BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

Generation of a Perfusable 3D Lung Cancer Model by Digital Light Processing.

Lung cancer still has one of the highest morbidity and mortality rates among all types of cancer. Its incidence continues to increase, especially in developing countries. Although the medical field has witnessed the development of targeted therapies, new treatment options need to be developed urgently. For the discovery of new drugs, human cancer models are required to study drug efficiency in a relevant setting. Here, we report the generation of a non-small cell lung cancer model with a perfusion system. The bioprinted model was produced by digital light processing (DLP). This technique has the advantage of including simulated human blood vessels, and its simple assembly and maintenance allow for easy testing of drug candidates. In a proof-of-concept study, we applied gemcitabine and determined the IC50 values in the 3D models and 2D monolayer cultures and compared the response of the model under static and dynamic cultivation by perfusion. As the drug must penetrate the hydrogel to reach the cells, the IC50 value was three orders of magnitude higher for bioprinted constructs than for 2D cell cultures. Compared to static cultivation, the viability of cells in the bioprinted 3D model was significantly increased by approximately 60% in the perfusion system. Dynamic cultivation also enhanced the cytotoxicity of the tested drug, and the drug-mediated apoptosis was increased with a fourfold higher fraction of cells with a signal for the apoptosis marker caspase-3 and a sixfold higher fraction of cells positive for PARP-1. Altogether, this easily reproducible cancer model can be used for initial testing of the cytotoxicity of new anticancer substances. For subsequent in-depth characterization of candidate drugs, further improvements will be necessary, such as the generation of a multi-cell type lung cancer model and the lining of vascular structures with endothelial cells.

Comprehensive comparison of pore-scale models for multiphase flow in porous media.

Multiphase flows in porous media are important in many natural and industrial processes. Pore-scale models for multiphase flows have seen rapid development in recent years and are becoming increasingly useful as predictive tools in both academic and industrial applications. However, quantitative comparisons between different pore-scale models, and between these models and experimental data, are lacking. Here, we perform an objective comparison of a variety of state-of-the-art pore-scale models, including lattice Boltzmann, stochastic rotation dynamics, volume-of-fluid, level-set, phase-field, and pore-network models. As the basis for this comparison, we use a dataset from recent microfluidic experiments with precisely controlled pore geometry and wettability conditions, which offers an unprecedented benchmarking opportunity. We compare the results of the 14 participating teams both qualitatively and quantitatively using several standard metrics, such as fractal dimension, finger width, and displacement efficiency. We find that no single method excels across all conditions and that thin films and corner flow present substantial modeling and computational challenges.

Cost-effectiveness of Practice Team-Supported Exposure Training for Panic Disorder and Agoraphobia in Primary Care: a Cluster-Randomized Trial.

BACKGROUND: Primary care is the main treatment setting for panic disorder and should be supplemented by collaborative care programs. However, shortage of mental health professionals prevents collaborative care programs from being effectively implemented. The PARADISE study showed the efficacy of a self-managed, cognitive-behavioural therapy (CBT)-oriented exposure training for patients with panic disorder with or without agoraphobia in primary care delivered by the family practice team. OBJECTIVE: To assess the cost-effectiveness of the PARADISE intervention. DESIGN: Cost-effectiveness analysis from the societal perspective based on data from a cluster-randomized controlled trial over a time horizon of 12 months. PARTICIPANTS: Four hundred nineteen adult panic disorder patients with or without agoraphobia. INTERVENTIONS: A self-managed, CBT-oriented exposure training for patients with panic disorder with or without agoraphobia in primary care delivered by the primary care practice team in comparison to routine care. MAIN MEASURES: Total costs from the societal perspective. Direct costs and disease-specific costs. Quality-adjusted life years based on the EQ-5D-3L. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. KEY RESULTS: Patients in the intervention group caused lower costs (mean, €1017; 95% confidence interval [-€3306; €1272]; p = 0.38) and gained on average more QALY (mean, 0.034 QALY (95% confidence interval [0.005; 0.062]; p = 0.02). Therefore, the intervention dominated the control treatment. The probability of cost-effectiveness of the intervention at a willingness-to-pay margin of €50,000 per QALY was 96%. Results from supplementary analyses considering direct or disease-specific costs instead of total costs showed comparable results. CONCLUSION: The PARADISE intervention is cost effective. This conclusion is valid for total costs, generic health care (direct) costs, disease-specific health care costs. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004386 Current Controlled Trials: ISRCTN64669297.

The allocation of resources in the care for patients with panic disorder in Germany: an excess cost analysis informing policy and science.

BACKGROUND: Panic disorder is a mental disorder of high prevalence, which frequently co-occurs with agoraphobia. There is a lack of studies measuring excess costs of panic disorder patients with and without agoraphobia. We compared costs of panic disorder patients with or without agoraphobia with costs of the anxiety-free population in Germany. METHODS: Primary data from a cluster-randomized trial of adults suffering from panic disorder (n = 419) and from a representative survey of the German general population (N = 5005) were collected between 2012 and 2014. Missing data from the cluster-randomized trial were first imputed by multiple imputation using chained equations and subsequently balanced with the data from the survey by Entropy Balancing. The societal perspective was chosen. Excess costs were calculated by generalized linear models and two-part-models. RESULTS: Entropy Balancing led to an exact match between the groups. We found 6-month total excess costs of 3220€ (95% CI 1917€-4522€) for panic disorder patients without agoraphobia and of 3943€ (95% CI 2950€-4936€) for patient with agoraphobia. Panic disorder patients with or without agoraphobia had significantly higher costs for psychotherapy, general practitioners, general hospital stays and informal care Indirect costs accounted for approximately 60% of the total excess costs. CONCLUSIONS: Panic disorder with or without agoraphobia is associated with significant excess costs. Agoraphobia changes the pattern of resource utilization. Especially indirect costs are relevant. Agoraphobia influences resource utilization in the inpatient sector.Trial registration ISRCTN64669297.

Leg structure explains host site preference in bat flies (Diptera: Streblidae) parasitizing neotropical bats (Chiroptera: Phyllostomidae).

Bat flies (Streblidae) are diverse, obligate blood-feeding insects and probably the most conspicuous ectoparasites of bats. They show preferences for specific body regions on their host bat, which are reflected in behavioural characteristics. In this study, we corroborate the categorization of bat flies into three ecomorphological groups, focusing only on differences in hind leg morphology. As no detailed phylogeny of bat flies is available, it remains uncertain whether these morphological differences reflect the evolutionary history of bat flies or show convergent adaptations for the host habitat type. We show that the division of the host bat into three distinct habitats contributes to the avoidance of interspecific competition of bat fly species. Finally, we found evidence for density-dependent competition between species belonging to the same ecomorphological group.

Suicidal ideation in primary care patients suffering from panic disorder with or without agoraphobia.

BACKGROUND: Suicidal ideation is common in patients suffering from panic disorder. The present study investigated rates of suicidal ideation and risk factors for suicidal ideation in a sample of primary care patients suffering from panic disorder with or without agoraphobia. METHODS: A total of N = 296 patients [n = 215 (72.6%) women; age: M = 43.99, SD = 13.44] were investigated. Anxiety severity, anxiety symptoms, avoidance behavior, comorbid depression diagnosis, severity of depression, age, sex, employment status, living situation and frequency of visits at the general practitioner were considered as risk factors of suicidal ideation. RESULTS: Suicidal ideation was experienced by 25% of the respondents. In a logistic regression analysis, depression diagnosis and depression severity emerged as significant risk factors for suicidal ideation. Anxiety measures were not associated with suicidal ideation. CONCLUSION: Suicidal ideation is common in primary care patients suffering from panic disorder with or without agoraphobia. Individuals with greater burden of mental illness in terms of mood disorder comorbidity and depressive symptomatology are especially likely to suffer from suicidal ideation.

Generation of a 3D Liver Model Comprising Human Extracellular Matrix in an Alginate/Gelatin-Based Bioink by Extrusion Bioprinting for Infection and Transduction Studies.

Bioprinting is a novel technology that may help to overcome limitations associated with two-dimensional (2D) cell cultures and animal experiments, as it allows the production of three-dimensional (3D) tissue models composed of human cells. The present study describes the optimization of a bioink composed of alginate, gelatin and human extracellular matrix (hECM) to print human HepaRG liver cells with a pneumatic extrusion printer. The resulting tissue model was tested for its suitability for the study of transduction by an adeno-associated virus (AAV) vector and infection with human adenovirus 5 (hAdV5). We found supplementation of the basic alginate/gelatin bioink with 0.5 and 1 mg/mL hECM provides desirable properties for the printing process, the stability of the printed constructs, and the viability and metabolic functions of the printed HepaRG cells. The tissue models were efficiently transduced by AAV vectors of serotype 6, which successfully silenced an endogenous target (cyclophilin B) by means of RNA interference. Furthermore, the printed 3D model supported efficient adenoviral replication making it suitable to study virus biology and develop new antiviral compounds. We consider the approach described here paradigmatic for the development of 3D tissue models for studies including viral vectors and infectious viruses.

Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior.

BACKGROUND: The liver is the major site for alcohol metabolism in the body and therefore the primary target organ for ethanol (EtOH)-induced toxicity. In this study, we investigated the in vitro response of human liver cells to different EtOH concentrations in a perfused bioartificial liver device that mimics the complex architecture of the natural organ. METHODS: Primary human liver cells were cultured in the bioartificial liver device and treated for 24 hours with medium containing 150 mM (low), 300 mM (medium), or 600 mM (high) EtOH, while a control culture was kept untreated. Gene expression patterns for each EtOH concentration were monitored using Affymetrix Human Gene 1.0 ST Gene chips. Scaled expression profiles of differentially expressed genes (DEGs) were clustered using Fuzzy c-means algorithm. In addition, functional classification methods, KEGG pathway mapping and also a machine learning approach (Random Forest) were utilized. RESULTS: A number of 966 (150 mM EtOH), 1,334 (300 mM EtOH), or 4,132 (600 mM EtOH) genes were found to be differentially expressed. Dose-response relationships of the identified clusters of co-expressed genes showed a monotonic, threshold, or nonmonotonic (hormetic) behavior. Functional classification of DEGs revealed that low or medium EtOH concentrations operate adaptation processes, while alterations observed for the high EtOH concentration reflect the response to cellular damage. The genes displaying a hormetic response were functionally characterized by overrepresented "cellular ketone metabolism" and "carboxylic acid metabolism." Altered expression of the genes BAHD1 and H3F3B was identified as sufficient to classify the samples according to the applied EtOH doses. CONCLUSIONS: Different pathways of metabolic and epigenetic regulation are affected by EtOH exposition and partly undergo hormetic regulation in the bioartificial liver device. Gene expression changes observed at high EtOH concentrations reflect in some aspects the situation of alcoholic hepatitis in humans.

Bile canaliculi formation and biliary transport in 3D sandwich-cultured hepatocytes in dependence of the extracellular matrix composition.

Primary human hepatocytes (PHH) are still considered as gold standard for investigation of in vitro metabolism and hepatotoxicity in pharmaceutical research. It has been shown that the three-dimensional (3D) cultivation of PHH in a sandwich configuration between two layers of extracellular matrix (ECM) enables the hepatocytes to adhere three dimensionally leading to formation of in vivo like cell-cell contacts and cell-matrix interactions. The aim of the present study was to investigate the influence of different ECM compositions on morphology, cellular arrangement and bile canaliculi formation as well as bile excretion processes in PHH sandwich cultures systematically. Freshly isolated PHH were cultured for 6 days between two ECM layers made of collagen and/or Matrigel in four different combinations. The cultures were investigated by phase contrast microscopy and immunofluorescence analysis with respect to cell-cell connections, repolarization as well as bile canaliculi formation. The influence of the ECM composition on cell activity and viability was measured using the XTT assay and a fluorescent dead or alive assay. Finally, the bile canalicular transport was analyzed by live cell imaging to monitor the secretion and accumulation of the fluorescent substance CDF in bile canaliculi. Using collagen and Matrigel in different compositions in sandwich cultures of hepatocytes, we observed differences in morphology, cellular arrangement and cell activity of PHH in dependence of the ECM composition. Sandwich-cultured hepatocytes with an underlay of collagen seem to represent the best in vivo tissue architecture in terms of formation of trabecular cell arrangement. Cultures overlaid with collagen were characterized by the formation of abundant bile canaliculi, while the bile canaliculi network in hepatocytes cultured on a layer of Matrigel and overlaid with collagen showed the most branched and stable canalicular network. All cultures showed a time-dependent leakage of CDF from the bile canaliculi into the culture supernatant with variations in dependence on the used matrix combination. In conclusion, the results of this study show that the choice of ECM has an impact on the morphology, cell assembly and bile canaliculi formation in PHH sandwich cultures. The morphology and the multicellular arrangement were essentially influenced by the underlaying matrix, while bile excretion and leakage of sandwich-cultured hepatocytes were mainly influenced by the overlay matrix. Leaking and damaged bile canaliculi could be a limitation of the investigated sandwich culture models in long-term excretion studies.

Psychometric evaluation and Rasch analyses of the German Overall Anxiety Severity and Impairment Scale (OASIS-D).

The Overall Anxiety Severity and Impairment Scale (OASIS) is a 5-item self-report measure that captures symptoms of anxiety and associated functional impairments. This study evaluates a German version (OASIS-D) that was administered to a convenience sample of 1398 primary care patients of whom 419 were diagnosed with panic disorder with/without agoraphobia. Psychometric properties were analyzed using classical test theory as well as probabilistic test theory. Factor analyses suggested a unitary (latent) factor structure. The internal consistency was good to excellent. Convergent as well as discriminant validity with other self-report measures was found. A sum score (range 0-20) of ≥ 8 emerged as optimal cut-score for screening purposes. A difference score of ≥ 5 was indicative of reliable individual change. A Rasch analysis of local item independence suggested response dependency between the first two items. Rasch analyses of measurement invariance detected noninvariant subgroups associated with age and gender. Analyses of validity and optimal cut-off score were solely based on self-report measures, which may have introduced method effects. In sum, the findings support the transcultural validity of the OASIS and indicate its applicability to naturalistic primary care settings. Caution is warranted when using the scale to compare groups that differ in age or gender.

Five new species of Gloeandromyces (Fungi, Laboulbeniales) from tropical American bat flies (Diptera, Streblidae), revealed by morphology and phylogenetic reconstruction.

This paper describes and illustrates five new species of Gloeandromyces (Ascomycota, Laboulbeniales) associated with tropical American bat flies (Diptera, Streblidae). These are Gloeandromyces cusucoensis sp. nov. from Trichobius uniformis in Costa Rica and Honduras, G. diversiformis sp. nov. from Strebla wiedemanni in Costa Rica, G. plesiosaurus sp. nov. from Trichobius yunkeri in Panama, G. pseudodickii sp. nov. from Trichobius longipes in Ecuador and Panama, and G. verbekeniae sp. nov. from Strebla galindoi in Ecuador and Panama. The description of these five species doubles the number of known species in the genus. Morphological characteristics, host association, and a three-locus (18S nuc rDNA, 28S nuc rDNA, TEF1) phylogenetic reconstruction support placement of these taxa in the genus Gloeandromyces. Three of the new species are polymorphic; they have multiple morphotypes that grow in specific positions on the host integument: G. diversiformis f. diversiformis, f. musiformis, and f. vanillicarpiformis; G. plesiosaurus f. asymmetricus and f. plesiosaurus; and G. verbekeniae f. verbekeniae and f. inflexus. Finally, a dichotomous key to all species and morphotypes is presented.

Patient characteristics and changes in anxiety symptoms in patients with panic disorder: Post-hoc analysis of the PARADIES cluster randomised trial.

Anxiety disorders are among the most common mental health problems in primary care. The PARADIES (Patient Activation foR Anxiety DIsordErS) intervention combined elements of cognitive behavioural therapy with case management and has demonstrated efficacy. Our aim was to explore patient characteristics, which may influence the course of anxiety symptoms over a 12 months period. Multiple linear regression was used to quantify associations of baseline characteristics (demographics, clinical parameters, medication use) with changes in anxiety symptoms as measured by the Beck anxiety inventory. Treatment modalities (e.g. adherence to appointment schedules) were considered as confounders. We examined univariate associations between dependent and independent variables before considering all independent variables in a multivariate final model. To find the best model to explain BAI score changes, we performed step-wise selection of independent variables based on Akaike information criteria. We tested for interaction terms between treatment allocation (intervention vs control) and independent variables using the multivariate model. We repeated these analyses in control vs intervention groups separately. From the original trial (N = 419), 236 patients (56.3%) were included. In the multivariate model, receiving the intervention (p<0.001), higher anxiety symptom severity (p<0.001) and longer illness duration at baseline (p = 0.033) were significantly associated with changes in anxiety symptom severity to the better while depression severity at baseline (p<0.001) was significantly associated with changes in anxiety symptoms to the worse. In stratified analyses, the control group showed significant associations between depression symptom severity and illness duration with anxiety symptom changes while baseline severity of anxiety symptoms remained significantly associated with anxiety symptom changes in both groups. A brief primary-care-based exposure training combined with case management is effective in a broad range of patients with panic disorder with/without agoraphobia, including those with longer illness duration and co-existing symptoms of depression at baseline.

[Health Assistants Perspectives on Team-Led Program for Patients with Panic Disorder in General Practice - A Qualitative Study]. / Perspektiven von Medizinischen Fachangestellten zu teambasierter Behandlung von Patienten mit Panikstörung in der Hausarztpraxis ­ Eine qualitative Studie.

AIM OF THE STUDY: Investigation of the perspective of medical assistants (MA) regarding their participation in behaviour-therapy oriented interventions in family practice. METHOD: 15 MA (w, 39.5 years old), case managers in a general practitioner supported exercise programme for patients with panic disorder (ICD-10: F41.0), were interviewed using semi-structured interview guidelines on the recruitment and interaction of/with patients, communication of the exercises and implementation in everyday practice. The interviews (n = 14) were documented, transcribed and qualitatively analysed according to Mayring. RESULTS: MA perceived their contribution to the intervention regarding recruitment and monitoring of patients through telephone contacts as positive. CONCLUSION: Strengthening the role of MAs' can help to provide targeted support for patients with mental health problems in GP care as part of a low-threshold intervention and relieve the workload on the GP.

On the Fly: Tritrophic Associations of Bats, Bat Flies, and Fungi.

Parasitism is one of the most diverse and abundant modes of life, and of great ecological and evolutionary importance. Notwithstanding, large groups of parasites remain relatively understudied. One particularly unique form of parasitism is hyperparasitism, where a parasite is parasitized itself. Bats (Chiroptera) may be parasitized by bat flies (Diptera: Hippoboscoidea), obligate blood-sucking parasites, which in turn may be parasitized by hyperparasitic fungi, Laboulbeniales (Ascomycota: Laboulbeniomycetes). In this study, we present the global tritrophic associations among species within these groups and analyze their host specificity patterns. Bats, bat flies, and Laboulbeniales fungi are shown to form complex networks, and sixteen new associations are revealed. Bat flies are highly host-specific compared to Laboulbeniales. We discuss possible future avenues of study with regard to the dispersal of the fungi, abiotic factors influencing the parasite prevalence, and ecomorphology of the bat fly parasites.

Mortality of native and invasive ladybirds co-infected by ectoparasitic and entomopathogenic fungi.

Harmonia axyridis is an invasive alien ladybird in North America and Europe. Studies show that multiple natural enemies are using Ha. axyridis as a new host. However, thus far, no research has been undertaken to study the effects of simultaneous infection by multiple natural enemies on Ha. axyridis. We hypothesized that high thallus densities of the ectoparasitic fungus Hesperomyces virescens on a ladybird weaken the host's defenses, thereby making it more susceptible to infection by other natural enemies. We examined mortality of the North American-native Olla v-nigrum and Ha. axyridis co-infected with He. virescens and an entomopathogenic fungus-either Beauveria bassiana or Metarhizium brunneum. Laboratory assays revealed that He. virescens-infected O. v-nigrum individuals are more susceptible to entomopathogenic fungi, but Ha. axyridis does not suffer the same effects. This is in line with the enemy release hypothesis, which predicts that invasive alien species in new geographic areas experience reduced regulatory effects from natural enemies compared to native species. Considering our results, we can ask how He. virescens affects survival when confronted by other pathogens that previously had little impact on Ha. axyridis.

A case of silent invasion: Citizen science confirms the presence of Harmonia axyridis (Coleoptera, Coccinellidae) in Central America.

Harmonia axyridis (Coleoptera, Coccinellidae) is a globally invasive ladybird. It has been intentionally introduced in many countries as a biological control agent, whereas it has been unintentionally released in many others. Climatic factors are important in limiting the spread of H. axyridis. For example, very few records are known from tropical or desert regions. Currently, no published reports are known from Central America. Here, we report H. axyridis from Costa Rica, Guatemala, Honduras, Panama, and Puerto Rico. Specimens were either observed by the authors, discovered in dried insect collections, or retrieved from searching through online photographs available from the citizen science project iNaturalist and the photo-sharing website Flickr. These new records and the wide distribution of H. axyridis in Latin America suggest several invasion events, which have gone unnoticed until now. We stress the need for further, large-scale monitoring and show the advantage of citizen science to assess the presence of invasive alien species.

Symptom trajectories in patients with panic disorder in a primary care intervention: Results from a randomized controlled trial (PARADISE).

This analysis aims to identify and characterize symptom trajectories in primary care patients with panic disorder with/without agoraphobia (PD/AG) who participated in a primary care team based training involving elements of cognitive behavioural therapy (CBT). Growth Mixture Modeling was used to identify different latent classes of change in patients with PD/AG (N = 176) who underwent treatment including CBT elements. We identified three patient classes with distinct similar trajectories. Class 1 (n = 58, mean age: 46.2 years ± 13.4 years, 81% women) consisted of patients with an initially high symptom burden, but symptoms declined constantly over the intervention period. Symptoms of patients in class 2 (n = 89, mean age: 44.2 years ± 14.5 years, 67.4% women) declined rapidly at the beginning, then patients went into a plateau-phase. The third class (n = 29, mean age: 47.0 years ± 12.4 years, 65.5% women) was characterized by an unstable course and had the worse outcome. Our findings show that only a minority did not respond to the treatment. To identify this minority and refer to a specialist would help patients to get intensive care in time.

Panic Disorder in Primary Care.

BACKGROUND: We evaluated a team-based program of exercises for patients with panic disorder with or without agoraphobia (PDA) in primary care. METHODS: 419 patients with PDA (mean age 46.2 years, standard deviation 14.4 years; 74% female) were included in this cluster-randomized, controlled intervention trial. The patients were blinded with respect to their group assignment at baseline. Patients in the intervention group (36 primary-care practices, 230 patients) underwent a 23-week exercise program combined with case management, while patients in the control group (37 practices, 189 patients) received standard care. Symptoms of anxiety (according to the Beck Anxiety Inventory, BAI) at six months were the primary endpoint. Patients were followed up at six months (n = 338, 81%) and at twelve months (n = 318, 76%). The analysis was by intention to treat. RESULTS: Symptoms of anxiety improved to a significantly greater extent in the intervention group (p = 0.008). The intergroup dif- ference in the reduction of the BAI score (range: 0-63) was 3.0 points (95% confidence interval [-5.8; -0.2]) at six months and 4.0 points [-6.9; -1.2] at twelve months. In the intervention group, there was a significantly greater reduction in the frequency of panic attacks (p = 0.019), in avoidant behavior (p = 0.016), and in depressiveness (p<0.001), as well as a greater improvement of the quality of treatment (p<0.001). CONCLUSION: In primary-care patients who have panic disorder with or without agoraphobia, a team-based exercise program combined with case management can improve symptoms to a greater extent than standard primary-care treatment.

Host Biology and Anthropogenic Factors Affect Hepadnavirus Infection in a Neotropical Bat.

The tent-making bat hepatitis B virus (TBHBV) is a hepadnavirus closely related to human hepatitis B virus. The ecology of TBHBV is unclear. We show that it is widespread and highly diversified in Peters' tent-making bats (Uroderma bilobatum) within Panama, while local prevalence varied significantly between sample sites, ranging from 0 to 14.3%. Females showed significantly higher prevalence than males, and pregnant females were more often acutely infected than non-reproductive ones. The distribution of TBHBV in bats was significantly affected by forest cover, with higher infection rates in areas with lower forest cover. Our data indicate that loss of natural habitat may lead to positive feedback on the biotic factors driving infection possibility. These results underline the necessity of multidisciplinary studies for a better understanding of mechanisms in pathogen-host relationships and for predictions in disease ecology.