The association between common mental disorders and tuberculosis: a case-control study from Guinea-Bissau.

OBJECTIVE: The aim of the study was to explore the association between tuberculosis (TB) and common mental disorders (CMD), in an area with high prevalence of TB. METHODS: We performed a case-control study of TB patients and unmatched healthy controls, from a demographic surveillance site in Guinea-Bissau. Screening for CMD was performed once for controls and at inclusion and follow-up for TB patients. Kessler 10 (K-10) and a brief version of Hopkins Symptom Checklist 25 (SCL-8d) were used as screening instruments. RESULTS: 571 controls were interviewed and 416 interviews were performed for 215 TB cases. Estimated CMD prevalence at the time of diagnosis of TB was 33.6 % (SCL-8d) and 46.2 % (K-10), compared with 6.8 % (SCL-8d) and 6.7 % (K-10) among controls; adjusted OR 7.18 (95 % CI 4.07 to 12.67) and 14.52 (95 % CI 8.15 to 25.84), respectively. No significant difference in CMD prevalence rates was observed between TB patients, after 6 months of treatment, and controls. CONCLUSION: Psychological distress and common mental disorders were more prevalent among TB patients at the time of diagnosis compared with the background population, but after completion of TB treatment no increased prevalence of psychological distress was found.

Second-generation distal attachment cuff for adenoma detection in screening colonoscopy: a randomized multicenter study.

BACKGROUND AND AIMS: Randomized studies have demonstrated that a distal attachment cap with rubber side arms, the Endocuff Vision (ECV; Olympus America, Center Valley, Pa, USA), increased colonoscopic adenoma detection rate (ADR) in various mixed patient collectives. This is the first study to evaluate its use in a primary colonoscopic screening program. METHODS: Patients over age 55 years undergoing screening colonoscopy in 9 German private offices in Berlin and Hamburg were randomized to either the study group using ECV or the control group using high-definition colonoscopies (standard of care). The main outcome parameter was ADR, whereas secondary outcomes were detection rates of all adenomas per colonoscopy (APCs), of adenoma subgroups, and of hyperplastic polyps. RESULTS: Of 1416 patients (mean age, 61.1 years; 51.8% women), with a median of 41 examinations per examiner (n = 23; interquartile range, 12-81), 700 were examined with ECV and 716 without. Adjusting for the effects of the colonoscopies, ADR was 39.5% (95% confidence interval [CI], 32.6%-46.3%) in the ECV group versus 32.2% (95% CI, 25.9%-38.6%) in the control group, which resulted in an increase of 7.2% (95% CI, 2.3%-12.2%; P = .004). The increase in ADR was mainly because of small polyps, with adjusted ADRs for adenomas <10 mm of 33.3% (95% CI, 26.5%-40.2%) for study patients versus 24.0% (95% CI, 18.2%-29.8%) for control patients (P < .001). APC was also significantly increased (.57 ECV vs .51 control subjects, P = .045). CONCLUSIONS: A distal attachment cap with side arms significantly increased the ADR in patients undergoing primary colonoscopic screening. Because of the correlation of ADR and interval cancer, its use should be encouraged, especially in this setting. (Clinical trial registration number: NCT03442738.).

Fully discrete approximation schemes for rate-independent crack evolution.

Over the past two decades, several distinct solution concepts for rate-independent evolutionary systems driven by non-convex energies have been suggested in an attempt to model properly jump discontinuities in time. Much attention has been paid in this context to the modelling of crack propagation. This paper studies two fully discrete (in time and space) approximation schemes for the rate-independent evolution of a single crack in a two-dimensional linear elastic material. The crack path is assumed to be known in advance, and the evolution of the crack tip along it relies on the Griffith theory. On the time-discrete level, the first scheme is based on local minimization, whereas the second scheme is a regularized version of the first one. The crucial feature of the schemes is their adaptive time-stepping nature, with finer time steps at those points where the evolution of the crack tip might develop a discontinuity. The set of discretization parameters includes the mesh size, crack increment, locality parameter and regularization parameter. In both cases, we explore the interplay between the discretization parameters and derive sufficient conditions on them ensuring the convergence of discrete interpolants to parametrized balanced viscosity solutions of the continuous model. To illustrate the performance of the approximation schemes, we support our theoretical analysis with numerical simulations. This article is part of the theme issue 'Non-smooth variational problems and applications'.

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.

Feasibility of group-based acceptance and commitment therapy for adolescents (AHEAD) with multiple functional somatic syndromes: a pilot study.

BACKGROUND: Recurrent and impairing functional somatic syndromes (FSS) are common in adolescents. Despite a high need for care, empirically supported treatments are lacking for youth. The aim of this uncontrolled pilot study was to assess feasibility and treatment potential of a new intervention with group-based Acceptance and Commitment Therapy (ACT) in a generic treatment approach for adolescents with multiple FSS. METHODS: Twenty-one patients received 'ACT for Health in Adolescents' (AHEAD) (30 h), specifically developed for adolescents (aged 15-19 years) with moderate to severe FSS. Close relatives attended an information meeting to facilitate support of the patients throughout treatment. Treatment satisfaction was evaluated by means of self-report and relatives' impressions. Self-reported physical health at 3 months follow-up (FU) after end of treatment was the primary outcome whereas secondary outcomes included symptom burden, limitation due to symptoms, illness worry, emotional distress and physical and emotional symptoms. Treatment targets were assessed by measures on illness behaviour, illness perception and psychological inflexibility. RESULTS: Nineteen patients (90.5%) completed the treatment with a high overall attendance rate of 93%. All would recommend the treatment to a friend with similar problems. Close relatives rated it valuable to participate in an information meeting. Patients' physical health improved significantly from assessment to FU with a clinically relevant mean change of 8.9 points (95% CI [5.4; 12.4]; SRM 0.91 [0.26;1.57]). Improvement was also seen on all secondary outcome measures, from assessment to FU. Maladaptive illness behaviours and perceptions as well as psychological inflexibility showed a significant decline from assessment to FU. CONCLUSION: AHEAD was feasible and potentially efficacious and warrants testing in a larger clinical trial. TRIAL REGISTRATION: Clinical Trials gov NCT04464447 , registration date July 9th, 2020. Retrospectively registered.

Prevalence of functional somatic syndromes and bodily distress syndrome in the Danish population: the DanFunD study.

Aims: Little is known about the prevalence and characteristics of functional somatic syndromes (FSS) such as irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), whiplash associated disorders (WAD), multiple chemical sensitivity (MCS), and bodily distress syndrome (BDS) in the general population when they are investigated simultaneously. Method: This cross-sectional study is based on the Danish Study of Functional Disorders (DanFunD) cohort consisting of 9656 adults from the general population. FSS and BDS were identified by questionnaires and characterized by age, sex, vocational training, physical health and comorbidity with physical and psychiatric disease. Results: In total, 16.3% (95% CI: 15.6-17.1) of the participants fulfilled the criteria for at least one FSS, ranging from 1.7% for WAD to 8.6% for CFS, and 16.1% (95% CI: 15.4-16.9) fulfilled the criteria for BDS. Cases had a high risk of poor self-perceived health, limitations in daily activities, and a high psychiatric comorbidity, all increasing with the number of syndromes in each individual. However, the associations differed across the various FSS. Mutual overlaps of IBS, FM and CFS were greater than could be expected by chance. Conclusions: FSS and BDS are prevalent in the adult Danish population, and cases have high risk of poor self-perceived health, limitation in daily activities, and psychiatric comorbidity. These associations were particularly strong for cases with multiple FSS and multi-organ BDS.

Low Sensitivity of Simtomax Point of Care Test in Detection of Celiac Disease in a Prospective Multicenter Study.

BACKGROUND & AIMS: Point of care tests (POCTs) might be used to identify patients with undiagnosed celiac disease who require further evaluation. We performed a large multicenter study to determine the performance of a POCT for celiac disease and assessed celiac disease prevalence in endoscopy centers. METHODS: We performed a prospective study of 1055 patients (888 adults; median age, 48 yrs and 167 children; median age, 10 yrs) referred to 8 endoscopy centers in Germany, for various indications, from January 2016 through June 2017. Patients were tested for celiac disease using Simtomax, which detects immunoglobulin (Ig)A and IgG antibodies against deamidated gliadin peptides (DGP). Results were compared with findings from histologic analyses of duodenal biopsies (reference standard). The primary aim was to determine the accuracy of this POCT for the detection of celiac disease, to identify candidates for duodenal biopsy. A secondary aim was to determine the prevalence of celiac disease in adult and pediatric populations referred for outpatient endoscopic evaluation. RESULTS: The overall prevalence of celiac disease was 4.1%. The POCT identified individuals with celiac disease with 79% sensitivity (95% CI, 64%-89%) and 94% specificity (95% CI, 93%-96%). Positive and negative predictive values were 37% and 99%. When we analyzed the adult and pediatric populations separately, we found the test to identify adults with celiac disease (prevalence 1.2%) with 100% sensitivity and 95% specificity. In the pediatric population (celiac disease prevalence 19.6%), the test produced false-negative results for 9 cases; the test therefore identified children with celiac disease with 72% sensitivity (95% CI 53%-86%). Analyses of serologic data revealed significantly lower DGP titers in the false-negative vs the true-positive group. CONCLUSIONS: In a study of more than 1000 adults and children, we found the Simtomax POCT to detect celiac disease with lower overall levels of sensitivity than expected. Although the test identifies adults with celiac disease with high levels of sensitivity and specificity, the prevalence of celiac disease was as low as 1.2% among adults. The test's lack of sensitivity might be due to the low intensity of the POCT bands and was associated with low serum DGP titers. Study ID no: DRKS00012499.

A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer.

CV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400-1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD+CD38hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8-6.3) and 10.8 months (8.1-16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Acceptance and Commitment group Therapy for patients with multiple functional somatic syndromes: a three-armed trial comparing ACT in a brief and extended version with enhanced care.

BACKGROUND: Psychological treatment for functional somatic syndromes (FSS) has been found moderately effective. Information on how much treatment is needed to obtain improvement is sparse. We assessed the efficacy of a brief and extended version of group-based Acceptance and Commitment Therapy (ACT) v. enhanced care (EC) for patients with multiple FSS operationalised as Bodily Distress Syndrome multi-organ type. METHODS: In a randomised controlled three-armed trial, consecutively referred patients aged 20-50 with multiple FSS were randomly assigned to either (1) EC; (2) Brief ACT: EC plus 1-day workshop and one individual consultation; or (3) Extended ACT: EC plus nine 3-h group-based sessions. Primary outcome was patient-rated overall health improvement on the five-point clinical global improvement scale 14 months after randomisation. A proportional odds model was used for the analyses. RESULTS: A total of 180 patients were randomised; 60 to EC, 61 to Brief ACT, and 59 to Extended ACT. Improvement on the primary outcome after Extended ACT was significantly greater than after EC with an unadjusted OR of 2.9 [95% CI (1.4-6.2), p = 0.006]. No significant differences were found between Brief ACT and EC. Of the 18 secondary outcomes, the only significant difference found was for physical functioning in the comparison of Extended ACT with EC. CONCLUSIONS: Patients rated their overall health status as more improved after Extensive ACT than after EC; however, clinically relevant secondary outcome measures did not support this finding. Discrepancies between primary and secondary outcomes in this trial are discussed.

Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction.

The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane-cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus.

Irritable bowel symptoms, use of healthcare, costs, sickness and disability pension benefits: A long-term population-based study.

Objectives: Irritable bowel syndrome (IBS) is associated with increased healthcare use and work absenteeism. We aimed to investigate long-term use of healthcare services and social benefits across IBS symptom groups. Additionally, we estimated excess healthcare costs. Methods: A longitudinal population-based study comprising two 5-year follow-up studies: The Danish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (Dan-MONICA) 1 (1982-1987) and Inter99 (1999-2004) recruited from the western part of Copenhagen County. The total study population (n = 7278) was divided into symptom groups according to degree of IBS definition fulfillment at baseline and/or 5-year follow-up and was followed until 31 December 2013 in Danish central registries. Poisson regression was used for the analyses adjusting for age, sex, length of education, comorbidity, cohort membership and mental vulnerability. Results: IBS symptom groups compared to no IBS symptoms were associated with an increased number of contacts with primary and secondary healthcare, as well as weeks on sickness and disability benefits. Accounting for mental vulnerability decreased the estimates and all but two associations between IBS symptom groups and outcomes remained statistically significant. The two associations that became insignificant were contacts with psychiatric hospitals and weeks on disability pension. The excess unadjusted healthcare costs for IBS were 680 Euros per year and the overall association between symptom groups and total healthcare costs were statistically significant. Conclusions: IBS symptoms influence the long-term use and costs of healthcare, as well as the use of social benefits in the general population. Mental vulnerability explained some, but not all, of the use of healthcare and social benefits.

Persistent Physical Symptoms as Perceptual Dysregulation: A Neuropsychobehavioral Model and Its Clinical Implications.

OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear. In this article, we proposed a model for this clinical phenomenon that is designed to be coherent with an underlying, relatively new model of the normal brain functions involved in the experience of bodily signals. METHODS: Based on a review of recent literature, we describe central elements of this model and its clinical implications. RESULTS: In the model, the brain is seen as an active predictive processing or inferential device rather than one that is passively waiting for sensory input. A central aspect of the model is the attempt of the brain to minimize prediction errors that result from constant comparisons of predictions and sensory input. Two possibilities exist: adaptation of the generative model underlying the predictions or alteration of the sensory input via autonomic nervous activation (in the case of interoception). Following this model, persistent physical symptoms can be described as "failures of inference" and clinically well-known factors such as expectation are assigned a role, not only in the later amplification of bodily signals but also in the very basis of symptom perception. CONCLUSIONS: We discuss therapeutic implications of such a model including new interpretations for established treatments as well as new options such as virtual reality techniques combining exteroceptive and interoceptive information.

Effects of two instrument-generation changes on adenoma detection rate during screening colonoscopy: results from a prospective randomized comparative study.

BACKGROUND: Previous studies have shown that multiple colonoscope features have to be changed before an improvement in adenoma detection rate (ADR) becomes obvious, such as with changing from one instrument generation to the next but one. We wanted to evaluate whether such an effect can also be observed in a private-practice screening setting. METHODS: In a randomized study, we compared the latest generation colonoscopes from one company (Olympus Exera III, 190) with the next to last one (Olympus 165), including only patients presenting for screening colonoscopy. The primary outcome was ADR achieved with 190 colonoscopes (190-C) in comparison with 165 colonoscopes (165-C). RESULTS: 1221 patients (46.1 % men; mean age 62.2 years, standard deviation 6.6) were included (599 screened with the Olympus Exera III, 190). The ADR difference in favor of the 190-C instrument (32 % [95 % confidence interval (CI) 26 % to 39 %] vs. 28 % [95 %CI 22 % to 34 %] in the 165-C group) failed to reach statistical significance (P = 0.10); only the rate of small (< 5 mm) adenomas was significantly increased at 22.5 % (95 %CI 19 % to 26 %) vs. 15.6 % (95 %CI 13 % to 18 %; P = 0.002). Furthermore, significantly more adenomas were found in the 190-C group, with an adenoma rate (all adenomas/all patients) of 0.57 (95 %CI 0.53 to 0.61) vs. 0.47 (95 %CI 0.43 to 0.51; P < 0.001). CONCLUSIONS: This randomized comparative trial in a private-practice screening setting only partially confirmed the results of prior studies that, with multiple imaging improvements achieved over two instrument generations, an increase in overall adenoma number becomes measurable.

Diffusion MRI findings in patients with extensive and minimal post-concussion symptoms after mTBI and healthy controls: a cross sectional study.

PRIMARY OBJECTIVES: We hypothesized that the microstructure of the corpus callosum, thalamus and hippocampus, as measured with diffusion and Mean of the Kurtosis Tensor (MKT) MRI, differs between healthy subjects and patients with extensive and minimal post-concussion symptoms (PCS) and that MKT measures correlate with PCS severity and self-reported cognitive symptoms. RESEARCH DESIGN: A cross-sectional study comparing patients with extensive PCS and patients with minimal PCS 2-5 months after mild traumatic brain injury (mTBI) with each other and with an external healthy control group. METHODS AND PROCEDURES: Diffusion MRI was obtained in 25 patients with extensive PCS and in 25 patients with minimal PCS as measured by the Rivermead Post-concussion Symptoms Questionnaire. The patients were matched on age, sex and time since accident. Data from an external healthy control group (n = 27) was included. MAIN OUTCOME AND RESULTS: There was no difference in MKT between the two groups with mTBI and no correlation between MKT and PCS. There was no difference between the three groups in other diffusion measures. CONCLUSIONS: Our results did not point to microstructural changes in the corpus callosum, thalamus and hippocampus in relation to PCS after mTBI.

Psychological Interventions for Children with Functional Somatic Symptoms: A Systematic Review and Meta-Analysis.

OBJECTIVE: To analyze the effectiveness of psychological treatments on symptom load and associated disability in children with functional somatic symptoms, and to explore potential moderators of effects. STUDY DESIGN: Cochrane, PubMed, PsycINFO, EMBASE, and CINAHL were searched for randomized controlled trials published in peer-reviewed journals. Randomized controlled trials studying the effect of a psychological treatment on symptom load and disability in children with functional somatic symptoms were selected. Data on symptom load, disability, and school absence directly post-treatment and at follow-up were extracted by 2 assessors. Studies were appraised with the Cochrane risk of bias tool. Standardized mean differences were pooled in a random-effects model. Heterogeneity in effect-sizes was explored by use of meta-regressions. PROSPERO Registration ID: CRD42015029667. RESULTS: Out of 4098 identified records, 27 studies were included in this review of which 21 were included in meta-analyses. Psychological treatments reduced symptom load (Hedges g = -0.61), disability (Hedges g = -0.42), and school absence (Hedges g = -0.51) post-treatment in children suffering from various functional somatic symptoms. Effects were maintained at follow-up. Type and duration of symptoms, age, and treatment dose did not explain heterogeneity in effect-sizes between studies. Effect-sizes should be interpreted with caution because of the variety in outcome measures, unexplained heterogeneity in found effects and potential publication bias. CONCLUSIONS: Psychological interventions reduce symptom load, disability, and school absence in children with functional somatic symptoms. Future research should clarify which patient and treatment characteristics modify outcomes.

Core Outcome Domains for Clinical Trials on Somatic Symptom Disorder, Bodily Distress Disorder, and Functional Somatic Syndromes: European Network on Somatic Symptom Disorders Recommendations.

OBJECTIVE: The harmonization of core outcome domains in clinical trials facilitates comparison and pooling of data, and simplifies the preparation and review of research projects and comparison of risks and benefits of treatments. Therefore, we provide recommendations for the core outcome domains that should be considered in clinical trials on the efficacy and effectiveness of interventions for somatic symptom disorder, bodily distress disorder, and functional somatic syndromes. METHODS: The European Network on Somatic Symptom Disorders group of more than 20 experts in the field met twice in Hamburg to discuss issues of assessment and intervention research in somatic symptom disorder, bodily distress disorder, and functional somatic syndromes. The consensus meetings identified core outcome domains that should be considered in clinical trials evaluating treatments for somatic symptom disorder and associated functional somatic syndromes. RESULTS: The following core domains should be considered when defining ascertainment methods in clinical trials: a) classification of somatic symptom disorder/bodily distress disorder, associated functional somatic syndromes, and comorbid mental disorders (using structured clinical interviews), duration of symptoms, medical morbidity, and prior treatments; b) location, intensity, and interference of somatic symptoms; c) associated psychobehavioral features and biological markers; d) illness consequences (quality of life, disability, health care utilization, health care costs; e) global improvement and treatment satisfaction; and f) unwanted negative effects. CONCLUSIONS: The proposed criteria are intended to improve synergies of clinical trials and to facilitate decision making when comparing different treatment approaches. These recommendations should not result in inflexible guidelines, but increase consistency across investigations in this field.

Gastrointestinal symptoms related to the irritable bowel syndrome - a longitudinal population-based register study.

OBJECTIVE: Functional gastrointestinal (GI) symptoms can develop into persistent states often categorised as the irritable bowel syndrome (IBS). In the severe end of the GI symptom continuum, other coexisting symptoms are common. We aimed to investigate the GI symptom continuum in relation to mortality and development of GI diseases, and to examine if coexisting symptoms had an influence on the outcomes. MATERIAL AND METHODS: A longitudinal population-based study comprising two 5-year follow-up studies: Dan-Monica1 (1982-1987) and Inter99 (1999-2004). IBS was defined according to a population-based IBS definition. The pooled cohort (n = 7278) was followed until December 2013 in Central Registries. RESULTS: Fifty-one percent had no GI symptoms, 39% had GI symptoms but never fulfilled the IBS definition, 8% had fluctuating IBS and 2% had persisting IBS. There was no significant association between symptom groups and mortality (p = 0.47). IBS and GI symptoms with abdominal pain were significantly associated with development of GI diseases. Only GI symptoms with abdominal pain were associated with development of severe GI diseases (HR: 1.38; 95% CI: [1.06-1.79]). There were no statistically significant interactions between symptom groups and coexisting symptoms in relation to the two outcomes. CONCLUSIONS: GI diseases were seen more frequently, but IBS was not associated with severe GI diseases or increased mortality. Clinicians should be more aware when patients do not fulfil the IBS definition, but continue to report frequent abdominal pain. Coexisting symptoms did not influence mortality and development of GI diseases.

At-line determining spore germination of Penicillium chrysogenum bioprocesses in complex media.

Spore inoculum quality in filamentous bioprocesses is a critical parameter associated with viable spore concentration (1) and spore germination (2). It influences pellet morphology and, consequently, process performance. The state-of-the-art method to measure viable spore concentration is tedious, associated with significant inherent bias, and not applicable in real-time. Therefore, it is not usable as process analytical technology (PAT). Spore germination has so far been monitored using image analysis, which is hampered by complex medium background often observed in filamentous bioprocesses. The method presented here is based on the combination of viability staining and large-particle flow cytometry which enables measurements in real-time and hence aims to be applicable as a PAT tool. It is compatible with the complex media background and allows the quantification of metabolically active spores and the monitoring of spore germination. A distinction of germinated spores and not germinated spores was based on logistic regression, using multiparameteric data from flow cytometry. In a first step, a significant correlation between colony-forming unit (CFU) counts and viable spore concentration (1) in an industrially relevant model bioprocess was found. Spore germination (2) was followed over the initial process phase with close temporal resolution. The validation of the method showed an error below 5 %. Differences in spore germination for various spore inocula ages and spore inoculum concentrations were monitored. The real-time applicability of the method suggests the implementation as a PAT tool in filamentous bioprocesses.

Yeast mating and image-based quantification of spatial pattern formation.

Communication between cells is a ubiquitous feature of cell populations and is frequently realized by secretion and detection of signaling molecules. Direct visualization of the resulting complex gradients between secreting and receiving cells is often impossible due to the small size of diffusing molecules and because such visualization requires experimental perturbations such as attachment of fluorescent markers, which can change diffusion properties. We designed a method to estimate such extracellular concentration profiles in vivo by using spatiotemporal mathematical models derived from microscopic analysis. This method is applied to populations of thousands of haploid yeast cells during mating in order to quantify the extracellular distributions of the pheromone α-factor and the activity of the aspartyl protease Bar1. We demonstrate that Bar1 limits the range of the extracellular pheromone signal and is critical in establishing α-factor concentration gradients, which is crucial for effective mating. Moreover, haploid populations of wild type yeast cells, but not BAR1 deletion strains, create a pheromone pattern in which cells differentially grow and mate, with low pheromone regions where cells continue to bud and regions with higher pheromone levels and gradients where cells conjugate to form diploids. However, this effect seems to be exclusive to high-density cultures. Our results show a new role of Bar1 protease regulating the pheromone distribution within larger populations and not only locally inside an ascus or among few cells. As a consequence, wild type populations have not only higher mating efficiency, but also higher growth rates than mixed MATa bar1Δ/MATα cultures. We provide an explanation of how a rapidly diffusing molecule can be exploited by cells to provide spatial information that divides the population into different transcriptional programs and phenotypes.