Philipp Kohler

TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription

Production of TNF-α and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-α and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-α on the circadian timing system. TNF-α is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-α on clock genes is shared by IL-1β, but not by IFN-α, and IL-6. Furthermore, TNF-α interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-α is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-α and IL-1β, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.

Prolonged Outbreak of Mycobacterium chimaera Infection After Open-Chest Heart Surgery

BACKGROUND Invasive Mycobacterium chimaera infections were diagnosed in 2012 in 2 heart surgery patients on extracorporeal circulation. We launched an outbreak investigation to identify the source and extent of the potential outbreak and to implement preventive measures. METHODS We collected water samples from operating theaters, intensive care units, and wards, including air samples from operating theaters. Mycobacterium chimaera strains were characterized by randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Case detection was performed based on archived histopathology samples and M. chimaera isolates since 2006, and the patient population at risk was prospectively surveyed. RESULTS We identified 6 male patients aged between 49 and 64 years with prosthetic valve endocarditis or vascular graft infection due to M. chimaera, which became clinically manifest with a latency of between 1.5 and 3.6 years after surgery. Mycobacterium chimaera was isolated from cardiac tissue specimens, blood cultures, or other biopsy specimens. We were able also to culture M. chimaera from water circuits of heater-cooler units connected to the cardiopulmonary bypass, and air samples collected when the units were in use. RAPD-PCR demonstrated identical patterns among M. chimaera strains from heater-cooler unit water circuits and air samples, and strains in 2 patient clusters. CONCLUSIONS The epidemiological and microbiological features of this prolonged outbreak provided evidence for the airborne transmission of M. chimaera from contaminated heater-cooler unit water tanks to patients during open-heart surgery.

Transmission of Mycobacterium chimaera from Heater-Cooler Units during Cardiac Surgery despite an Ultraclean Air Ventilation System.

All such units should be separated from air that can gain access to sterile areas.

The HIV care cascade in Switzerland: reaching the UNAIDS/WHO targets for patients diagnosed with HIV.

Objectives:To describe the HIV care cascade for Switzerland in the year 2012. Design/methods:Six levels were defined: (i) HIV-infected, (ii) HIV-diagnosed, (iii) linked to care, (iv) retained in care, (v) on antiretroviral treatment (ART), and (vi) with suppressed viral load. We used data from the Swiss HIV Cohort Study (SHCS) complemented by a nationwide survey among SHCS physicians to estimate the number of HIV-patients not registered in the cohort. We also used Swiss ART sales data to estimate the number of patients treated outside the SHCS network. Based on the number of patients retained in care, we inferred the estimates for levels (i) to (iii) from previously published data. Results:We estimate that (i) 15 200 HIV-infected individuals lived in Switzerland in 2012 (margins of uncertainty, 13 400–19 300). Of those, (ii) 12 300 (81%) were diagnosed, (iii) 12 200 (80%) linked, and (iv) 11 900 (79%) retained in care. Broadly based on SHCS network data, (v) 10 800 (71%) patients were receiving ART, and (vi) 10 400 (68%) had suppressed (<200 copies/ml) viral loads. The vast majority (95%) of patients retained in care were followed within the SHCS network, with 76% registered in the cohort. Conclusion:Our estimate for HIV-infected individuals in Switzerland is substantially lower than previously reported, halving previous national HIV prevalence estimates to 0.2%. In Switzerland in 2012, 91% of patients in care were receiving ART, and 96% of patients on ART had suppressed viral load, meeting recent UNAIDS/WHO targets.

Can the UNAIDS 90-90-90 target be achieved? A systematic analysis of national HIV treatment cascades

Background In 2014, the Joint United Nations Programme on HIV and AIDS (UNAIDS) and partners set the ‘90-90-90 targets’; aiming to diagnose 90% of all HIV positive people, provide antiretroviral therapy (ART) for 90% of those diagnosed and achieve viral suppression for 90% of those treated, by 2020. This results in 81% of all HIV positive people on treatment and 73% of all HIV positive people achieving viral suppression. We aimed to analyse how effective national HIV treatment programmes are at meeting these targets, using HIV care continuums or cascades. Methods We searched for HIV treatment cascades for 196 countries in published papers, conference presentations, UNAIDS databases and national reports. Cascades were constructed using reliable, generalisable, recent data from national, cross-sectional and longitudinal study cohorts. Data were collected for four stages; total HIV positive people, diagnosed, on treatment and virally suppressed. The cascades were categorised as complete (four stages) or partial (3 stages), and analysed for ‘break points’ defined as a drop >10% in coverage between consecutive 90-90-90 targets. Results 69 country cascades were analysed (32 complete, 37 partial). Diagnosis (target one—90%) ranged from 87% (the Netherlands) to 11% (Yemen). Treatment coverage (target two—81% on ART) ranged from 71% (Switzerland) to 3% (Afghanistan). Viral suppression (target three—73% virally suppressed) was between 68% (Switzerland) and 7% (China). Conclusions No country analysed met the 90-90-90 targets. Diagnosis was the greatest break point globally, but the most frequent key break point for individual countries was providing ART to those diagnosed. Large disparities were identified between countries. Without commitment to standardised reporting methodologies, international comparisons are complex.

Reemergence of Mycobacterium chimaera in Heater–Cooler Units despite Intensified Cleaning and Disinfection Protocol

Invasive Mycobacterium chimaera infections after open-heart surgery have been reported internationally. These devastating infections result from aerosols generated by contaminated heater–cooler units used with extracorporeal circulation during surgery. Despite intensified cleaning and disinfection, surveillance samples from factory-new units acquired during 2014 grew nontuberculous mycobacteria after a median of 174 days.

Sputum DNA sequencing in cystic fibrosis: non-invasive access to the lung microbiome and to pathogen details

BackgroundCystic fibrosis (CF) is a life-threatening genetic disorder, characterized by chronic microbial lung infections due to abnormally viscous mucus secretions within airways. The clinical management of CF typically involves regular respiratory-tract cultures in order to identify pathogens and to guide treatment. However, culture-based methods can miss atypical or slow-growing microbes. Furthermore, the isolated microbes are often not classified at the strain level due to limited taxonomic resolution.ResultsHere, we show that untargeted metagenomic sequencing of sputum DNA can provide valuable information beyond the possibilities of culture-based diagnosis. We sequenced the sputum of six CF patients and eleven control samples (including healthy subjects and chronic obstructive pulmonary disease patients) without prior depletion of human DNA or cell size selection, thus obtaining the most unbiased and comprehensive characterization of CF respiratory tract microbes to date. We present detailed descriptions of the CF and healthy lung microbiome, reconstruct near complete pathogen genomes, and confirm that the CF lungs consistently exhibit reduced microbial diversity. Crucially, the obtained genomic sequences enabled a detailed identification of the exact pathogen strain types, when analyzed in conjunction with existing multi-locus sequence typing databases. We also detected putative pathogenicity islands and indicators of antibiotic resistance, in good agreement with independent clinical tests.ConclusionsUnbiased sputum metagenomics provides an in-depth profile of the lung pathogen microbiome, which is complementary to and more detailed than standard culture-based reporting. Furthermore, functional and taxonomic features of the dominant pathogens, including antibiotics resistances, can be deduced—supporting accurate and non-invasive clinical diagnosis.

First documented outbreak of KPC-2-producing Klebsiella pneumoniae in Switzerland: infection control measures and clinical management

Abstract We report the epidemiological and clinical features of the first outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) type 2 in Switzerland. The outbreak took place in the medical intensive care unit (MICU) of our tertiary care hospital and affected three severely ill patients. After the implementation of strict infection control measures, no further patients colonised with KPC-KP could be detected by the screening of exposed patients. Successful treatment of patients infected with KPC-KP consisted of a combination therapy of meropenem, colistin and tigecycline.

FungiScope™—Global Emerging Fungal Infection Registry

Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope™ is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope™ was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web‐based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope™ have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope™ registry.

Hand hygiene adherence in relation to influenza season during 6 consecutive years

HighlightsInfluenza season is an independent predictor of increased hand hygiene adherence.This finding suggests a higher awareness of hand hygiene during influenza seasons.Implications for healthcare worker education on hand hygiene should be considered. &NA; Hand hygiene (HH) is the single most important measure in reducing the burden of healthcare‐acquired infections. Based on 12,740 HH opportunities observed during 6 consecutive years at our tertiary care center, HH adherence among healthcare workers (HCWs) was significantly better during influenza season compared to non‐influenza periods, after controlling for important covariables (odds ratio = 1.17, 95% confidence interval 1.05‐1.30). This finding suggests that HH awareness is increased during influenza periods, which could have implications for HCW education.