for ≥2 TAM 1, P Wilcoxon = 0.009). Frequencies of 8 polymorphic mutations (K43E, V60I, S68G, S162C, T165I, I202V, R211K, F214L) were significantly different between groups. Logistic regression showed that F214L and V60I were associated with the emergence of Q151M/TAM 2 opposed to 69 insertion/TAM 1. S68G, T165I, and I202V were associated with Q151M instead of TAM 2. CONCLUSIONS: Besides antiretroviral therapy, polymorphic mutations may contribute to the emergence of specific MNR mutations.

Characteristics and outcome of 27 elbow periprosthetic joint infections: results from a 14-year cohort study of 358 elbow prostheses.

Elbow arthroplasty is increasingly performed in patients with rheumatic and post-traumatic arthritis. Data on elbow periprosthetic joint infection (PJI) are limited. We investigated the characteristics and outcome of elbow PJI in a 14-year cohort of total elbow arthroplasties in a single centre. Elbow prosthesis, which were implanted between 1994 and 2007 at Schulthess Clinic in Zurich, were retrospectively screened for infection. PJI was defined as periprosthetic purulence, the presence of sinus tract or microbial growth. A Kaplan-Meier survival method and Cox proportional hazard analysis were performed. Of 358 elbow prostheses, PJI was identified in 27 (7.5%). The median patient age (range) was 61 (39-82) years; 63% were females. Seventeen patients (63%) had a rheumatic disorder and ten (37%) had osteoarthritis. Debridement and implant retention was performed in 78%, followed by exchange or removal of the prosthesis (15%) or no surgery (7%).The relapse-free survival (95% CI) was 79% (63-95%) after 1 year and 65% (45-85%) after 2 years. The outcome after 2 years was significantly better when patients were treated according to the algorithm compared to patients who were not (100% vs. 33%, p &lt;0.05). In 21 patients treated with debridement and retention, the cure rate was also higher when the algorithm was followed (100% vs. 11%, p &lt;0.05). The findings of the present study suggest that the treatment algorithm developed for hip and knee PJI can be applied to elbow PJI. With proper patient selection and antimicrobial therapy, debridement and retention of the elbow prosthesis is associated with good treatment outcome.

Systemic antibodies can inhibit mouse mammary tumor virus-driven superantigen response in mucosa-associated lymphoid tissues.

Many mucosal pathogens invade the host by initially infecting the organized mucosa-associated lymphoid tissue (o-MALT) such as Peyer's patches or nasal cavity-associated lymphoid tissue (NALT) before spreading systemically. There is no clear demonstration that serum antibodies can prevent infections in o-MALT. We have tested this possibility by using the mouse mammary tumor virus (MMTV) as a model system. In peripheral lymph nodes or in Peyer's patches or NALT, MMTV initially infects B lymphocytes, which as a consequence express a superantigen (SAg) activity. The SAg molecule induces the local activation of a subset of T cells within 6 days after MMTV infection. We report that similar levels of anti-SAg antibody (immunoglobulin G) in serum were potent inhibitors of the SAg-induced T-cell response both in peripheral lymph nodes and in Peyer's patches or NALT. This result clearly demonstrates that systemic antibodies can gain access to Peyer's patches or NALT.

Computer-generated reminders delivered on paper to healthcare professionals; effects on professional practice and health care outcomes.

BACKGROUND: Clinical practice does not always reflect best practice and evidence, partly because of unconscious acts of omission, information overload, or inaccessible information. Reminders may help clinicians overcome these problems by prompting the doctor to recall information that they already know or would be expected to know and by providing information or guidance in a more accessible and relevant format, at a particularly appropriate time. OBJECTIVES: To evaluate the effects of reminders automatically generated through a computerized system and delivered on paper to healthcare professionals on processes of care (related to healthcare professionals' practice) and outcomes of care (related to patients' health condition). SEARCH METHODS: For this update the EPOC Trials Search Co-ordinator searched the following databases between June 11-19, 2012: The Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Library (Economics, Methods, and Health Technology Assessment sections), Issue 6, 2012; MEDLINE, OVID (1946- ), Daily Update, and In-process; EMBASE, Ovid (1947- ); CINAHL, EbscoHost (1980- ); EPOC Specialised Register, Reference Manager, and INSPEC, Engineering Village. The authors reviewed reference lists of related reviews and studies.  SELECTION CRITERIA: We included individual or cluster-randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) that evaluated the impact of computer-generated reminders delivered on paper to healthcare professionals on processes and/or outcomes of care. DATA COLLECTION AND ANALYSIS: Review authors working in pairs independently screened studies for eligibility and abstracted data. We contacted authors to obtain important missing information for studies that were published within the last 10 years. For each study, we extracted the primary outcome when it was defined or calculated the median effect size across all reported outcomes. We then calculated the median absolute improvement and interquartile range (IQR) in process adherence across included studies using the primary outcome or median outcome as representative outcome. MAIN RESULTS: In the 32 included studies, computer-generated reminders delivered on paper to healthcare professionals achieved moderate improvement in professional practices, with a median improvement of processes of care of 7.0% (IQR: 3.9% to 16.4%). Implementing reminders alone improved care by 11.2% (IQR 6.5% to 19.6%) compared with usual care, while implementing reminders in addition to another intervention improved care by 4.0% only (IQR 3.0% to 6.0%) compared with the other intervention. The quality of evidence for these comparisons was rated as moderate according to the GRADE approach. Two reminder features were associated with larger effect sizes: providing space on the reminder for provider to enter a response (median 13.7% versus 4.3% for no response, P value = 0.01) and providing an explanation of the content or advice on the reminder (median 12.0% versus 4.2% for no explanation, P value = 0.02). Median improvement in processes of care also differed according to the behaviour the reminder targeted: for instance, reminders to vaccinate improved processes of care by 13.1% (IQR 12.2% to 20.7%) compared with other targeted behaviours. In the only study that had sufficient power to detect a clinically significant effect on outcomes of care, reminders were not associated with significant improvements. AUTHORS' CONCLUSIONS: There is moderate quality evidence that computer-generated reminders delivered on paper to healthcare professionals achieve moderate improvement in process of care. Two characteristics emerged as significant predictors of improvement: providing space on the reminder for a response from the clinician and providing an explanation of the reminder's content or advice. The heterogeneity of the reminder interventions included in this review also suggests that reminders can improve care in various settings under various conditions.

Upper and lower respiratory tract viral infections and acute graft rejection in lung transplant recipients.

Background: Lung transplant recipients are frequently exposed to respiratory viruses and are particularly at risk for severe complications. The aim of this study was to assess the association among the presence of a respiratory virus detected by molecular assays in bronchoalveolar lavage (BAL) fluid, respiratory symptoms, and acute rejection in adult lung transplant recipients. Methods: Upper (nasopharyngeal swab) and lower (BAL) respiratory tract specimens from 77 lung transplant recipients enrolled in a cohort study and undergoing bronchoscopy with BAL and transbronchial biopsies were screened using 17 different polymerase chain reaction-based assays. Result: BAL fluid and biopsy specimens from 343 bronchoscopic procedures performed in 77 patients were analyzed. We also compared paired nasopharyngeal and BAL fluid specimens collected in a subgroup of 283 cases. The overall viral positivity rate was 29.3% in the upper respiratory tract specimens and 17.2% in the BAL samples (). We observed a significant association P < .001 between the presence of respiratory symptoms and positive viral detection in the lower respiratory tract (Pp. 012). Conversely, acute rejection was not associated with the presence of viral infection (odds ratio, 0.41; 95% confidence interval, 0.20-0.88). The recovery of lung function was significantly slower when acute rejection and viral infection were both present. Conclusions: A temporal relationship exists between acute respiratory symptoms and positive viral nucleic acid detection in BAL fluid from lung transplant recipients. We provide evidence suggesting that respiratory viruses are not associated with acute graft rejection during the acute phase of infection.

Frequent accesses to totally implanted vascular ports in pediatric oncology patients are associated with higher infection rates.

PURPOSE: Totally implanted vascular (TIVA) ports are used in children for repeated blood samples or intravenous treatments. We have recently published a prospective evaluation of surgical incidents and early complications associated with these devices. This work is the final part of the same study, assessing late complications over a follow-up of 2 yrs. METHODS: From January 2006 to January 2008, children older than 1 yr of age with a diagnosis of solid or blood cell malignancy were included. Insertion technique and care of the device were standardized. Every manipulation was prospectively recorded by specialized nurses. Obstruction was documented clinically. When bacteremia was suspected, routine central and peripheral blood cultures were drawn. RESULTS: Forty-five consecutive patients were enrolled in the study. Mean age at the time of the procedure was 8.5 yrs. There was no catheter-related infection within the first 4 weeks post-surgery. No device had to be removed because of infection or obstruction during follow-up. Frequent accesses to the port (=3 per day over a 10-day period) were associated with an 8-fold risk of infection. CONCLUSION: Insertion and use of TIVA devices were frequently associated with complications. No device had to be removed because of infection or obstruction over the follow-up period, although no prophylactic antibiotic agent was used. Restrictive use of antibiotics may prevent opportunistic infection. Frequent access to the device was significantly associated with line infection (odds ratio=8.43). No risk factor was identified for obstruction which occurred at a rate of 5.3 per 10,000 accesses.