Pulmonary Aspergillosis in People with Cystic Fibrosis.

In the last decade, fungal respiratory diseases have been increasingly investigated for their impact on the clinical course of people with cystic fibrosis (CF), with a particular focus on infections caused by Aspergillus spp. The most common organisms from this genus detected from respiratory cultures are Aspergillus fumigatus and Aspergillus terreus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans. These species have been identified to be both chronic colonizers and sources of active infection and may negatively impact lung function in people with CF. This review article discusses definitions of aspergillosis, challenges in clinical practice, and current literature available for laboratory findings, clinical diagnosis, and treatment options for pulmonary diseases caused by Aspergillus spp. in people with CF.

Electrical Cardiometry during transition and short-term outcome in very preterm infants: a prospective observational study.

The purpose of this study is to evaluate the association of Electrical Cardiometry (EC)-derived cardiac output indexed to weight (CO) and its changes during the first 48 h in relation to adverse short-term outcome in very preterm infants. In this prospective observational study of preterm infants < 32 weeks gestational age (GA), the combined adverse outcome was defined as mortality or abnormal cranial ultrasound (any grade intracranial hemorrhage (ICH) or periventricular leukomalacia) within the first 2 weeks postnatally. Logistic regression models were used to investigate the association between median CO and outcome and mixed-effects models for the time trajectory of CO. In the absence of device-specific thresholds for low or high CO, no thresholds were used in our analysis. Fifty-three infants (median (IQR) GA 29.0 (25.4-30.6) weeks, birthweight 1020 (745-1505) g) were included in the analysis. Median CO was 241 (197-275) mL/kg/min for the adverse outcome and 198 (175-227) mL/kg/min for normal outcome (odds ratio (OR) (95% confidence interval (95% CI)), 1.01 (1.00 to 1.03); p = 0.028). After adjustment for GA, the difference was not significant (adjusted OR (95% CI), 1.01 (0.99 to 1.02); p = 0.373). CO trajectory did not differ by outcome (p = 0.352). A post hoc analysis revealed an association between CO time trajectory and ICH ≥ grade 2.          Conclusions: EC-derived CO estimates within 48 h postnatally were not independently associated with brain injury (any grade) or mortality in the first 14 days of life. CO time trajectory was found to be associated with ICH ≥ grade 2. What is Known: • Bioreactance-derived cardiac output indexed to bodyweight (CO) in the transitional period has been associated with adverse short-term outcome in preterm infants. What is New: • Electrical Cardiometry (EC)-derived CO measurements in very preterm infants during the transitional period are not independently associated with adverse outcome (death or ultrasound detected brain damage) within 2 weeks postnatally. • In the first 48 h EC-derived CO increases over time and is higher in extremely preterm infants compared to very preterm and differs from previously reported bioreactance-derived CO values.

Emerging Fungal Threats in Cystic Fibrosis.

In the past three decades, fungal respiratory colonization and fungal respiratory infections increasingly raised concern in cystic fibrosis (CF). Reasons for this are a better knowledge of the pathogenicity of fungi, whereby detection is sought in more and more CF centers, but also improvement of detection methods. However, differences in fungal detection rates within and between geographical regions exist and indicate the need for standardization of mycological examination of respiratory secretions. The still existing lack of standardization also complicates the assessment of fungal pathogenicity, relevance of fungal detection and risk factors for fungal infections. Nevertheless, numerous studies have now been conducted on differences in detection methods, epidemiology, risk factors, pathogenicity and therapy of fungal diseases in CF. Meanwhile, some research groups now have classified fungal disease entities in CF and developed diagnostic criteria as well as therapeutic guidelines.The following review presents an overview on fungal species relevant in CF. Cultural detection methods with their respective success rates as well as susceptibility testing will be presented, and the problem of increasing azole resistance in Aspergillus fumigatus will be highlighted. Next, current data and conflicting evidence on the epidemiology and risk factors for fungal diseases in patients with CF will be discussed. Finally, an overview of fungal disease entities in CF with their current definitions, diagnostic criteria and therapeutic options will be presented.

Hygrophorus sect. Olivaceoumbrini: new boundaries, extended biogeography and unexpected diversity unravelled by transatlantic studies.

As currently delineated, Hygrophorus sect. Olivaceoumbrini is a polyphyletic assembly within subg. Colorati, encompassing glutinous and pigmented taxa. According to available literature, between a dozen and twenty species may belong in the section, mostly represented in continental and boreal forests of Europe and North America. However, the limited phylogenetic and biogeographic coverage of the genus does not presently allow for a reliable assessment of its taxonomic boundaries, nor does it provide a complete picture of species diversity within sect. Olivaceoumbrini. In an ongoing effort to confer an evolutionary backbone to Hygrophorus systematics, we assembled and analysed a dataset comprising 268 intercontinental sequences, including holotypes of 7 taxa previously not positioned phylogenetically, and enriched with collections from largely unexplored Mediterranean and Anatolian ecosystems. Overall, 30 clades are identified within 5 distinct lineages, including 11 species putatively new to science. Seven of these are formally described here as H. agathosmoides, H. albofloccosus, H. canadensis, H. limosus, H. marcocontui, H. pinophilus and H. pustulatoides spp. nov. This enriched coverage of section Olivaceoumbrini s.lat. calls for a re-evaluation of its natural boundaries into a core monophyletic clade, including H. olivaceoalbus and five closely related lookalikes, as well as the assignment of the section rank to the four remaining lineages: sect. Fuscocinerei sect. nov., sect. Limacini sect. nov., sect. Nudolidi sect. nov. and sect. Tephroleuci, respectively. We also stabilize the usage of six historical names, H. glutinifer, H. hyacinthinus, H. mesotephrus, H. olivaceoalbus, H. pustulatus and H. tephroleucus, through designation of two neotypes, three lectotypes and four epitypes. Citation: Bellanger J-M, Lebeuf R, Sesli E, et al. 2021. Hygrophorus sect. Olivaceoumbrini: new boundaries, extended biogeography and unexpected diversity unravelled by transatlantic studies. Persoonia 46: 272-312. https://doi.org/10.3767/persoonia.2021.46.10.

Awareness and accuracy of height and weight among mothers and their preschool-aged children.

OBJECTIVES: A constant challenge in addressing the issue of obesity is the validity and reliability of self-reported measurements to calculate body mass index, that assesses the prevalence of obesity in a population. The objective of this study is to analyze both awareness and accuracy of mothers who are overweight or obese, in reporting their own and their child's height and weight measurements. STUDY DESIGN: cross-sectional study. METHODS: In this study, mothers were asked over phone to self-report height and weight for them and their child. This was followed by objective measurement of maternal and child height and weight by study staff in a clinical setting. The descriptive and statistical analysis of the data obtained were carried out using SAS software. RESULTS: 1) The mean weight of mothers who inaccurately self-reported their weight was 9.5 kg greater than the mean weight of those who reported accurately (P < 0.001). (2) Despite being aware of, and reporting their own measurements, 50% (n = 116) of mothers reported not knowing their child's height and 23% (n = 54) of them reported not knowing their child's weight. CONCLUSION: Strategies to tackle both maternal awareness and accuracy of child's measurements can help with early identification of child's obesity risk and prevention of long-term consequences.

Tau uptake in agrammatic primary progressive aphasia with and without apraxia of speech.

BACKGROUND AND PURPOSE: The non-fluent/agrammatic variant of primary progressive aphasia (agPPA) is a heterogeneous diagnosis wherein some individuals have apraxia of speech (AOS). When agPPA includes AOS, a tauopathy is the likely underlying pathology. Recently, [18F]AV-1451 was developed for the in-vivo assessment of tau. In this study, we compared patterns of tau tracer uptake in patients with agPPA with and without AOS. METHODS: Nine patients with agPPA (four without AOS) underwent tau positron emission tomography imaging with [18F]AV-1451. Uptake of [18F]AV-1451 was assessed as cortical to cerebellar crus ratio (standard uptake value ratio) in cortical regions of interest measured using the MCALT atlas and compared voxel-wise in SPM12. Each patient was age- and sex-matched to three controls. RESULTS: The agPPA without AOS showed uptake in the left frontal and temporal lobes, whereas agPPA with AOS showed uptake in the bilateral supplementary motor areas, frontal lobes, precuneus and precentral gyrus relative to controls. The left precentral gyrus had uptake in agPPA with AOS relative to those without AOS. CONCLUSIONS: This cross-sectional study suggests that [18F]AV-1451 uptake in the precentral gyrus is implicated in AOS in agPPA.

Fungal Pathogens in CF Airways: Leave or Treat?

Chronic airway infection plays an essential role in the progress of cystic fibrosis (CF) lung disease. In the past decades, mainly bacterial pathogens, such as Pseudomonas aeruginosa, have been the focus of researchers and clinicians. However, fungi are frequently detected in CF airways and there is an increasing body of evidence that fungal pathogens might play a role in CF lung disease. Several studies have shown an association of fungi, particularly Aspergillus fumigatus and Candida albicans, with the course of lung disease in CF patients. Mechanistically, in vitro and in vivo studies suggest that an impaired immune response to fungal pathogens in CF airways renders them more susceptible to fungi. However, it remains elusive whether fungi are actively involved in CF lung disease pathologies or whether they rather reflect a dysregulated airway colonization and act as microbial bystanders. A key issue for dissecting the role of fungi in CF lung disease is the distinction of dynamic fungal-host interaction entities, namely colonization, sensitization or infection. This review summarizes key findings on pathophysiological mechanisms and the clinical impact of fungi in CF lung disease.

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

[Cystic fibrosis : A new disease pattern in adult medicine]. / Zystische Fibrose : Ein neues Krankheitsbild in der Erwachsenenmedizin.

Cystic fibrosis (CF) is an inherited incurable multi-organ disease. Improvement in treatment approaches over the last 20 years have led to an increased life expectancy where the number of adult patients has doubled and will continue to increase exponentially. Due to the use of new substances which modulate the basic defect, a substantial improvement in the prognosis can be assumed but the existing healthcare structures in Germany do not meet these rising needs. With more than 50% of patients being adults, there are only very few internal medicine centers available. Only approximately one third of the patients are treated in adult health centers. Adolescence in particular is a very vulnerable phase of the disease, the risk of comorbidities is increased and adherence to the very laborious treatment recommendations is as a rule low. While in many other countries transition programs have been evaluated and implemented for more than 20 years, in Germany there have only been rudimentary approaches to transition. Meanwhile investigations are available on the perceptions of adolescents with respect to coping with the disease and their treatment needs, including the perception of the time when the transition process should begin. Successful transition seems to be performed best in combined pediatric and adult centers, with the back-up of an experienced multidisciplinary team of healthcare providers.

Regulatory T Cells Promote Natural Killer Cell Education in Mixed Chimeras.

Therapeutic administration of regulatory T cells (Tregs) leads to engraftment of conventional doses of allogeneic bone marrow (BM) in nonirradiated recipient mice conditioned with costimulation blockade and mammalian target of rapamycin inhibition. The mode of action responsible for this Treg effect is poorly understood but may encompass the control of costimulation blockade-resistant natural killer (NK) cells. We show that transient NK cell depletion at the time of BM transplantation led to BM engraftment and persistent chimerism without Treg transfer but failed to induce skin graft tolerance. In contrast, the permanent absence of anti-donor NK reactivity in mice grafted with F1 BM was associated with both chimerism and tolerance comparable to Treg therapy, implying that NK cell tolerization is a critical mechanism of Treg therapy. Indeed, NK cells of Treg-treated BM recipients reshaped their receptor repertoire in the presence of donor MHC in a manner suggesting attenuated donor reactivity. These results indicate that adoptively transferred Tregs prevent BM rejection, at least in part, by suppressing NK cells and promote tolerance by regulating the appearance of NK cells expressing activating receptors to donor class I MHC.

MRI of cystic fibrosis lung manifestations: sequence evaluation and clinical outcome analysis.

AIM: To evaluate different magnetic resonance imaging (MRI) sequences for diagnosis of pulmonary manifestations of cystic fibrosis (CF) in comparison to chest computed tomography (CT), including an extended outcome analysis. MATERIALS AND METHODS: Twenty-eight patients with CF (15 male, 13 female, mean age 30.5±9.4 years) underwent CT and MRI of the lung. MRI (1.5 T) included different T2- and T1-weighted sequences: breath-hold HASTE (half Fourier acquisition single shot turbo spin echo) and VIBE (volumetric interpolated breath-hold examination, before and after contrast medium administration) sequences and respiratory-triggered PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) sequences with and without fat signal suppression, and perfusion imaging. CT and MRI images were evaluated by the modified Helbich and the Eichinger scoring systems. The clinical follow-up analysis assessed pulmonary exacerbations within 24 months. RESULTS: The highest concordance to CT was achieved for the PROPELLER sequences without fat signal suppression (concordance correlation coefficient CCC of the overall modified Helbich score 0.93 and of the overall Eichinger score 0.93). The other sequences had the following concordance: PROPELLER with fat signal suppression (CCCs 0.91 and 0.92), HASTE (CCCs 0.87 and 0.89), VIBE (CCCs 0.84 and 0.85) sequences. In the outcome analysis, the combined MRI analysis of all five sequences and a specific MRI protocol (PROPELLER without fast signal suppression, VIBE sequences, perfusion imaging) reached similar correlations to the number of pulmonary exacerbations as the CT examinations. CONCLUSION: An optimum lung MRI protocol in patients with CF consists of PROPELLER sequences without fat signal suppression, VIBE sequences, and lung perfusion analysis to enable high diagnostic efficacy and outcome prediction.

The Immunosuppressive Effect of CTLA4 Immunoglobulin Is Dependent on Regulatory T Cells at Low But Not High Doses.

B7.1/2-targeted costimulation blockade (CTLA4 immunoglobulin [CTLA4-Ig]) is available for immunosuppression after kidney transplantation, but its potentially detrimental impact on regulatory T cells (Tregs) is of concern. We investigated the effects of CTLA4-Ig monotherapy in a fully mismatched heart transplant model (BALB/c onto C57BL/6). CTLA4-Ig was injected chronically (on days 0, 4, 14, and 28 and every 4 weeks thereafter) in dosing regimens paralleling clinical use, shown per mouse: low dose (LD), 0.25 mg (≈10 mg/kg body weight); high dose (HD), 1.25 mg (≈50 mg/kg body weight); and very high dose (VHD), 6.25 mg (≈250 mg/kg body weight). Chronic CTLA4-Ig therapy showed dose-dependent efficacy, with the LD regimen prolonging graft survival and with the HD and VHD regimens leading to >95% long-term graft survival and preserved histology. CTLA4-Ig's effect was immunosuppressive rather than tolerogenic because treatment cessation after ≈3 mo led to rejection. FoxP3-positive Tregs were reduced in naïve mice to a similar degree, independent of the CTLA4-Ig dose, but recovered to normal values in heart recipients under chronic CTLA4-Ig therapy. Treg depletion (anti-CD25) resulted in an impaired outcome under LD therapy but had no detectable effect under HD therapy. Consequently, the immunosuppressive effect of partially effective LD CTLA4-Ig therapy is impaired when Tregs are removed, whereas CTLA4-Ig monotherapy at higher doses effectively maintains graft survival independent of Tregs.

Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade.

The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.

Surgical resection of metastases to the adrenal gland: a single center experience.

BACKGROUND: Only limited data exist on the treatment and outcome of adrenal metastases that derive from different primary tumor entities. Due to the lack of evidence, it is difficult to determine the indication for surgical resection. METHODS: We assessed the outcome of 45 patients (28 men, 17 women) with adrenal metastases who underwent surgery (1990-2014). The median age at the time of adrenal surgery was 62 years (range 44-77 years). We were able to evaluate follow-up data of 41 patients. RESULTS: Primary tumor types were liver n = 12 (hepatocellular carcinoma n = 9, cholangiocellular carcinoma n = 2, sarcoma n = 1), upper GI tract n = 5 (esophagus n = 2, stomach n = 3), lung n = 9, kidney n = 6, neuroendocrine tumors n = 3, colon n = 2, ovarial n = 2, melanoma n = 2, others n = 4. The overall median survival time was 14 months (95 % CI 8.375-19.625). The survival rates at 1, 2, 5, and 10 years were 60, 31, 21, and 11 %, respectively. There were statistically significant differences in the survival time according to the resection status (R0 vs. R1/R2) (p < 0.001) and the type of the primary tumor (p = 0.009), while the metachronous or synchronous occurrence of adrenal metastases did not affect the prognosis. CONCLUSIONS: Resection of adrenal metastases can improve the survival if patients are carefully selected, the tumor is completely resected, and the intervention is integrated into a multidisciplinary oncologic treatment strategy.

Phytate in pig and poultry nutrition.

Phosphorus (P) is primarily stored in the form of phytates in plant seeds, thus being poorly available for monogastric livestock, such as pigs and poultry. As phytate is a polyanionic molecule, it has the capacity to chelate positively charged cations, especially calcium, iron and zinc. Furthermore, it probably compromises the utilization of other dietary nutrients, including protein, starch and lipids. Reduced efficiency of utilization implies both higher levels of supplementation and increased discharge of the undigested nutrients to the environment. The enzyme phytase catalyses the stepwise hydrolysis of phytate. In respect to livestock nutrition, there are four possible sources of this enzyme available for the animals: endogenous mucosal phytase, gut microfloral phytase, plant phytase and exogenous microbial phytase. As the endogenous mucosal phytase in monogastric organisms appears incapable of hydrolysing sufficient amounts of phytate-bound P, supplementation of exogenous microbial phytase in diets is a common method to increase mineral and nutrient absorption. Plant phytase activity varies greatly among species of plants, resulting in differing gastrointestinal phytate hydrolysis in monogastric animals. Besides the supplementation of microbial phytase, processing techniques are alternative approaches to reduce phytate contents. Thus, techniques such as germination, soaking and fermentation enable activation of naturally occurring plant phytase among others. However, further research is needed to tap the potential of these technologies. The main focus herein is to review the available literature on the role of phytate in pig and poultry nutrition, its degradation throughout the gut and opportunities to enhance the utilization of P as well as other minerals and nutrients which might be complexed by phytates.

Gender-specific effects of a phytogenic feed additive on performance, intestinal physiology and morphology in broiler chickens.

To date, most studies published were carried out on broilers of the same sex, and possible gender-specific effects of phytogenic substances have not been investigated so far. A 3 × 2 factorial study was performed to examine gender-specific effects of a PFA at two dietary levels (150, 1500 ppm) on growth performance, carcass traits and gastrointestinal attributes in broiler chickens versus an untreated control group. The addition of 150 ppm of the PFA led to a downregulation of trypsinogen mRNA in pancreas compared with the control group (p < 0.05). The number of goblet cells decreased in jejunum compared with the unsupplemented group, whereby this effect was more pronounced in male birds (p < 0.05). Furthermore, higher methylamine contents compared with the control group were measured (p < 0.01). In proximal ileum, female birds, supplemented with 150 ppm PFA, had lower crypt depths than their litters in the 1500 ppm treatment (p < 0.05). In distal ileum, villus height:crypt depth ratio was higher in birds fed the PFA at 150 ppm than in the control group (p < 0.05). The 1500 ppm dosage of the PFA increased jejunal histamine concentration compared with the negative control group (p < 0.05). Jejunal histamine concentration was also affected by the interaction PFA × sex (p < 0.05). Regardless of inclusion level, total amount of biogenic amines and other microbial metabolites in digesta samples was not affected by the PFA. These results demonstrate variable, partially gender-specific effects of the tested PFA. Although the supplementation of 150 ppm showed little effect on mRNA expression level of selected marker genes for nutrient digestion, beneficial effects on gut morphology were observed. The 10-fold higher dosage of the PFA did not adversely affect growth performance as well as most investigated parameters compared with the control group.

[Foetal Mortality in Singleton Foetuses at and beyond Term - An Analysis of German Perinatal Data 2004-2013]. / Fetale Mortalität bei Einlingen ab Termin - eine Analyse bundesdeutscher Perinataldaten 2004-2013.

BACKGROUND: Foetal mortality appears to increase in postmature pregnancies. There is debate on the optimal timing of induction of labour vs. watchful waiting. The literature on retrospective analyses of secondary data is inconclusive. Different approaches to calculate foetal risk exist. Recent and relevant data are needed in order to realise an appropriate discussion. MATERIAL AND METHODS: Mortality in singleton foetuses in Germany, between 2004 and 2013 was analysed in relation to gestational age. Risk for foetal death is described comparing stillbirths per 1,000 births at a particular gestational age (GA) vs. stillbirths per 1,000 ongoing pregnancies ("fetus-at-risk" model). Access to German routine perinatal data was granted. We included all stillbirths in singleton foetuses with no malformations after 36+6 weeks gestational age from 2004 until 2013. RESULTS: 5,933,117 births fulfilled our inclusion criteria. Foetal mortality per 1,000 births during that week of pregnancy is lowest between 41+0 and 41+6 days of (0.7/1,000). Mortality then increases to 2.3/1,000 in 42+0 to 42+6 GA. With the "fetus-at-risk" model, mortality is low between 37+0 and 39+6 GA, ranging from 0.2/1,000 ongoing pregnancies, increasing to 0.6/1,000 between 41+0 and 41+6, and 2.3/1,000 in the following week. For pregnancies lasting longer than 42+6 weeks, the stillbirth risk is identical at 6.3/1,000 with both calculation methods. CONCLUSION: Fetal mortality is low until 41+6 weeks of pregnancy. Interpretation of current data does not support a policy of routine IOL before this gestational age in singleton foetuses.

[Cystic fibrosis and associated complications]. / Zystische Fibrose und ihre Komplikationen.

Cystic fibrosis (CF) is an autosomal recessive inherited metabolic disease. The mutation is located on the long arm of chromosome 7. Due to a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, chloride ion transport is reduced across the cell membrane. As a result, the disease can be described as an exocrinopathy. In all organs with exocrine glands, disorders occur in association with the defective chloride transport. The main impact of this defect is manifested in the lungs. Therefore, the most common cause of death is pulmonary disease with respiratory insufficiency due to recurrent infections. Unfortunately, a cure for the disease is still not available. However, new therapies that may affect the CFTR mutation more specifically give new hope for better therapeutic options in the future. The long-term goal of therapy is to develop a causal therapy for all six different mutation classes and thus for about 2000 mutations.

Impact of proton pump inhibitor use on magnesium homoeostasis: a cross-sectional study in a tertiary emergency department.

BACKGROUND: To date, the use of proton pump inhibitors (PPIs) has been associated with a low risk of hypomagnesaemia and associated adverse outcomes. We hypothesised that a better risk estimate could be derived from a large cohort of outpatients admitted to a tertiary emergency department (ED). METHODS: A cross-sectional study was performed in 5118 patients who had measurements of serum magnesium taken on admission to a large tertiary care ED between January 2009 and December 2010. Hypomagnesaemia was defined as a serum magnesium concentration < 0.75 mmol/l. Demographical data, serum electrolyte values, data on medication, comorbidities and outcome with regard to length of hospital stay and mortality were analysed. RESULTS: Serum magnesium was normally distributed where upon 1246 patients (24%) were hypomagnesaemic. These patients had a higher prevalence of out-of-hospital PPI use and diuretic use when compared with patients with magnesium levels > 0.75 mmol/l (both p < 0.0001). In multivariable regression analyses adjusted for PPIs, diuretics, renal function and the Charlson comorbidity index score, the association between use of PPIs and risk for hypomagnesaemia remained significant (OR = 2.1; 95% CI: 1.54-2.85). While mortality was not directly related to low magnesium levels (p = 0.67), the length of hospitalisation was prolonged in these patients even after adjustment for underlying comorbid conditions (p < 0.0001). CONCLUSION: Use of PPIs predisposes patients to hypomagnesaemia and such to prolonged hospitalisation irrespective of the underlying morbidity, posing a critical concern.

Transcriptional remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

The molecular mechanisms that drive essential developmental patterning events in the mammalian embryo remain poorly understood. To generate a conceptual framework for gene regulatory processes during germ layer specification, we analyzed transcription factor (TF) expression kinetics around gastrulation and during in vitro differentiation. This approach identified Otx2 as a candidate regulator of definitive endoderm (DE), the precursor of all gut- derived tissues. Analysis of multipurpose degron alleles in gastruloid and directed differentiation models revealed that loss of OTX2 before or after DE specification alters the expression of core components and targets of specific cellular signaling pathways, perturbs adhesion and migration programs as well as de-represses regulators of other lineages, resulting in impaired foregut specification. Key targets of OTX2 are conserved in human DE. Mechanistically, OTX2 is required to establish chromatin accessibility at candidate enhancers, which regulate genes critical to establishing an anterior cell identity in the developing gut. Our results provide a working model for the progressive establishment of spatiotemporal cell identity by developmental TFs across germ layers and species, which may facilitate the generation of gut cell types for regenerative medicine applications.