Search

Objective: RSV bronchiolitis is a leading cause of hospitalization in infants and young children. We aimed to document the economic burden and epidemiology of RSV over seven seasons in Southern Austria. Patients and Methods: All RSV‐associated hospitalized (PCR‐proven) children ≤ 5 years of age between 1 October 2015 and 30 April 2022 were collected retrospectively. Demographic and epidemiologic data, along with hospitalization costs (direct and indirect), were calculated. Results: Among 976 children hospitalized due to RSV infection, 87% were healthy term infants, and 79% were < 12 months old. Prematurity (13%) and pre‐existing conditions (11%) significantly impacted older children—59% of cases in the 2nd compared with 68% in the 1st year of live. RSV‐related hospital costs were approximately €2.0 millions per year (of a total of 60 millions per year). RSV accounted for 19% of hospitalizations due to acute respiratory illness (ARI) in children ≤ 5 years, 37% of all ARI < 6 months, 28% of all ARI < 12 and 6.3% of all‐cause hospitalizations < 12 months of age, respectively. Conclusions: Every 5th hospitalization due to respiratory illness in children ≤ 5 years of age was associated with RSV, representing 7.9% of all hospitalizations and 3.3% of all paediatric hospitalization costs. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to determine the burden of respiratory syncytial virus (RSV) and influenza disease during the COVID-19 pandemic at 2 Austrian urban pediatric centers between October 1, 2019 and April 30, 2022., Methods: We performed a retrospective observational 2-center study on RSV- and influenza virus-associated hospitalizations in infants and children up to 18 years at the University Hospital of Graz and the Clinic Donaustadt of Vienna from October 1, 2019 to April 30, 2022. Hospitalization had to be associated with the infectious disease, proven by polymerase chain reaction, including presence of respiratory symptoms. Demographic data including underlying diseases and treatment strategies were compared between centers and diseases, respectively., Results: There were 826 cases in Graz and 379 in Vienna with significant more RSV cases in Graz and more influenza cases in Vienna (RSV: 76% vs. 59%, influenza: 24% vs. 41%; both P < 0.001). One death occurred in Graz due to RSV and another due to influenza in Vienna. Seasonality only slightly differed between centers and severity of diseases was not aggravated when measured by pediatric intensive care unit admission rates, need for supplemental oxygen and respiratory support between first and last seasons. Treatment regimen differed regarding higher use of antibiotics and rates of intravenous fluids in Vienna compared to higher rates of bronchodilators, corticosteroids and nose drops in Graz., Conclusions: We observed higher numbers of hospitalizations due to both viruses after the lockdown but not increased severity of the diseases; and mortality remained extremely low. Preventive measures should be implemented with high priority especially focused on infants with underlying diseases., Competing Interests: H.K. received honoraria for oral presentations and travel support from AstraZeneca and Abbvie and Milupa (Danone). G.S.-Y. received honoraria from Sanofi. E.R. received travel support from Milupa (Danone). C.V.K., C.G. and L.T. have no conflicts of interest to disclose. B.R. received honoraria for oral presentations and travel support from Milupa (Danone), Nestle, Germania, Abbvie, AstraZeneca, Sanofi, GSK and Chiesi., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Diagnosis of neonatal sepsis is difficult due to nonspecific signs and symptoms. Interleukin-6 (IL-6) is a promising marker for neonatal sepsis. We aimed to test the accuracy of IL-6 in neonates after 72 h of life in case of late onset sepsis (LOS). We searched for studies regarding IL-6 accuracy for the diagnosis of LOS between 1990 and 2020 using the PubMed database. Following study selection, the reported IL-6 sensitivities and specificities ranged between 68% and 100% and 28% and 100%, with median values of 85.7% and 82% and pooled values of 88% and 78% (respectively) in the 15 studies including 1306 infants. Subgroup analysis revealed a better sensitivity (87% vs. 82%), but not specificity (both 86%), in preterm infants compared to term infants or mixed populations. Early sample collection revealed the highest sensitivity (84%), but had the lowest specificity (86%). To assess quality, we used a STARD checklist adapted for septic neonates and the QUADAS criteria. Limitations of this review include the heterogeneous group of studies on the one side and the small number of studies on the other side that analyzed different combinations of biomarkers. We concluded that IL-6 demonstrated good performance especially in the preterm infant population and the best results were achieved by measurements at the time of LOS suspicion.

Background: The COVID-19 pandemic challenged the management of technical and human resources in intensive care units (ICU) across the world. Several long-term predictors for COVID-19 disease progression have been discovered. However, predictors to support short-term planning of resources and medication that can be translated to future pandemics are still missing. A workflow was established to identify a predictor for short-term COVID-19 disease progression in the acute phase of intensive care patients to support clinical decision-making., Methods: Thirty-two patients with SARS-CoV-2 infection were recruited on admission to the ICU and clinical data collected. During their hospitalization, plasma samples were acquired from each patient on multiple occasions, excepting one patient for which only one time point was possible, and the proteome (Inflammation, Immune Response and Organ Damage panels from Olink® Target 96), metabolome and lipidome (flow injection analysis and liquid chromatography-mass spectrometry) analyzed for each sample. Patient visits were grouped according to changes in disease severity based on their respiratory and organ function, and evaluated using a combination of statistical analysis and machine learning. The resulting short-term predictor from this multi-omics approach was compared to the human assessment of disease progression. Furthermore, the potential markers were compared to the baseline levels of 50 healthy subjects with no known SARS-CoV-2 or other viral infections., Results: A total of 124 clinical parameters, 271 proteins and 782 unique metabolites and lipids were assessed. The dimensionality of the dataset was reduced, selecting 47 from the 1177 parameters available following down-selection, to build the machine learning model. Subsequently, two proteins (C-C motif chemokine 7 (CCL7) and carbonic anhydrase 14 (CA14)) and one lipid (hexosylceramide 18:2; O2/20:0) were linked to disease progression in the studied SARS-CoV-2 infections. Thus, a predictor delivering the prognosis of an upcoming worsening of the patient's condition up to five days in advance with a reasonable accuracy (79 % three days prior to event, 84 % four to five days prior to event) was found. Interestingly, the predictor's performance was complementary to the clinicians' capabilities to foresee a worsening of a patient., Conclusion: This study presents a workflow to identify omics-based biomarkers to support clinical decision-making and resource management in the ICU. This was successfully applied to develop a short-term predictor for aggravation of COVID-19 symptoms. The applied methods can be adapted for future small cohort studies., Competing Interests: Declaration of competing interest ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p < 0.001), a higher clinical global impression scale score (p = 0.030), and a higher risk for suicide (p = 0.032). Medication status did not influence protein levels significantly (p ≥ 0.074), but psychotropic co-medication (p ≤ 0.009) did. In conclusion, our data suggest the presence of two distinct biotypes in adults with ADHD. Higher levels of inflammatory proteins in ADHD are linked to higher levels of chronic perceived stress in a linear fashion. Further research on inflammation in adults with ADHD should take stress levels into account., (© 2024. The Author(s).)

The definitive diagnosis and early treatment of many immune-mediated inflammatory diseases (IMIDs) is hindered by variable and overlapping clinical manifestations. Psoriatic arthritis (PsA), which develops in ~30% of people with psoriasis, is a key example. This mixed-pattern IMID is apparent in entheseal and synovial musculoskeletal structures, but a definitive diagnosis often can only be made by clinical experts or when an extensive progressive disease state is apparent. As with other IMIDs, the detection of multimodal molecular biomarkers offers some hope for the early diagnosis of PsA and the initiation of effective management and treatment strategies. However, specific biomarkers are not yet available for PsA. The assessment of new markers by genomic and epigenomic profiling, or the analysis of blood and synovial fluid/tissue samples using proteomics, metabolomics and lipidomics, provides hope that complex molecular biomarker profiles could be developed to diagnose PsA. Importantly, the integration of these markers with high-throughput histology, imaging and standardized clinical assessment data provides an important opportunity to develop molecular profiles that could improve the diagnosis of PsA, predict its occurrence in cohorts of individuals with psoriasis, differentiate PsA from other IMIDs, and improve therapeutic responses. In this review, we consider the technologies that are currently deployed in the EU IMI2 project HIPPOCRATES to define biomarker profiles specific for PsA and discuss the advantages of combining multi-omics data to improve the outcome of PsA patients.

A causal contribution of hyperhomocysteinemia to cognitive decline and Alzheimer's disease (AD), as well as potential prevention or mitigation of the pathology by dietary intervention, have frequently been subjects of controversy. In the present in vivo study, we attempted to further elucidate the impact of elevated homocysteine (HCys) and homocysteic acid (HCA) levels, induced by dietary B-vitamin deficiency, and micronutrient supplementation on AD-like pathology, which was simulated using the amyloid-based App NL-G-F knock-in mouse model. For this purpose, cognitive assessment was complemented by analyses of ex vivo parameters in whole blood, serum, CSF, and brain tissues from the mice. Furthermore, neurotoxicity of HCys and HCA was assessed in a separate in vitro assay. In confirmation of our previous study, older App NL-G-F mice also exhibited subtle phenotypic impairment and extensive cerebral amyloidosis, whereas dietary manipulations did not result in significant effects. As revealed by proximity extension assay-based proteome analysis, the App NL-G-F genotype led to an upregulation of AD-characteristic neuronal markers. Hyperhomocysteinemia, in contrast, indicated mainly vascular effects. Overall, since there was an absence of a distinct phenotype despite both a significant amyloid-β burden and serum HCys elevation, the results in this study did not corroborate the pathological role of amyloid-β according to the "amyloid hypothesis," nor of hyperhomocysteinemia on cognitive performance. Nevertheless, this study aided in further characterizing the App NL-G-F model and in elucidating the role of HCys in diverse biological processes. The idea of AD prevention with the investigated micronutrients, however, was not supported, at least in this mouse model of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nieraad, de Bruin, Arne, Hofmann, Pannwitz, Resch, Luckhardt, Schneider, Trautmann, Schreiber, Gurke, Parnham, Till and Geisslinger.)

This is a narrative review on the role of biomarkers in the diagnosis of neonatal sepsis. We describe the difficulties to obtain standardized definitions in neonatal sepsis and discuss the limitations of published evidence of cut-off values and their sensitivities and specificities. Maternal risk factors influence the results of inflammatory markers as do gestational age, the time of sampling, the use of either cord blood or neonatal peripheral blood, and some non-infectious causes. Current evidence suggests that the use of promising diagnostic markers such as CD11b, CD64, IL-6, IL-8, PCT, and CRP, either alone or in combination, might enable clinicians discontinuing antibiotics confidently within 24-48 h. However, none of the current diagnostic markers is sensitive and specific enough to support the decision of withholding antibiotic treatment without considering clinical findings. It therefore seems to be justified that antibiotics are often initiated in ill term and especially preterm infants. Early markers like IL-6 and later markers like CRP are helpful in the diagnosis of neonatal sepsis considering the clinical aspect of the neonate, the gestational age, maternal risk factors and the time (age of the neonate regarding early-onset sepsis) of blood sampling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Eichberger, Resch and Resch.)

Although great progress has been made to advance the scientific understanding of oil spills, tools for integrated assessment modeling of the long-term impacts on ecosystems, socioeconomics and human health are lacking. The objective of this study was to develop a conceptual framework that could be used to answer stakeholder questions about oil spill impacts and to identify knowledge gaps and future integration priorities. The framework was initially separated into four knowledge domains (ocean environment, biological ecosystems, socioeconomics, and human health) whose interactions were explored by gathering stakeholder questions through public engagement, assimilating expert input about existing models, and consolidating information through a system dynamics approach. This synthesis resulted in a causal loop diagram from which the interconnectivity of the system could be visualized. Results of this analysis indicate that the system naturally separates into two tiers, ocean environment and biological ecosystems versus socioeconomics and human health. As a result, ocean environment and ecosystem models could be used to provide input to explore human health and socioeconomic variables in hypothetical scenarios. At decadal-plus time scales, the analysis emphasized that human domains influence the natural domains through changes in oil-spill related laws and regulations. Although data gaps were identified in all four model domains, the socioeconomics and human health domains are the least established. Considerable future work is needed to address research gaps and to create fully coupled quantitative integrative assessment models that can be used in strategic decision-making that will optimize recoveries from future large oil spills.

We performed a retrospective case-control cohort study following 146 preterm infants (≤32 weeks of gestation) who had been colonized with extended spectrum beta-lactamase producing Enterobacterales and compared them with 1:1 matched controls regarding rates of hospitalizations and outpatient visits because of infectious and gastrointestinal diseases and developmental impairment up to school age. Preterm infants with extended spectrum beta-lactamase producing Enterobacterales colonization did have neither higher rates of gastrointestinal or infectious diseases nor higher rates of developmental impairments up to the age of 6 years., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to identify alternative anti-inflammatory compounds that modulate the activity of a relevant transcription factor, CCAAT/enhancer binding protein delta (C/EBPδ). C/EBPδ is a master regulator of inflammatory responses in macrophages (Mϕ) and is mainly regulated at the level of CEBPD gene transcription initiation. To screen for CEBPD -modulating compounds, we generated a THP-1-derived reporter cell line stably expressing secreted alkaline phosphatase (SEAP) under control of the defined CEBPD promoter ( CEBPD::SEAP ). A high-throughput screening of LOPAC ®1280 and ENZO ®774 libraries on LPS- and IFN-γ-activated THP-1 reporter Mϕ identified four epigenetically active hits: two bromodomain and extraterminal domain (BET) inhibitors, I-BET151 and Ro 11-1464, as well as two histone deacetylase (HDAC) inhibitors, SAHA and TSA. All four hits markedly and reproducibly upregulated SEAP secretion and CEBPD::SEAP mRNA expression, confirming screening assay reliability. Whereas BET inhibitors also upregulated the mRNA expression of the endogenous CEBPD , HDAC inhibitors completely abolished it. All hits displayed anti-inflammatory activity through the suppression of IL-6 and CCL2 gene expression. However, I-BET151 and HDAC inhibitors simultaneously upregulated the mRNA expression of pro-inflammatory IL-1ß . The modulation of CEBPD gene expression shown in this study contributes to our understanding of inflammatory responses in Mϕ and may offer an approach to therapy for inflammation-driven disorders.

Purpose: Microbial dysbiosis has been found preceding necrotizing enterocolitis (NEC) in preterm infants; thus, we aimed to investigate whether there is evidence that neonates with extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) positive stool cultures are at higher risk for NEC at the NICU., Methods: We included very preterm inborn infants of ≤ 32 weeks of gestational age being fecal carriers of ESBL-E and compared them with 1:1 matched (gestational age, birth weight, gender and year) controls tested negative for ESBL-E in the stool between 2005 and 2016. An association with NEC was defined as the first detection of ESBL-E before or at the time of definite diagnosis of NEC., Results: During the study period, we diagnosed 217 infants with a total of 270 ESBL-E. We identified ten different species with ESBL-producing Klebsiella oxytoca being the most common one (46%) followed by Klebsiella pneumoniae (19%), and Citrobacter freundii (17%). Ten out of 217 infants had any kind of NEC in the case group compared to two of the controls (p < 0.01), but only four cases with predefined criteria were associated with NEC ≥ stage IIa (1.8 vs. 0.5%, p = 0.089, OR 4.1, CI95% 0.45-36.6). NEC mortality rate was 2/8 (25%)., Conclusions: We observed a threefold increase of ESBL-E in stool surveillance cultures during study time and germs were dominated by ESBL-producing Klebsiella spp. There was no evidence that preterm infants colonized with ESBL-E in the stool were at higher risk for definite NEC.

Extracellular vesicles (EVs) are active components of red blood cell (RBC) concentrates and may be associated with beneficial and adverse effects of transfusion. Elucidating controllable factors associated with EV release in RBC products is thus important to better manage the quality and properties of RBC units. Erythrocyte-derived EVs (EEVs) and platelet-derived EVs (PEVs) were counted in 1226 RBC units (administered to 280 patients) using a standardized cytometry-based method. EV size and CD47 and annexin V expression were also measured. The effects of donor characteristics, processing methods, and storage duration on EV counts were analyzed by using standard comparison tests, and analysis of covariance was used to determine factors independently associated with EV counts. PEV as well as EEV counts were higher in whole-blood-filtered RBC units compared with RBC-filtered units; PEV counts were associated with filter type (higher with filters associated with higher residual platelets), and CD47 expression was higher on EEVs in RBC units stored longer. Multivariate analysis showed that EEV counts were strongly associated with filter type (P < .0001), preparation, and storage time (+25.4 EEV/µL per day [P = .01] and +42.4 EEV/µL per day [P < .0001], respectively). The only independent factor associated with PEV counts was the residual platelet count in the unit (+67.1 PEV/µL; P < .0001). Overall, processing methods have an impact on EV counts and characteristics, leading to large variations in EV quantities transfused into patients. RBC unit processing methods might be standardized to control the EV content of RBC units if any impacts on patient outcomes can be confirmed. The IMIB (Impact of Microparticles in Blood) study is ancillary to the French ABLE (Age of Transfused Blood in Critically Ill Adults) trial (ISRCTN44878718)., (© 2020 by The American Society of Hematology.)

Short linear motifs (SLiMs) drive dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN)/PP2B, the Ca 2+ -activated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in vivo SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including NOTCH1, which we establish as a CN substrate. Unexpectedly, CN shows SLiM-dependent proximity to centrosomal and nuclear pore complex (NPC) proteins-structures where Ca 2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear transport reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca 2+ and CN signaling and demonstrates synergy between experimental and computational methods, establishing a blueprint for examining SLiM-based networks., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1 , ASIC2 , ASIC3 , ASIC4 , TRPA1 , TRPC1 , TRPM2 , TRPM3 , TRPM4 , TRPM5 , TRPM8 , TRPV1 , TRPV2 , TRPV3, and TRPV4 . Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.

Objective: The aim of this study was to determine the respiratory syncytial virus (RSV) epidemiology and to analyze the influence of risk factors and coinfections over the last years., Methods: Retrospectively all infants, children and adolescents hospitalized due to respiratory disease with positive RSV test [hospitalized for RSV infection (RSV-H)] between January 1, 2009, and December 31, 2015, at a tertiary care center in the southern part of Austria were included for analysis. Patients were all identified by a search via International Classification of Diseases and Related Health Problems, 10th Edition codes, and all medical data were collected from the local electronic databases called openMedocs. RSV tests had to prove true infection case definition., Results: During a 7-year study period, 745 infants, children and adolescents exhibited RSV-H. Main diagnosis was bronchiolitis (70%). Nearly half of all cases (44%) were born during the first half of the RSV season (November-January), and seasonal peak of RSV-H was in January. Predominant underlying condition was history of prematurity in 15% followed by neurologic impairment (3.5%) and hemodynamically significant congenital heart disease (2.95%). Age ≤2 months and underlying conditions/morbidities were associated with more severe disease. The majority of cases (96%) had an age below 24 months, and 91% below 12 months. Viral coinfection (most common influenza virus, adenovirus and rhinovirus) was diagnosed in 37 cases (5%) resulting in a more severe course of disease. Main risk factors of coinfection were siblings and crowding. Mortality was 0.27% (2/745). Both children had coinfection with influenza A virus and were multihandicapped (15 and 20 years of age, respectively)., Conclusions: Prematurity and underlying morbidities play a marked role in RSV-H. Viral coinfections aggravated disease with death in 2 multihandicapped adolescents.

Background: ECMO therapy is worldwide declining in the neonatal population; hence, its therapeutic value is sometimes questioned. Objectives: To report our experience with neonatal ECMO due to respiratory failure over a 28 year time period. Methods: Retrospective single center observational study including all neonates admitted to ECMO due to respiratory failure between 1989 and 2016 at Graz, Austria. Data were collected regarding survival rate, duration of ECMO, complications, length of hospital stay, changes over time, and follow-up. Results: Sixty-seven neonates were admitted and 43 (64%) needed ECMO-median birth weight 3390 grams (range 1810-4150) and gestational age 39 weeks (32-43). Survival rate was 65% (28/43); with higher rates in meconium aspiration syndrome (MAS) 89% vs. congenital diaphragmatic hernia (CDH) 46% and septic shock 44% ( p = 0.005 and p = 0.006, respectively). ECMO duration was median 5 days (1-30) and veno-arterial ECMO (52%) dominated. Need for ECMO therapy decreased over time ( p < 0.001). Complications occurred in 31 (72%) neonates. Five neonates had cerebral hemorrhages (11.4%) and four had cerebral infarction (9.1%). Of 26 survivors 17 (65%) showed normal neurodevelopmental outcome at median follow-up of 73 months. Motor deficits were present in one case, cognitive deficits in 9 (35%). Median length of hospital stay was 78 days in those with deficits and 29 in those with normal neurodevelopmental outcome ( p < 0.001). Conclusions: Survival rate did not change over the study time but indications for ECMO did. Cognitive impairment was the major long-term deficit following neonatal ECMO being associated with longer hospital stay.

We evaluated the causes for neonatal thrombocytopenia (NT), the duration of NT, and the indications of platelet transfusions (PT) by means of a retrospective cohort study over a 23-year period. Neonates with NT were identified via ICD-10 code D69.6. Of 371 neonates (1.8/1000 live births) with NT, the majority (312; 84.1%) had early onset thrombocytopenia, and 282 (76%) were preterm born. The most frequent causes for NT were early and late onset sepsis and asphyxia. The mean duration of thrombocytopenia was 10.2 days and was negatively correlated (KK = - 0.35) with the number of PT. PT were given to 78 (21%) neonates, 38 (49%) of whom had very severe NT. The duration of NT was positively related to the severity of NT and the number of subsequent PT. A mortality rate of 10.8% was significantly associated with bleeding signs (p < 0.05) and correlated with increasing number of PT (p < 0.05) but not with the severity of NT (p = 0.4). In the case of relevant hemorrhage, PT did not influence the mortality rate (p = 0.09). All deaths followed neonatal sepsis., Conclusions: Prematurity and diagnoses including early and late onset sepsis and asphyxia were the most common causes of NT. Mortality was not associated with the severity of NT but increased with the number of PT. What is Known: • The causes for neonatal thrombocytopenia (NT) are well known. • The effects of platelet transfusions (PT) and its indications are still a matter of debate and recommendations differ widely. What is New: • The duration of NT is positively related to the severity of NT and the number of subsequent PT. • The mortality rate is not associated with the severity of NT but increases with increasing numbers of PT and in the case of relevant intraventricular hemorrhage (≥ grade II), PT does not influence the mortality rate.

Heat pain and its modulation by capsaicin varies among subjects in experimental and clinical settings. A plausible cause is a genetic component, of which TRPV1 ion channels, by their response to both heat and capsaicin, are primary candidates. However, TRPA1 channels can heterodimerize with TRPV1 channels and carry genetic variants reported to modulate heat pain sensitivity. To address the role of these candidate genes in capsaicin-induced hypersensitization to heat, pain thresholds acquired before and after topical application of capsaicin and TRPA1/TRPV1 exomic sequences derived by next-generation sequencing were assessed in n = 75 healthy volunteers and the genetic information comprised 278 loci. Gaussian mixture modeling indicated 2 phenotype groups with high or low capsaicin-induced hypersensitization to heat. Unsupervised machine learning implemented as swarm-based clustering hinted at differences in the genetic pattern between these phenotype groups. Several methods of supervised machine learning implemented as random forests, adaptive boosting, k-nearest neighbors, naive Bayes, support vector machines, and for comparison, binary logistic regression predicted the phenotype group association consistently better when based on the observed genotypes than when using a random permutation of the exomic sequences. Of note, TRPA1 variants were more important for correct phenotype group association than TRPV1 variants. This indicates a role of the TRPA1 and TRPV1 next-generation sequencing-based genetic pattern in the modulation of the individual response to heat-related pain phenotypes. When considering earlier evidence that topical capsaicin can induce neuropathy-like quantitative sensory testing patterns in healthy subjects, implications for future analgesic treatments with transient receptor potential inhibitors arise.

Objective: Preeclampsia often complicates pregnancies after maternal kidney transplantation. We aimed to assess whether preeclampsia is associated with kidney function decline either during the pregnancy or in the long term., Methods: We performed an international multicenter retrospective cohort study. Renal function at conception, pregnancy outcomes, and short- and long-term graft outcomes were collected for women who were pregnant after renal transplantation and had transplant and obstetric care at the participating centers. In women who had multiple pregnancies during the study period, only the last pregnancy was included. Univariate and multivariable analyses were performed., Results: We retrieved pregnancy outcomes and long-term renal outcomes for 52 women. Chronic hypertension was present at baseline in 27%. Mean estimated glomerular filtration rate (GFR) at start of pregnancy was 52.4±17.5 mL/min/1.73 m. Mean estimated GFR at delivery was 47.6±21.6 mL/min/1.73 m, which was significantly lower than at conception (P=.03). Twenty women (38%) developed preeclampsia. In multivariable analysis, women who developed preeclampsia had a 10.7-mL/min/1.73 m higher drop in estimated GFR between conception and delivery than women who did not develop preeclampsia (P=.02). Long-term estimated GFR follow-up was obtained at a median of 5.8 years (range 1.3-27.5 years). Mean estimated GFR at last follow-up was 38±23 mL/kg/1.73 m. Seventeen women (33%) experienced graft loss over the follow-up period. Incidence of graft loss was similar in women with and without preeclampsia in their last pregnancy (30% and 34%, respectively; P=.99). In multivariable analysis, the decrease in estimated GFR between conception and last follow-up was similar in women who experienced preeclampsia during pregnancy and those who did not (difference -2.69 mL/min/1.73 m, P=.65)., Conclusion: Preeclampsia commonly complicates pregnancies after renal transplantation but is not associated with long-term renal dysfunction or graft loss.

The formation of complex tissues from simple epithelial sheets requires the regional subdivision of the developing tissue. This is initially accomplished by a sequence of gene regulatory hierarchies that set up distinct fates within adjacent territories, and rely on cross-regulatory interactions to do so. However, once adjacent territories are established, cells that confront one another across territorial boundaries must actively participate in maintaining separation from each other. Classically, it was assumed that adhesive differences would be a primary means of sorting cells to their respective territories. Yet it is becoming clear that no single, simple mechanism is at play. In the few instances studied, an emergent theme along developmental boundaries is the generation of asymmetry in cell mechanical properties. The repertoire of ways in which cells might establish and then put mechanical asymmetry to work is not fully appreciated since only a few boundaries have been molecularly studied. Here, we characterize once such boundary in the develop leg epithelium of Drosophila. The region of the pretarsus / tarsus is a known gene expression boundary that also exhibits a lineage restriction (Sakurai et al., 2007). We now show that the interface comprising this boundary is strikingly aligned compared to other cell interfaces across the disk. The boundary also exhibits an asymmetry for both Myosin II accumulation as well as one of its activators, Rho Kinase. Furthermore, the enrichment correlates with increased mechanical tension across that interface, and that tension is Rho Kinase-dependent. Lastly, interfering with actomyosin contractility, either by depletion of myosin heavy chain or expression of a phosphomimetic variant of regulatory light chain causes defects in alignment of the interfaces. These data suggest strongly that mechanical asymmetries are key in establishing and maintaining this developmental boundary., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B'-family PP2A regulatory subunits and holoenzymes. The B'-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B'α-binding motifs serve as common binding sites for B' subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation-responsive B'-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B' holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B' that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B' holoenzymes in various cellular processes., Competing Interests: The authors declare no conflict of interest.

Macrophages (Mφ) undergo activation to pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes in response to pathophysiologic stimuli and dysregulation of the M1-M2 balance is often associated with diseases. Therefore, studying mechanisms of macrophage polarization may reveal new drug targets. Human Mφ polarization is generally studied in primary monocyte-derived Mφ (PBMC Mφ) and THP-1-derived Mφ (THP-1 Mφ). We compared the polarization profile of THP-1 Mφ with that of PBMC Mφ to assess the alternative use of THP-1 for polarization studies. Cellular morphology, the expression profiles of 18 genes and 4 cell surface proteins, and phagocytosis capacity for apoptotic cells and S. aureus bioparticles were compared between these Mφ, activated towards M1, M2a, or M2c subsets by stimulation with LPS/IFNγ, IL-4, or IL-10, respectively, for 6h, 24h and 48h. The Mφ types are unique in morphology and basal expression of polarization marker genes, particularly CCL22, in a pre-polarized state, and were differentially sensitive to polarization stimuli. Generally, M1 markers were instantly induced and gradually decreased, while M2 markers were markedly expressed at a later time. Expression profiles of M1 markers were similar between the polarized Mφ types, but M2a cell surface markers demonstrated an IL-4-dependent upregulation only in PBMC Mφ. Polarized THP-1 Mφ but not PBMC Mφ showed distinctive phagocytic capacity for apoptotic cells and bacterial antigens, respectively. In conclusion, our data suggest that THP-1 may be useful for performing studies involving phagocytosis and M1 polarization, rather than M2 polarization., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

More than 20% of adults worldwide experience different types of chronic pain, which are frequently associated with several comorbidities and a decrease in quality of life. Several approved painkillers are available, but current analgesics are often hampered by insufficient efficacy and/or severe adverse effects. Consequently, novel strategies for safe, highly efficacious treatments are highly desirable, particularly for chronic pain. Epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs (miRNAs) strongly affect the regulation of gene expression, potentially for long periods over years or even generations, and have been associated with pathophysiological pain. Several studies, mostly in animals, revealed that inhibitors of DNA methylation, activators and inhibitors of histone modification and modulators of miRNAs reverse a number of pathological changes in the pain epigenome, which are associated with altered expression of pain-relevant genes. This epigenetic modulation might then reduce the nociceptive response and provide novel therapeutic options for analgesic therapy of chronic pain states. However, a number of challenges, such as nonspecific effects and poor delivery to target cells and tissues, hinder the rapid development of such analgesics. In this Review, we critically summarize data on epigenetics and pain, focusing on challenges in clinical development as well as possible new approaches to the drug modulation of the pain epigenome.