PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass-spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T-cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

[Consensus-Based Guidelines for Diagnosis, Prevention and Treatment of Tuberculosis in Children and Adolescents - A Guideline on Behalf of the German Society for Pediatric Infectious Diseases (DGPI)]. / S2k-Leitlinie zur Diagnostik, Prävention und Therapie der Tuberkulose im Kindes- und Jugendalter.

Recently, epidemiological data shows an increase of childhood tuberculosis in Germany. In addition to this, drug resistant tuberculosis becomes more frequent. Therefore, diagnosis, prevention and therapy in childhood and adolescence remain a challenge. Adult guidelines do not work for children, as there are age specific differences in manifestation, risk of progression and diagnostic as well as therapeutic pathways.The German Society for Pediatric Infectious Diseases (DGPI) has initiated a consensus-based (S2k) process and completed a paediatric guideline in order to improve and standardize care for children and adolescents with tuberculosis exposure, infection or disease.Updated dosage recommendations take age dependant pharmacokinetics in the treatment of drug sensitive but also drug resistant tuberculosis in account. In addition to this, there is a detailed chapter on perinatal exposure and disease as well as extrapulmonary manifestations.

Response to Comment on "Permanent human occupation of the central Tibetan Plateau in the early Holocene".

We show that Zhang and Li's sedimentological model for the Chusang travertine neglects the three-dimensional information from multiple outcrops and that their optically stimulated luminescence (OSL) age of about 20,000 years for the human imprints is untenable. We highlight the robustness of our chronology and explore reasons why Zhang and Li's OSL age is a gross overestimation of the real depositional age of the imprinted travertine.

Response to Comment on "Permanent human occupation of the central Tibetan Plateau in the early Holocene".

Zhang et al contest that Chusang was part of an annual mobility round that "more likely" included seasonal use of high-elevation environments than permanent use. We show that their probabilistic statement hinges on indefensible claims about hunter-gatherer mobility. In the context of quantitative data from hunter-gatherer ethnography, our travel model shows that seasonal-use models are highly unlikely to explain Chusang.

Establishing an ICD-10 code based SARI-surveillance in Germany - description of the system and first results from five recent influenza seasons.

BACKGROUND: Syndromic surveillance of severe acute respiratory infections (SARI) is important to assess seriousness of disease as recommended by WHO for influenza. In 2015 the Robert Koch Institute (RKI) started to collaborate with a private hospital network to develop a SARI surveillance system using case-based data on ICD-10 codes. This first-time description of the system shows its application to the analysis of five influenza seasons. METHODS: Since week 40/2015, weekly updated anonymized data on discharged patients overall and on patients with respiratory illness including ICD-10 codes of primary and secondary diagnoses are transferred from the network data center to RKI. Retrospective datasets were also provided. Our descriptive analysis is based on data of 47 sentinel hospitals collected between weeks 1/2012 to 20/2016. We applied three different SARI case definitions (CD) based on ICD-10 codes for discharge diagnoses of respiratory tract infections (J09 - J22): basic CD (BCD), using only primary diagnoses; sensitive CD (SCD), using primary and secondary diagnoses; timely CD (TCD), using only primary diagnoses of patients hospitalized up to one week. We compared the CD with regard to severity, age distribution and timeliness and with results from the national primary care sentinel system. RESULTS: The 47 sentinel hospitals covered 3.6% of patients discharged from all German hospitals in 2013. The SCD comprised 2.2 times patients as the BCD, and 3.6 times as many as the TCD. Time course of SARI cases corresponded well to results from primary care surveillance and influenza virus circulation. The patients fulfilling the TCD had been completely reported after 3 weeks, which was fastest among the CD. The proportion of SARI cases among patients was highest in the youngest age group of below 5-year-olds. However, the age group 60 years and above contributed most SARI cases. This was irrespective of the CD used. CONCLUSIONS: In general, available data and the implemented reporting system are appropriate to provide timely and reliable information on SARI in inpatients in Germany. Our ICD-10-based approach proved to be useful for fulfilling requirements for SARI surveillance. The exploratory approach gave valuable insights in data structure and emphasized the advantages of different CD.

Permanent human occupation of the central Tibetan Plateau in the early Holocene.

Current models of the peopling of the higher-elevation zones of the Tibetan Plateau postulate that permanent occupation could only have been facilitated by an agricultural lifeway at ~3.6 thousand calibrated carbon-14 years before present. Here we report a reanalysis of the chronology of the Chusang site, located on the central Tibetan Plateau at an elevation of ~4270 meters above sea level. The minimum age of the site is fixed at ~7.4 thousand years (thorium-230/uranium dating), with a maximum age between ~8.20 and 12.67 thousand calibrated carbon-14 years before present (carbon-14 assays). Travel cost modeling and archaeological data suggest that the site was part of an annual, permanent, preagricultural occupation of the central plateau. These findings challenge current models of the occupation of the Tibetan Plateau.

European Neolithic societies showed early warning signals of population collapse.

Ecosystems on the verge of major reorganization-regime shift-may exhibit declining resilience, which can be detected using a collection of generic statistical tests known as early warning signals (EWSs). This study explores whether EWSs anticipated human population collapse during the European Neolithic. It analyzes recent reconstructions of European Neolithic (8-4 kya) population trends that reveal regime shifts from a period of rapid growth following the introduction of agriculture to a period of instability and collapse. We find statistical support for EWSs in advance of population collapse. Seven of nine regional datasets exhibit increasing autocorrelation and variance leading up to collapse, suggesting that these societies began to recover from perturbation more slowly as resilience declined. We derive EWS statistics from a prehistoric population proxy based on summed archaeological radiocarbon date probability densities. We use simulation to validate our methods and show that sampling biases, atmospheric effects, radiocarbon calibration error, and taphonomic processes are unlikely to explain the observed EWS patterns. The implications of these results for understanding the dynamics of Neolithic ecosystems are discussed, and we present a general framework for analyzing societal regime shifts using EWS at large spatial and temporal scales. We suggest that our findings are consistent with an adaptive cycling model that highlights both the vulnerability and resilience of early European populations. We close by discussing the implications of the detection of EWS in human systems for archaeology and sustainability science.

Recommendations of the German Central Committee against Tuberculosis (DZK) and the German Respiratory Society (DGP) for the Diagnosis and Treatment of Non-tuberculous Mycobacterioses.

Non-tuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis-complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide, a rising prevalence and significance of non-tuberculous mycobacterioses is recognized. The present recommendations summarise current aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of non-tuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

Settlement-Size Scaling among Prehistoric Hunter-Gatherer Settlement Systems in the New World.

Settlement size predicts extreme variation in the rates and magnitudes of many social and ecological processes in human societies. Yet, the factors that drive human settlement-size variation remain poorly understood. Size variation among economically integrated settlements tends to be heavy tailed such that the smallest settlements are extremely common and the largest settlements extremely large and rare. The upper tail of this size distribution is often formalized mathematically as a power-law function. Explanations for this scaling structure in human settlement systems tend to emphasize complex socioeconomic processes including agriculture, manufacturing, and warfare-behaviors that tend to differentially nucleate and disperse populations hierarchically among settlements. But, the degree to which heavy-tailed settlement-size variation requires such complex behaviors remains unclear. By examining the settlement patterns of eight prehistoric New World hunter-gatherer settlement systems spanning three distinct environmental contexts, this analysis explores the degree to which heavy-tailed settlement-size scaling depends on the aforementioned socioeconomic complexities. Surprisingly, the analysis finds that power-law models offer plausible and parsimonious statistical descriptions of prehistoric hunter-gatherer settlement-size variation. This finding reveals that incipient forms of hierarchical settlement structure may have preceded socioeconomic complexity in human societies and points to a need for additional research to explicate how mobile foragers came to exhibit settlement patterns that are more commonly associated with hierarchical organization. We propose that hunter-gatherer mobility with preferential attachment to previously occupied locations may account for the observed structure in site-size variation.

Age-related prevalence of cross-reactive antibodies against influenza A(H3N2) variant virus, Germany, 2003 to 2010.

To estimate susceptibility to the swine-origin influenza A(H3N2) variant virus (A(H3N2)v) in the German population, we investigated cross-reactive antibodies against this virus and factors associated with seroprotective titre using sera from representative health examination surveys of children and adolescents (n = 815, 2003­06) and adults (n = 600, 2008­10). Antibodies were assessed by haemagglutination inhibition assay (HI); in our study an HI titre ≥ 40 was defined as seroprotective. We investigated associated factors by multivariable logistic regression. Overall, 41% (95% confidence interval (CI): 37­45) of children and adolescents and 39% (95% CI: 34­44) of adults had seroprotective titres. The proportion of people with seroprotective titre was lowest among children younger than 10 years (15%; 95% CI: 7­30) and highest among adults aged 18 to 29 years (59%; 95% CI: 49­67). Prior influenza vaccination was associated with higher odds of having seroprotective titre (odds ratio (OR) for children and adolescents: 3.4; 95% CI: 1.8­6.5; OR for adults: 2.4; 95% CI: 1.7­3.4). Young children showed the highest and young adults the lowest susceptibility to the A(H3N2)v virus. Our results suggest that initial exposure to circulating seasonal influenza viruses may predict long-term cross-reactivity that may be enhanced by seasonal influenza vaccination.

[Current epidemiology of tuberculosis in Germany]. / Aktuelle Epidemiologie der Tuberkulose in Deutschland.

BACKGROUND: In addition to malaria and HIV/AIDS, tuberculosis (TB) is one of the world's most important infectious diseases. Also in Germany tuberculosis still remains a relevant public health problem that needs special attention. OBJECTIVES: This article provides an overview of the tuberculosis epidemiology in Germany with emphasis on drug resistance and population groups that are predominantly affected. METHODS: Based on surveillance data provided in the notification system, the TB-situation in Germany is presented-particularly with respect to drug resistance, origin of patients (country of birth and nationality) and treatment outcome. RESULTS: Since 2009, the continuous decline in case numbers has slowed down and is now stagnating as observed in several other industrialized nations. Since 2007, the proportion of foreign-born patients has continuously increased and accounts for over half of all cases registered in Germany. Special attention deserves the current drug resistance situation: With a proportion of 3.4% in 2013, multidrug-resistant tuberculosis (MDR-TB) has increased significantly compared to the previous year (2.1%) and the rate is therefore higher than in many other European low-incidence countries. Particularly high levels of MDR-TB were observed among foreign-born patients originating from a former Soviet Union country. On average, treatment success was observed in 79% of the cases. Thus, Germany does not reach the WHO target of 85% treatment success. Stagnating case numbers together with the observed drug resistance trend clearly indicate the need for continued efforts in tuberculosis control in Germany including focused strategies for the most affected population groups.

Bacteriological confirmation of pulmonary tuberculosis in children with gastric aspirates in Germany, 2002-2010.

OBJECTIVE: To assess bacteriological confirmation of pulmonary tuberculosis (TB) in children using nucleic acid amplification tests (NAAT) and culture of gastric aspirates in Germany. DESIGN: We analysed 2002-2010 TB notification data to determine the use of gastric aspirates, NAAT and culture performance, including test agreement among pulmonary TB patients aged <15 years (grouped into <1, 1-4, 5-9 and 10-14 years). RESULTS: Gastric aspirates were used among 59% (769/1307) of the patients with available diagnostic information. For 454 patients, gastric aspirates were the only reported specimen, and both NAAT and culture were performed. Among these, culture was positive in 53% (95%CI 48-58), NAAT in 48% (95%CI 44-53) and either test in 63% (95%CI 59-68), with an overall test agreement of 74% (95%CI 70-78). Infants < 1 year had the highest positivity rate (79%, 95%CI 68-88, either test). Test agreement was the highest among 10-14 year olds (79%, 95%CI 67-89). CONCLUSIONS: Routine notification data document a wide use of gastric aspirates and high yield of both NAAT and culture for bacteriological confirmation of TB with gastric aspirates, particularly in infants. Imperfect test agreement supports the combined use of molecular assays and culture-whenever available-in the diagnosis of childhood TB.

Laboratory diagnosis of paediatric tuberculosis in the European Union/European Economic Area: analysis of routine laboratory data, 2007 to 2011.

Laboratory confirmation of paediatric tuberculosis (TB) is frequently lacking. We reviewed the range of routine laboratory tests and their performance in different biological samples used to diagnose active TB in children. A questionnaire-based survey was conducted among the European Reference Laboratory Network for TB followed by collection of routine laboratory data on 10,549 paediatric samples tested in 2007 to 2011 at six reference laboratories (in Croatia, Germany, Italy, Latvia, Lithuania and the United Kingdom (UK)). The questionnaire showed that all laboratories used rapid assays. Non-respiratory samples were collected more often in Germany (135/275, 49.1%) and the UK (490/2,140, 22.9%) compared with Croatia (138/2,792, 4.9%), Latvia (222/2,401, 9.2%) and Lithuania (76/1,549, 4.9%). Overall laboratory positivity rates (isolation of Mycobacterium tuberculosis complex and/or identification of its nucleic acids in a sample) were higher in lymph node and gastric aspirate samples (14/203 (6.9%) and 43/1,231 (3.5%)) than in sputum samples (89/4,684 (1.9%)). Pooled sensitivity, specificity, positive and negative predictive values and accuracy of molecular assays assessed against solid or liquid culture were 79.2%, 93.6%, 67.1%, 96.5% and 91.6%, respectively. A more intensive approach in obtaining gastric aspirate and non-respiratory samples may increase laboratory confirmation of paediatric TB. Major effort is needed in optimisation and validation of molecular tests in these samples.

Epidemiology of tuberculosis in big cities of the European Union and European Economic Area countries.

This cross-sectional survey aimed to examine the epidemiology of tuberculosis (TB) in European Union (EU) and European Economic Area (EEA) cities with populations greater than 500,000. National TB programme managers were asked to provide data on big city population size, total number of notified TB cases in big cities and national notification rate for 2009. A rate ratio was calculated using the big city TB notification rate as a numerator and country TB notification rate, excluding big city TB cases and population, as a denominator. Twenty of the 30 EU/EEA countries had at least one big city. Pooled rate ratios were 2.5, 1.0, and 0.7 in low-, intermediate- and high-incidence countries respectively. In 15 big cities, all in low-incidence countries, rate ratios were twice the national notification rate. These data illustrate the TB epidemiology transition, a situation whereby TB disease concentrates in big cities as national incidence falls, most likely as a result of the higher concentration of risk groups found there. This situation requires targeted interventions and we recommend that big city TB data, including information about patients' risk factors, are collected and analysed systematically, and that successful interventions are shared.

Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement.

In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective. Lessons can be learnt from across the EU and this consensus statement on TB control in big cities and urban risk groups was prepared by a working group representing various EU big cities, brought together on the initiative of the European Centre for Disease Prevention and Control. The consensus statement describes general and specific social, educational, operational, organisational, legal and monitoring TB control interventions in EU big cities, as well as providing recommendations for big city TB control, based upon a conceptual TB transmission and control model.

[Recommendations for diagnosis and treatment of nontuberculous mycobacterioses of the German Central Committee against tuberculosis and the German Respiratory Society]. / Empfehlungen zur Diagnostik und Therapie nichttuberkulöser Mykobakteriosen des Deutschen Zentralkomitees zur Bekämpfung der Tuberkulose (DZK) und der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP).

Nontuberculous mycobacterioses comprise a group of diseases caused by mycobacteria which do not belong to the Mycobacterium (M.) tuberculosis complex and are not ascribed to M. leprae. These mycobacteria are characterized by a broad variety as to environmental distribution and adaptation. Some of the species may cause specific diseases, especially in patients with underlying immunosuppressive diseases, chronic pulmonary diseases or genetic predisposition, respectively. Worldwide a rising prevalence and significance of nontuberculous mycobacterioses can be recognized. The present recommendations summarise actual aspects of epidemiology, pathogenesis, clinical aspects, diagnostics - especially microbiological methods including susceptibility testing -, and specific treatment for the most relevant species. Diagnosis and treatment of nontuberculous mycobacterioses during childhood and in HIV-infected individuals are described in separate chapters.

The burden of extrapulmonary and meningitis tuberculosis: an investigation of national surveillance data, Germany, 2002 to 2009.

Tuberculosis (TB) surveillance commonly focuses on pulmonary (PTB) where the main organ affected is the lung. This might lead to underestimate extrapulmonary TB (EPTB) forms, where in addition to the lung other sites are affected by TB. In Germany, TB notification data provide the main site and the secondary site of disease. To gain an overview of all the different EPTB forms, we analysed German TB notification data between 2002 and 2009 using information on both main and secondary disease site to describe all individual EPTB forms. Further, we assessed factors associated with meningitis using multivariable logistic regression. Solely analysing the main site of disease, lead to one third of EPTB manifestations being overlooked. Case characteristics varied substantially across individual extrapulmonary forms. Of 46,349 TB patients, 422 (0.9%) had meningitis as main or secondary site. Of those, 105 (25%) of the 415 with available information had died. Multivariable analysis showed that meningitis was more likely in children younger than five years and between five and nine years-old (odds ratio (OR): 4.90; 95% confidence interval (CI): 3.40­7.07 and OR: 2.65; 95% CI: 1.40­5.00), in females (OR: 1.42; 95% CI: 1.17­1.73), and in those born in the World Health Organization (WHO) regions of south-east Asia (OR: 2.38; 95% CI: 1.66­3.43) and eastern Mediterranean (OR: 1.51; 95% CI: 1.02­2.23). Overall, EPTB manifestations, including meningitis, which is often fatal, were underestimated by routine analysis. We thus recommend using all information on disease manifestation generated by surveillance to monitor severe forms and to transfer the gained knowledge to TB case management where awareness of EPTB is most important.

Challenges in diagnosing extrapulmonary tuberculosis in the European Union, 2011.

In the European Union (EU) 72,334 tuberculosis (TB) cases were notified in 2011, of which 16,116 (22%) had extrapulmonary tuberculosis (EPTB). The percentage of TB cases with EPTB ranged from 4% to 48% in the reporting countries. This difference might be explained by differences in risk factors for EPTB or challenges in diagnosis. To assess the practices in diagnosis of EPTB we asked European Union/European Economic Area (EU/EEA) countries to participate in a report describing the diagnostic procedures and challenges in diagnosing EPTB. Eleven EU Member States participated and reports showed that in the majority EPTB is diagnosed by a pulmonologist, sometimes in collaboration with the doctor who is specialised in the organ where the symptoms presented. In most countries a medical history and examination is followed by invasive procedures, puncture or biopsy, to collect material for confirmation of the disease (by culture/histology/cytology). Some countries also use the tuberculin skin test or an interferon-gamma-release-assay. A wide variety of radiological tests may be used. Countries that reported challenges in the diagnosis of EPTB reported that EPTB is often not considered because it is a rare disease and most medical professionals will not have experience in diagnosing EPTB. The fact that EPTB can present with a variety of symptoms that may mimic symptoms of other pathologies does pose a further challenge in diagnosis. In addition, obtaining an appropriate sample for confirmation of EPTB was frequently mentioned as a challenge. In summary, diagnosis of EPTB poses challenges due to the diversity of symptoms with which EPTB may present, the low level of suspicion of clinicians, and due to the difficulty in obtaining an adequate sample for confirmation.