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BackgroundLarge register-based studies have reported an association between head trauma and increased risk of multiple sclerosis (MS). We aimed to investigate possible interactions between head trauma and MS-associated HLA genes in relation to MS risk.MethodsWe used a Swedish population-based case-control study (2807 incident cases, 5950 matched controls with HLA genotypes available for 2057 cases, 2887 controls). Subjects with and without a history of self-reported head trauma were compared regarding MS risk, by calculating ORs with 95% CIs using logistic regression models. Additive interaction between head trauma, HLA-DRB1*1501and absence of HLA-A*0201, was assessed by calculating the attributable proportion (AP) due to interaction.ResultsA history of head trauma was associated with a 30% increased risk of subsequently developing MS (OR 1.34, 95% CI 1.17 to 1.53), with a trend showing increased risk of MS with increasing number of head impacts (p=0.03). We observed synergistic effects between recent head trauma and HLA-DRB1*15:01as well as absence of HLA*02:01in relation to MS risk (each AP 0.40, 95% CI 0.1 to 0.7). Recent head trauma in individuals with both genetic risk factors rendered an 18-fold increased risk of MS, compared with those with neither the genetic risk factors nor a history of head trauma (OR 17.7, 95% CI 7.13 to 44.1).ConclusionsOur findings align with previous observations of a dose-dependent association between head trauma and increased risk of MS and add a novel aspect of this association by revealing synergistic effects between recent head trauma and MS-associated HLA genes.

There is limited research targeting communication interventions for children with severe/profound intellectual and multiple disabilities. This study addressed outcomes from a communication course for parents of children with severe/profound intellectual and multiple disabilities and follows up on a previous publication by Rensfeldt Flink et al.(2020). Potential observable changes in the children’s and parents’ communicative behavior were studied as well as the parents’ experiences of the intervention process and the effect of the course on parent–child communication. A mixed-methods design with a case-study framework was used. Two mother–child dyads participated. Data were collected before, during, and after the course. Video-recorded repeated play interactions by the dyads were coded and analyzed for the mothers’ responsivity and use of augmentative and alternative communication and the children’s interactive engagement. Longitudinal interview data from the mothers were analyzed thematically. No clear signs of behavioral change were observed in the coded video data. However, thematic analyses showed that the mothers experienced changes to communicative behaviors. Moreover, the course affected both mothers’ reasoning about communication with their child and their child’s communicative needs. The mothers’ narratives contributed insights into how reflective processes might guide action in parent-mediated communication interventions. The implications for research and clinical practice are discussed.

Interventions to improve dietary intake and reduce dietary greenhouse gas emissions (dGHGE) are urgently needed. Adolescence presents a unique time in life to promote sustainable diets. Detailed dietary data are needed to inform public health strategies aiming at improving adolescents’ diet quality and reducing dGHGE.

With the emergence and global proliferation of “sugar dating” websites, the phenomenon of sugar dating is increasingly on the public agenda. Sugar dating is described by these sites as dating arrangements based on an exchange of intimacy and companionship for financial or other forms of support. Given that sex is often part of the arrangements, claims are widespread, yet disputed, that sugar dating is a form of prostitution. Based on interviews and a survey questionnaire, this article maps the practice of heterosexual sugar dating in Sweden as described by “sugar babies” and “sugar daddies” themselves. It shows a striking diversity in regard to what sugar dating means for participants, both in terms of what they do when sugar dating and in terms of how money and/or other material goods are involved in arrangements. A further key difference between sugar dating arrangements is whether “sugar babies” enter them for purely instrumental reasons or enjoy them in and of themselves. Although not all kinds of sugar dating include sex, we argue that sugar dating sites should be seen as key actors in the expansion of the sex (and intimacy) industry, drawing on and articulating pre-existing tendencies within it.

Primary Sclerosing Cholangitis (PSC) is a hepatobiliary disease closely related to ulcerative colitis (UC). In PSC patients, colectomy has been linked to improved prognosis, especially following liver transplantation. This suggests an involvement of the gut‐liver axis in PSC etiology. We aimed to investigate the association between colectomy and the risk of future PSC in an epidemiological setting. Through nationwide registers, we identified all adults diagnosed with UC in Sweden 1990–2018 and retrieved information on PSC diagnosis and colectomy. Within the UC cohort (n= 61,993 patients), we matched 5577 patients withcolectomy to 15,078 withoutcolectomy. Matching criteria were sex, age at UC onset (±5 years), year of UC onset (±3 years), and proctitis at the time of colectomy. Incidence rates of PSC per 1000‐person year were calculated, and the Cox proportional hazard regression model estimated hazard ratios (HRs) for PSC until 31 December 2019. During the follow‐up, 190 (3.4%) colectomized UC patients and 450 (3.0%) UC comparators developed PSC, yielding incidence rates of 2.6 and 2.4 per 1000 person‐years (HR 1.07 [95% CI 0.90–1.28]). The cumulative incidence of colectomy decreased remarkably over calendar periods, but the cumulative incidence of PSC remained unchanged. The risk of developing PSC in colectomized versus comparators changed over time (HR 0.68 [95% CI; 0.48–0.96] in 1990‐97 and HR 2.10 [95% CI; 1.37–3.24] in 2011‐18). In UC patients, colectomy was not associated with a decreased risk of subsequent PSC. The observed differences in the risk of PSC development over calendar periods are likely due to changes in PSC‐diagnosis and UC‐treatment.

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

Nutritional quality, and health and climate impacts are important considerations in the design of sustainable diets.

Objectives.The aim of this systematic review was to describe interventions which promote safe patient handling and movement (PHM) among workers in healthcare by reviewing the literature on their effectiveness for work and health-related outcomes. Methods.Databases were searched for studies published during 1997–2018. Measures were operationalized broadly, capturing outcomes of work and health. Only randomized controlled trials (RCTs) and cohort studies with a control group were included. Quality was assessed using evidence-based checklists by the Swedish Agency for Health Technology Assessment and Assessment of Social Services. Results.The systematic review included 10 RCTs and 19 cohort studies. Providing work equipment and training workers is effective: it can increase usage. Training workers to be peer coaches is associated with fewer injuries. Other effective strategies are participatory ergonomics and management engagement in collaboration with workers, facilitating safe PHM. Conclusions.This systematic review suggests that interventions for safe PHM with an impact of health-related outcomes should include access to work equipment, training as well as employer and employee engagement. The additional impact of multifaceted interventions is inconclusive.

AbstractObjective:The aim of this study was to examine emergency preparedness behaviors among women with a recent live birth in Hawaii.Methods:Using the 2016 Hawaii Pregnancy Risk Assessment Monitoring System, we estimated weighted prevalence of 8 preparedness behaviors.Results:Among 1010 respondents (weighted response rate, 56.3%), 79.3% reported at least 1 preparedness behavior, and 11.2% performed all 8 behaviors. The prevalence of women with a recent live birth in Hawaii reporting preparedness behaviors includes: 63.0% (95% CI: 58.7-67.1%) having enough supplies at home for at least 7 days, 41.3% (95% CI: 37.1-45.6%) having an evacuation plan for their child(ren), 38.7% (95% CI: 34.5-43.0%) having methods to keep in touch, 37.8% (95% CI: 33.7-42.1%) having an emergency meeting place, 36.6% (95% CI: 32.6-40.9%) having an evacuation plan to leave home, 34.9% (95% CI: 30.9-39.2%) having emergency supplies to take with them if they have to leave quickly, 31.8% (95% CI: 27.9-36.0%) having copies of important documents, and 31.6% (95% CI: 27.7-35.8%) having practiced what to do during a disaster.Conclusions:One in 10 women practiced all 8 behaviors, indicating more awareness efforts are needed among this population in Hawaii. The impact of preparedness interventions implemented in Hawaii can be tracked with this question over time.

Real‐world data on clinical outcomes of ustekinumab in ulcerative colitis are lacking. To assess short‐ and long‐term clinical outcomes of ustekinumab in ulcerative colitis. Adult ulcerative colitis patients without previous colectomy starting ustekinumab treatment up until 11 December 2020 were identified through the Swedish Inflammatory Bowel Disease Register (SWIBREG). Prospectively recorded data were extracted from the SWIBREG. The primary outcome was persistence to ustekinumab 16 weeks after treatment initiation. Secondary outcomes included drug persistence beyond week 16, clinical remission (defined as a patient‐reported Mayo rectal bleeding subscore = 0 and stool frequency subscore ≤1), biochemical remission (defined as faecal‐calprotectin <250 μg/g) and changes in health‐related quality of life (HRQoL), as measured by the Short Health Scale (SHS). Logistic regression was used to identify potential predictors of ustekinumab persistence at 16 weeks. Of the 133 patients with ulcerative colitis, only three were naïve to biologics and tofacitinib. The persistence rates of ustekinumab were 115/133 (86%) at 16 weeks and 89/133 (67%) at last follow‐up, that is, after a median follow‐up of 32 (interquartile range 19–56) weeks. The clinical remission rates were 17% at 16 weeks and 32% at the last follow‐up. The corresponding rates for biochemical remission were 14% and 23%. The median faecal‐calprotectin concentration decreased from 740 μg/g at baseline to 98 μg/g at the last follow‐up (p< 0.01, n= 37). Improvement was seen in each dimension of the SHS between baseline and last follow‐up (p< 0.01 for each dimension, n= 46). Male sex was associated with ustekinumab persistence at 16 weeks (adjusted odds ratio = 4.00, 95% confidence interval: 1.35–11.83). In this nationwide real‐world cohort of ulcerative colitis patients with prior drug failures, including other biologics and tofacitinib, ustekinumab was associated with high drug persistence rates and improvements in clinical, biochemical and HRQoL measures.

Anecdotal reports of menstrual irregularities after receiving COVID-19 vaccines have been observed in post-authorisation and post-licensure monitoring. We aimed to identify and classify reports of menstrual irregularities and vaginal bleeding after COVID-19 vaccination submitted to a voluntary active surveillance system.

The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate1. Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms2. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration3. Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF)4,5. However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenesis required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.

MRF: What is the current management structure at Cascade, with you stepping out of the CEO position? Strid: For a long time, I've wanted to switch back to a more [...]

Genes encoding B lineage–restricted transcription factors are frequently mutated in B-lymphoid leukemias, suggesting a close link between normal and malignant B-cell development. One of these transcription factors is early B-cell factor 1 (EBF1), a protein of critical importance for lineage specification and survival of B-lymphoid progenitors. Here, we report that impaired EBF1 function in mouse B-cell progenitors results in reduced expression of Myc. Ectopic expression of MYC partially rescued B-cell expansion in the absence of EBF1 both in vivo and in vitro. Using chromosome conformation analysis in combination with ATAC-sequencing, chromatin immunoprecipitation–sequencing, and reporter gene assays, six EBF1-responsive enhancer elements were identified within the Myc locus. CRISPR-Cas9–mediated targeting of EBF1-binding sites identified one element of key importance for Myc expression and pro-B cell expansion. These data provide evidence that Myc is a direct target of EBF1. Furthermore, chromatin immunoprecipitation–sequencing analysis revealed that several regulatory elements in the Myc locus are targets of PAX5. However, ectopic expression of PAX5 in EBF1-deficient cells inhibits the cell cycle and reduces Myc expression, suggesting that EBF1 and PAX5 act in an opposing manner to regulate Myc levels. This hypothesis is further substantiated by the finding that Pax5 inactivation reduces requirements for EBF1 in pro–B-cell expansion. The binding of EBF1 and PAX5 to regulatory elements in the human MYC gene in a B-cell acute lymphoblastic leukemia cell line indicates that the EBF1:PAX5:MYC regulatory loop is conserved and may control both normal and malignant B-cell development.

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.

ObjectiveWe aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01.MethodsUsing population-based case–control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.ResultsThe effect of each DRB1*15:01allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01carriers without the protective A*02:01allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).ConclusionsThe strikingly increased MS risk among DRB*15:01homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

Graecobolanthuswas proposed in 2018 as a new generic name for the Greek species of the genus Bolanthus, the latter genus comprising the remaining species from Anatolia and the Levant according to the revising authors. However, the type of the two generic names, i.e., Graecobolanthus graecusfrom Greece and Bolanthus hirsutusfrom the Levant, undoubtedly belong to the same genus based on morphological and genetic similarity. Importantly, B. hirsutuswas not included in the molecular analysis by the revising authors. In summary, we note that (i) Graecobolanthusis taxonomically superfluous and Bolanthusis the correct generic name of the Greek‐endemic species; (ii) an extended Phrynellaand/or a new generic name might accommodate the Turkish taxa currently under Bolanthus, which were located on a distinct phylogenetic branch in the study by the revising authors.

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27−CD28−CD8+T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D–DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27−CD28−CD8+T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27−CD28−CD8+T cells to acquire a broad-spectrum, innate-like killing activity.

This piece is a collective exploration by seven doctoral researchers in Child Studies, who discuss notions of listening to children and young people in a Swedish context. We approach different aspects of listening in research and in practices such as education, psychiatry, and social work. The discussions in this collective writing are an invitation for continuous reflections about the contexts where listening to children is done, its challenges and possibilities.

Intra‐portal islet transplantation is currently the only clinically approved beta cell replacement therapy, but its outcome is hindered by limited cell survival due to a multifactorial reaction against the allogeneic tissue in liver. Adipose‐derived stromal cells (ASCs) can potentially improve the islet micro‐environment by their immunomodulatory action. The challenge is to combine both islets and ASCs in a relatively easy and consistent long‐term manner in a deliverable scaffold. Manufacturing the 3D bioprinted double‐layered scaffolds with primary islets and ASCs using a mix of alginate/nanofibrillated cellulose (NFC) bioink is reported. The diffusion properties of the bioink and the supportive effect of human ASCs on islet viability, glucose sensing, insulin secretion, and reducing the secretion of pro‐inflammatory cytokines are demonstrated. Diabetic mice transplanted with islet‐ASC scaffolds reach normoglycemia seven days post‐transplantation with no significant difference between this group and the group received islets under the kidney capsules. In addition, animals transplanted with islet‐ASC scaffolds stay normoglycemic and show elevated levels of C‐peptide compared to mice transplanted with islet‐only scaffolds. The data present a functional 3D bioprinted scaffold for islets and ASCs transplanted to the extrahepatic site and suggest a possible role of ASCs on improving the islet micro‐environment. Adipose‐derived stromal cells (ASCs) support survival and function of pancreatic islets in 3D bioprinted double‐layered alginate/nanocellulose‐based scaffold. Transplanting these scaffolds into the intraperitoneal site of a diabetic mouse model corrects diabetes seven days after transplantation with positive detection of C‐peptide from islets in scaffolds. This is accompanied with presence of ASCs in the scaffolds 60 days post‐transplantation.

The 10,200 ft-long Richmond Transport Facilities tunnel is being constructed beneath Seacliff, San Francisco's most prestigious neighborhood with elevated views of the Golden Gate bridge to the north and the [...]

Radiation curing allows powder coatings to expand into applications where line speed is a critical factor. The fact that powder coatings now have its own multinational trade show in Europe [...]

(Abstracted from MMWR Morb Mortal Wkly Rep2020;69:769–775)Pregnant women are at greater risk of severe respiratory infection due to immunologic and physiologic changes in the setting of several viral infections such as influenza. However, there are limited data among this population to date that determine the prevalence and severity of COVD-19 and whether its signs and symptoms differ between pregnant and nonpregnant women.

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.

To understand the developmental trajectories in early lymphocyte differentiation, we identified differentially expressed surface markers on lineage-negative lymphoid progenitors (LPs). Single-cell polymerase chain reaction experiments allowed us to link surface marker expression to that of lineage-associated transcription factors (TFs) and identify GFRA2 and BST1 as markers of early B cells. Functional analyses in vitro and in vivo as well as single-cell gene expression analyses supported that surface expression of these proteins defined distinct subpopulations that include cells from both the classical common LPs (CLPs) and Fraction A compartments. The formation of the GFRA2-expressing stages of development depended on the TF EBF1, critical both for the activation of stage-specific target genes and modulation of the epigenetic landscape. Our data show that consecutive expression of Ly6D, GFRA2, and BST1 defines a developmental trajectory linking the CLP to the CD19+ progenitor compartment.

To the Editor: The article 'Myth v. Fact' (January) was on the whole a welcome analysis of energy economics, addressing the constraints imposed by both limited supplies of fossil fuels [...]

Patients with ulcerative colitis often report fatigue. To investigate prevalence of and risk factors for fatigue in patients with ulcerative colitis with active disease and during deep remission. In this cross-sectional study, disease activity was evaluated with endoscopy and calprotectin, and patients were classified as having active disease (n?=?133) or being in deep remission (n?=?155). Blood samples were analysed to assess anaemia, iron deficiency and systemic immune activity. Patients completed questionnaires to assess fatigue, psychological distress, gastrointestinal symptoms and quality of life. The prevalence of high fatigue (general fatigue?=?13, Multidimensional Fatigue Inventory) was 40% in the full study population. Among patients with high fatigue, female gender and iron deficiency were more prevalent, and these patients had more severe disease activity and reported higher levels of anxiety, depression and decreased quality of life compared with patients with no/mild fatigue. A logistic regression analysis identified probable psychiatric disorder (odds ratio (OR) (confidence interval) 6.1 (3.1–12.2)), iron deficiency (OR 2.5 (1.2–5.1)), active disease (OR 2.2 (1.2–3.9)) and female gender (OR 2.1 (1.1–3.7)) as independent risk factors for high fatigue. Similar results were found concerning psychological distress, gender and quality of life, but immune markers did not differ in patients in deep remission with high vs. no/mild fatigue. Probable psychiatric disorder, iron deficiency, active disease and female gender are independent risk factors for high fatigue in patients with ulcerative colitis. Low-grade immune activity does not seem to be the cause of fatigue among patients in deep remission.

ObjectivesDepression can negatively impact work capacity, but treatment effects on sick leave and employment are unclear. This study evaluates if internet-based cognitive behavioural therapy (ICBT) or physical exercise (PE), with already reported positive effects on clinical outcome and short-term work ability, has better effects on employment, sick leave and long-term work ability compared with treatment as usual (TAU) for depressed primary care patients (German clinical trials: DRKS00008745).MethodsAfter randomisation and exclusion of patients not relevant for work-related analysis, patients were divided into two subgroups: initially unemployed (total n=118) evaluated on employment, and employed (total n=703) evaluated on long-term sick leave. Secondary outcomes were self-rated work ability and average number of sick days per month evaluated for both subgroups. Assessments (self-reports) were made at baseline and follow-up at 3 and 12 months.ResultsFor the initially unemployed subgroup, 52.6% were employed after 1 year (response rate 82%). Both PE (risk ratio (RR)=0.44; 95% CI 0.23 to 0.87) and ICBT (RR=0.37; 95% CI 0.16 to 0.84) showed lower rates compared with TAU after 3 months, but no difference was found after 1 year (PE: RR=0.97; 95% CI 0.69 to 1.57; ICBT: RR=1.23; 95% CI 0.72 to 2.13). For those with initial employment, long-term sick leave (response rate 75%) decreased from 7.8% to 6.5%, but neither PE (RR=1.4; 95% CI 0.52 to 3.74) nor ICBT (RR=0.99; 95% CI 0.39 to 2.46) decreased more than TAU, although a temporary positive effect for PE was found. All groups increased self-rated work ability with no differences found.ConclusionsNo long-term effects were found for the initially unemployed on employment status or for the initially employed on sick leave. New types of interventions need to be explored.

SPI1 (also known as PU.1) is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T-cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later down-regulated. Pioneering activity of PU.1 was tested in this developmentally dynamic context by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T-cell development and by using stage-specific gain- and loss-of-function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborator, CEBPA. RUNX motifs and RUNX1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without RUNX1. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative trade-offs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At nonpromoter sites, PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at nonpromoter sites where local chromatin accessibility depended on the presence of PU.1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA-binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition, served by non-DNA-binding domains of PU.1.

Patients with ankylosing spondylitis (AS) are at increased risk of developing inflammatory bowel disease (IBD). We aimed to determine the variation in fecal calprotectin in AS over 5 years in relation to disease activity and medication and also to study the incidence of and predictors for development of IBD. Fecal calprotectin was assessed at baseline (n= 204) and at 5-year follow-up (n= 164). The patients answered questionnaires and underwent clinical evaluations. At baseline and at 5-year follow-up, ileocolonoscopy was performed in patients with fecal calprotectin ≥500 mg/kg and ≥200 mg/kg, respectively. The medical records were checked for diagnoses of IBD during the follow-up period. Fecal calprotectin >50 mg/kg was found in two-thirds of the patients at both study visits. In 80% of the patients, fecal calprotectin changed by <200 mg/kg between the two measuring points. Baseline fecal calprotectin was positively correlated with Ankylosing Spondylitis Disease Activity Score based on C-reactive protein, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin at 5-year follow-up. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with higher fecal calprotectin, and 3-week cessation of NSAIDs resulted in a drop of a median 116 mg/kg in fecal calprotectin. The use of tumor necrosis factor (TNF) blockers was associated with lower fecal calprotectin at both visits, but the users of TNF receptor fusion proteins had significantly higher fecal calprotectin than users of anti-TNF antibodies at 5-year follow-up. The 5-year incidence of Crohn’s disease (CD) was 1.5% and was predicted by high fecal calprotectin. Fecal calprotectin was elevated in a majority of the patients and was associated with disease activity and medication at both visits. CD developed in 1.5% of the patients with AS, and a high fecal calprotectin was the main predictor thereof. The results support a link between inflammation in the gut and the musculoskeletal system in AS. We propose that fecal calprotectin may be a potential biomarker to identify patients with AS at risk of developing IBD. ClinicalTrials.gov identifier: NCT00858819. Registered 9 March 2009. Last updated 28 May 2015.

In language conferences, student papers, some linguistics textbooks, and wider culture, the critical period hypothesis is presented as factual despite still being fiercely debated in academic literature. The widespread popular acceptance of the hypothesis contrasts with a sharp debate and criticism of it in academic literature (Muñoz & Singleton, [Muñoz, C., 2011]; Ortega, [Ortega, L., 2009]). This article considers the basis of the hypothesis, a concept from biology that describes a species‐wide acquisition window for a trait that affects every member of the species and ends in a relatively abrupt manner (Knudson, [Knudson, E. I., 2004]). After a critical period passes, a member of the affected species has little or no hope of acquiring a trait, as if the window were permanently sealed. The article then discusses the evidence for and against the hypothesis from additional and native language acquisition, ultimately concluding that evidence best supports a sensitive period within the first 2 years of life (Muñoz & Singleton, [Muñoz, C., 2011]). Discussion then turns to what factors determine success in language learning, with consideration of how teachers can best support their students of all ages and how to change popular acceptance of the hypothesis and its inhibition of language learning.

The mechanistic relationship between IL-4/IL-13 and skin barrier function has been of interest since the filaggrin discovery and the subsequent in vitro demonstration that IL-4 and IL-13 downregulate filaggrin expression in cultured keratinocytes. Hönzke and colleagues explore these interactions further. The effects of IL-4/ll-13 may be context dependent, with differing roles in homeostasis and in disease.

Plants as well as other aerobic organisms constantly produce reactive oxygen species (ROS). At regulated low concentrations ROS may serve as signal molecules, while in excessive amounts these may cause oxidative damage to biomolecules. Actual cellular concentrations are controlled by a network of various antioxidants, and acclimation to stress conditions is achieved by a dynamic balance of ROS production and neutralization. Accordingly, plant stress physiology studies generally include an array of methods testing the occurrence of ROS as well as evaluating antioxidant capacities. The aim of the present work is to provide an overview of these methods, with special emphasis on avoiding errors that can possibly lead to either inaccurate data or misinterpretations of otherwise correct measurements.

To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19+ progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5+/−Ebf1+/− pro–B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5+/−Ebf1+/− pro–B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.