Observation of Beam Spin Asymmetries in the Process ep→e

The observation of beam spin asymmetries in two-pion production in semi-inclusive deep inelastic scattering off an unpolarized proton target is reported. The data presented here were taken in the fall of 2018 with the CLAS12 spectrometer using a 10.6 GeV longitudinally spin-polarized electron beam delivered by CEBAF at JLab. The measured asymmetries provide the first opportunity to extract the parton distribution function e(x), which provides information about the interaction between gluons and quarks, in a collinear framework that offers cleaner access than previous measurements. The asymmetries also constitute the first ever signal sensitive to the helicity-dependent two-pion fragmentation function G_{1}^{⊥}. A clear sign change is observed around the ρ mass that appears in model calculations and is indicative of the dependence of the produced pions on the helicity of the fragmenting quark.

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance.

BACKGROUND: Mutations in the γ-secretase enzyme subunits have been described in multiple kindreds with familial hidradenitis suppurativa (HS). OBJECTIVE: In this study, we report a novel nicastrin (NCSTN) mutation causing HS in a Dutch family. We sought to explore the immunobiological function of NCSTN mutations using data of the Immunological Genome Project. METHODS: Blood samples of three affected and two unaffected family members were collected. Whole-genome sequencing was performed using genomic DNA isolated from peripheral blood leucocytes. Sanger sequencing was done to confirm the causative NCSTN variant and the familial segregation. The microarray data set of the Immunological Genome Project was used for thorough dissection of the expression and function of wildtype NCSTN in the immune system. RESULTS: In a family consisting of 23 members, we found an autosomal dominant inheritance pattern of HS and detected a novel splice site mutation (c.1912_1915delCAGT) in the NCSTN gene resulting in a frameshift and subsequent premature stop. All affected individuals had HS lesions on non-flexural and atypical locations. Wildtype NCSTN appears to be upregulated in myeloid cells like monocytes and macrophages, and in mesenchymal cells such as fibroblastic reticular cells and fibroblasts. In addition, within the 25 highest co-expressed genes with NCSTN we identified CAPNS1, ARNT and PPARD. CONCLUSION: This study reports the identification a novel NCSTN gene splice site mutation which causes familial HS. The associated immunobiological functions of NCSTN and its co-expressed genes ARNT and PPARD link genetics to the most common environmental and metabolic HS risk factors which are smoking and obesity.

Observation of Transverse Λ/Λ[over ¯] Hyperon Polarization in e

We report the first observation of the spontaneous polarization of Λ and Λ[over ¯] hyperons transverse to the production plane in e^{+}e^{-} annihilation, which is attributed to the effect arising from a polarizing fragmentation function. For inclusive Λ/Λ[over ¯] production, we also report results with subtracted feed-down contributions from Σ^{0} and charm. This measurement uses a dataset of 800.4 fb^{-1} collected by the Belle experiment at or near a center-of-mass energy of 10.58 GeV. We observe a significant polarization that rises with the fractional energy carried by the Λ/Λ[over ¯] hyperon.

The anti-inflammatory potency of biologics targeting tumour necrosis factor-α, interleukin (IL)-17A, IL-12/23 and CD20 in hidradenitis suppurativa: an ex vivo study.

BACKGROUND: Biologics targeting inflammatory mediators can achieve clinical improvements in hidradenitis suppurativa (HS). However, their clinical efficacy shows great interpatient variability in daily practice. OBJECTIVES: To investigate the anti-inflammatory potency of a selection of currently available biologics and prednisolone for the treatment of HS in an ex vivo skin culture system using lesional HS biopsies. METHODS: Lesional skin samples from 10 patients with HS and skin samples from five healthy controls were cultured ex vivo and exposed to prednisolone or biologics targeting tumour necrosis factor (TNF)-α, interleukin (IL)-17A, IL-12/23p40 or CD20 (adalimumab, infliximab, secukinumab, ustekinumab and rituximab, respectively). Real-time quantitative polymerase chain reaction and cytokine bead arrays were used to measure the inhibitory effect of the biologics on cytokines and antimicrobial peptides (AMPs). RESULTS: The relative mRNA expression of all tested cytokines and AMPs was significantly downregulated by all anti-inflammatory agents (P < 0·001). The protein production of the proinflammatory cytokines TNF-α, interferon γ, IL-1ß, IL-6 and IL-17A was significantly inhibited by adalimumab, infliximab, ustekinumab, prednisolone (all P < 0·001) and rituximab (P = 0·0071), but not by secukinumab (P = 0·0663). On both mRNA and protein levels, adalimumab, infliximab and prednisolone reduced the levels of a broader mix of individual cytokines than secukinumab, ustekinumab and rituximab. Moreover, a significant inhibitory effect on mRNA expression levels of inflammatory markers in healthy control skin was observed only for TNF-α inhibitors (P < 0·001) and prednisolone (P = 0·0015). CONCLUSIONS: This ex vivo study suggests that TNF-α inhibitors and prednisolone are the most powerful inhibitors of proinflammatory cytokines and AMPs in HS lesional skin, which concurs with our clinical experience in patients with HS.

Correlation of the refined Hurley classification for hidradenitis suppurativa with patient-reported quality of life and objective disease severity assessment.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, debilitating, heterogeneous disease requiring different treatment approaches. Recently, we refined the classic Hurley classification into a seven-stage classification in order to guide these treatment choices. This new classification subdivides Hurley stage I and II into three substages, namely mild (A), moderate (B) and severe (C) HS disease. Hurley stage III is not subcategorized and is always severe. OBJECTIVES: To investigate the correlation between the given severity grades of Hurley I and Hurley II in the refined Hurley classification, and the patient-reported quality of life and physician-assessed objective severity score. MATERIALS AND METHODS: In this cross-sectional study, patients with HS participating in the observational cohorts of two Dutch tertiary referral centres were included before June 2017. The patient-reported Dermatology Life Quality Index (DLQI) and physician-assessed International HS Severity Score System (IHS4) scores were compared between the refined Hurley stages. RESULTS: In total, 433 patients were analysed. DLQI and IHS4 scores increased within Hurley stage I and II from A through C. There was a significant positive correlation of DLQI and IHS4 with increasing refined Hurley substages [refined Hurley stage I (A, B and C) to DLQI: rs = 0·259, P < 0·001 and refined Hurley stage II (A, B and C) to DLQI: rs = 0·185, P = 0·010; refined Hurley stage I (A, B and C) to IHS4: rs = 0·603, P < 0·001 and refined Hurley stage II (A, B and C) to IHS4: rs = 0·532, P < 0·001]. CONCLUSIONS: The refined Hurley classification accurately correlates with HS severity assessed by both patients and clinicians. Therefore, the refined Hurley classification is a useful tool for the quick assessment of severity in HS.

Marburg haemorrhagic fever in returning travellers: an overview aimed at clinicians.

Marburg virus haemorrhagic fever (MARV HF) is a dramatic disease that can occur in a traveller returning from an area where the virus is endemic. In this article, we provide an overview of MARV HF as an imported infection with an emphasis on clinical aspects. Although late features such as rash, signs of haemorrhagic diathesis and liver necrosis may point to the diagnosis, the initial clinical picture is non-specific. If in this early phase the patient's epidemiological exposure history is compatible with MARV HF, the patient should be isolated and managed according to viral haemorrhagic fever protocol and RT-PCR should be performed on the patient's blood as soon as possible to rule out MARV HF (or other possible viral haemorrhagic fevers). In severe cases, direct electron microscopy of blood in specialized centres (e.g. Bernhard-Nocht Institute in Hamburg, Germany) may be considered if the result of the RT-PCR is not readily available. Adequate diagnostics and empirical treatment for other acute life-threatening illnesses should not be withheld while test results are awaited, but all management and diagnostics should be weighed against the risks of nosocomial transmission.

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization - systematic review and recommendations from the HS ALLIANCE working group.

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence.

Apremilast for moderate hidradenitis suppurativa: no significant change in lesional skin inflammatory biomarkers.

BACKGROUND: Treatment with apremilast has recently demonstrated clinically meaningful improvement in moderate hidradenitis suppurativa (HS). OBJECTIVE: To evaluate the change in expression of inflammatory markers in lesional skin of HS patients receiving apremilast 30 mg twice daily (n = 15) for 16 weeks compared with placebo (n = 5). METHODS: At baseline, 5-mm punch biopsies were obtained from an index lesion (HSL) and non-lesional (HSN) skin in the same anatomical area. Subsequent HSL samples were taken as close as possible to the previously biopsied site at week 4 and week 16. After sampling, biopsies were split; one half was processed for in vivo mRNA analysis using real-time quantitative PCR; the other half was cultured for ex vivo protein analysis using a proximity extension assay (Olink). Linear mixed effects models were calculated to compare the levels of inflammatory markers in HSL skin between apremilast and placebo over time. RESULTS: At baseline, 17 proteins with a fold change >2 in HSL vs. HSN skin were identified in 20 patients. The top five were IL-17A (5), S100A12, CST5, IL-12/23p40, CD6 (1) with fold changes ranging from 6.6 to 1638, respectively (FDR <0.044). Linear mixed effects models for 75 assays were calculated. Protein levels of S100A12 decreased during treatment in the apremilast group compared with the placebo group (p = 0.014, FDR = 0.186). None of the 14 genes exhibited significant changes in expression over time. However, an evident downward trend in relative mRNA expression of IL-17A and IL-17F was demonstrated in patients receiving apremilast. CONCLUSION: We did not detect statistically significant changes in inflammatory markers in HSL skin of HS patients receiving apremilast compared with placebo, despite clinical improvement in the apremilast group. Nonetheless, S100A12 and IL-17A were significantly elevated in HSL skin and showed a decrease in response to apremilast. The translational model in clinical trials involving HS clearly needs further improvement.

[Measles after MMR-vaccination]. / 'De mazelen' na bmr-vaccinatie.

BACKGROUND: The Dutch national vaccination program provides vaccination for mumps, measles and rubella (MMR vaccine) for all children. After vaccination with live attenuated viruses, the virus replicates on a limited scale. Replication may lead to mild symptoms occurring 5-14 days after MMR-vaccination, including fever, conjunctivitis and rash. Symptoms are comparable to those of a wildtype measles infection. CASE DESCRIPTION: A 14-month-old boy was admitted to the hospital with an impressive rash 13 days after MMR-vaccination. Diagnostic tests were positive for measles. This test result caused the mother to doubt further vaccination. CONCLUSION: Within 14 days after MMR-vaccination, a child can present with symptoms very similar to a wildtype measles virus infection. The low incidence of wildtype measles infection strongly suggests that these symptoms will likely be a reaction to vaccination. Elaborate diagnostic procedures may cause the parents a lot of stress and therefore offering reassurance to parents may be more appropriate.

Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug.

INTRODUCTION: Many drugs are unavailable in suitable oral paediatric dosage forms, and pharmacists often have to compound drugs to provide paediatric patients with an acceptable formulation in the right dose. Liquid formulations offer the advantage of dosing flexibility and ease of administration to young patients, but drug substances often show poor aqueous solubility. The objective of this work was to study different solvents and matrices to design a liquid formulation for poorly water soluble drugs, using lorazepam as model drug. METHODS: Three different formulation strategies were explored to improve the solubility. Firstly, water-soluble organic solvents were used to improve the aqueous solubility directly, secondly, ionic surfactants were used to solubilise the model drug, and thirdly, complexation of lorazepam with cyclodextrin was studied. Specific attention was paid to excipients, adequate taste correction and palatability. For the final formulation, physical and chemical stability and microbiological quality were assessed for 12months. RESULTS: An organic solvent based formulation, containing a mixture of polyethylene glycol and glycerol 85%, with a minimum amount of propylene glycol, proved to be physically and chemically stable. Development of the non-ionic surfactants formulation was discontinued due to taste problems. The cyclodextrin formulations were physically stable, but lorazepam content declined to 90% within five months. The final formulation contained in volume concentration (%v/v) 87% glycerol, 10% polyethylene glycol 400 and 3% propylene glycol. Orange essence was the preferred taste corrector. The formulation remained stable for 12months at 4°C, with lorazepam content remaining >95%. Related substances increased during the study period but remained below 2%. In-use stability was proven up to 4weeks. CONCLUSION: An organic solvent based oral formulation was shown to be superior to a non-ionic surfactant based formulation or a cyclodextrin formulation. These results may help to formulate paediatric formulations of other poorly water soluble drugs, to aid pharmacy compounding.

Design and stability study of an oral solution of amlodipine besylate for pediatric patients.

INTRODUCTION: Amlodipine is an antihypertensive agent recommended for the management of hypertension in children and adolescents. The commercially available tablets of 5 and 10mg do not provide the necessary flexibility in dosing needed for treating children. Our goal was to develop a pediatric oral solution of amlodipine, using a robust manufacturing process suitable for ex-tempora and larger scale production. METHODS: The parameters API and preservative content, related substances, appearance and pH were studied under four different storage conditions. Samples were analyzed up to 12months. Microbiological quality was studied in an 18-week in-use test based on a two-times daily dosing schedule. RESULTS: The stability of the formulation was influenced by storage conditions and composition. A formulation containing amlodipine besylate, sucrose syrup and methyl paraben remained physically stable for 12months at 4°C with no loss of amlodipine content. Related substances increased during the study but remained below 0.5%. In-use stability was proven up to 18weeks. DISCUSSION: Storage under refrigerated conditions was necessary to prevent precipitation and to obtain an acceptable shelf-life. In conclusion, we have developed and validated an amlodipine oral solution, suitable for the pediatric population. This liquid formulation is preferred over manipulated commercial dosage forms or non-standardized extemporaneously compounded formulations.

Disease burden of congenital cytomegalovirus infection at school entry age: study design, participation rate and birth prevalence.

Congenital cytomegalovirus infection (cCMV) may lead to symptoms at birth and long-term consequences. We present a nationwide, retrospective cohort study on the outcome of cCMV up to age 6 years. For this study we identified cCMV, using polymerase chain reaction, by analysing dried blood spots, which are taken shortly after birth for neonatal screening. The group of children with cCMV were compared to a group of children who were cCMV negative at birth. Data were collected about their health and development up to age 6 years. Parents of 73 693 children were invited to participate, and 32 486 (44·1%) gave informed consent for testing of their child's dried blood spot for CMV. Of the 31 484 dried blood spots tested, 156 (0·5%) were positive for cCMV. Of these, four (2·6%) children had been diagnosed with cCMV prior to this study. This unique retrospective nationwide study permits the estimation of long-term sequelae of cCMV up to the age of 6 years. The birth prevalence of cCMV in this study was 0·5%, which is in line with prior estimates. Most (97·4%) children with cCMV had not been diagnosed earlier, indicating under-diagnosis of cCMV.

Cytomegalovirus infection in the Netherlands: seroprevalence, risk factors, and implications.

BACKGROUND: Cytomegalovirus (CMV) infections occur worldwide and are usually asymptomatic in healthy individuals. In fetuses and immunocompromised persons, they can cause severe disease and disabilities. OBJECTIVE: To determine the CMV seroprevalence and risk factors for CMV infection in the Netherlands. STUDY DESIGN: In a cross-sectional population-based study (PIENTER-2, 2006-2007), sera and questionnaire data were collected from 6386 individuals. Sera were tested for CMV-specific IgG antibodies using enzyme-linked immunosorbent assay (ELISA). RESULTS: The CMV seroprevalence in the general population (6 months-79 years) was 45.6%. Age and country of origin were the most prominent independent risk factors. The seroprevalence was significantly lower in native Dutch and Western individuals (41.5%) than in non-Western individuals (76.7%). Multivariable logistic regression analysis showed that age, lower educational level, first-generation migrancy, and among native Dutch/Western individuals, female gender and having contact with young children, were independently associated with CMV seropositivity. The geometric mean concentrations of antibodies increased with age and were higher in women than in men. CONCLUSION: CMV seroprevalence in the Netherlands is relatively low compared to other countries. This is in line with our finding of a higher seroprevalence among migrants compared to the native population. The higher seroprevalence in women and individuals who have contact with young children is especially important for women of reproductive age. Preventing CMV infection in these women, through counseling on hygiene or possible future vaccination, may lead to a decrease of congenital CMV infections.

Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient.

Pleconaril is a capsid inhibitor used previously to treat enterovirus infections. A pleconaril-resistant echovirus 11 (E11) strain was identified before pleconaril treatment was given in an immunocompromised patient. The patient was also treated with intravenous Ig (IVIg) for a long period but remained unresponsive. The pleconaril-resistant strains could not be neutralized in vitro, confirming IVIg treatment failure. To identify the basis of pleconaril resistance, genetic and structural analyses were conducted. Analysis of a modelled viral capsid indicated conformational changes in the hydrophobic pocket that could prevent pleconaril docking. Substitutions (V117I, V119M and I188L) in the pleconaril-resistant viruses were found in the pocket region of VP1. Modelling suggested that V119M could confer resistance, most probably due to the protruding sulfate side chain of methionine. Although pleconaril resistance induced in vitro in a susceptible E11 clinical isolate was characterized by a different substitution (I183M), resistance was suggested to also result from a similar mechanism, i.e. due to a protruding sulfate side chain of methionine. Our results showed that resistant strains that arise in vivo display different markers from those identified in vitro and suggest that multiple factors may play a role in pleconaril resistance in patient strains. Based on IVIg treatment failure, we predict that one of these factors could be immune related. Thus, both IVIg and capsid inhibitors target the viral capsid and can induce mutations that can be cross-reactive, enabling escape from both IVIg and the drug. This could limit treatment options and should be investigated further.

Varicella zoster reactivation after hematopoietic stem cell transplant in children is strongly correlated with leukemia treatment and suppression of host T-lymphocyte immunity.

BACKGROUND AND AIMS: Varicella zoster virus (VZV) reactivation following hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality. We undertook a retrospective study to determine the frequency and risk factors associated with VZV reactivation, including underlying disease, the use of fludarabine in high-risk leukemia chemotherapy protocols, and immune status before HSCT. PATIENTS AND METHODS: We studied 163 children who underwent a first HSCT between 2002 and 2008, before introduction of routine VZV prophylaxis on our unit. VZV diagnosis was based on clinical features and supported by polymerase chain reaction on plasma and/or vesical fluid. Patient data and possible risk factors pre- and post HSCT were recorded and compared using a multivariate regression analysis. RESULTS: Within this cohort, 41 (25%) patients developed VZV reactivation during the first year after transplantation at a median of 60 days post HSCT. VZV reactivation occurred more often within the subgroup of patients with acute leukemia compared with the remainder of patients (38% vs. 15%, P < 0.01). Multivariate Cox regression analysis revealed that, besides positive VZV serology in patients pre-HSCT (P = 0.03), acute leukemia as the indication for HSCT remained the only independent risk factor for VZV reactivation (P = 0.025, odds ratio 2.5, 95% confidence interval 1.1-5.6). This was associated with low pre-transplant T-cell counts, especially in the CD4(+) subset. No differences were found in relation to donor type, age, or use of serotherapy. CONCLUSION: VZV reactivation after HSCT predominates in acute leukemia patients and is associated with low T CD4(+) lymphocyte counts. This finding demonstrates the impact of pre-HSCT host immune suppression on VZV reactivation patterns after HSCT.

Precision measurement of charged pion and kaon differential cross sections in e+ e- annihilation at sqrt[s]=10.52 GeV.

Measurements of inclusive differential cross sections for charged pion and kaon production in e+ e- annihilation have been carried out at a center-of-mass energy of sqrt[s]=10.52 GeV. The measurements were performed with the Belle detector at the KEKB e+ e- collider using a data sample containing 113×10(6) e+ e- → qq events, where q={u,d,s,c}. We present charge-integrated differential cross sections dσ(h±)/dz for h±={π±,K±} as a function of the relative hadron energy z=2E(h)/sqrt[s] from 0.2 to 0.98. The combined statistical and systematic uncertainties for π± (K±) are 4% (4%) at z∼0.6 and 15% (24%) at z∼0.9. The cross sections are the first measurements of the z dependence of pion and kaon production for z>0.7 as well as the first precision cross section measurements at a center-of-mass energy far below the Z0 resonance used by the experiments at LEP and SLC.

Nucleoside plus nucleotide analogs and cessation of hepatitis B immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective.

BACKGROUND: After orthotopic liver transplantation (OLT) in chronic hepatitis B (HBV), adequate prophylaxis for recurrence of HBV in the graft is mandatory. OBJECTIVES: Evaluate safety of HBV prophylaxis with tenofovir and emtricitabine (TDF/FTC) after cessation of hepatitis B immunoglobulin (HBIG) after OLT in chronic HBV. STUDY DESIGN: In 17 consecutive patients after OLT in chronic HBV we started TDF/FTC after cessation of HBIG. All had received HBIG >6 months. 15/17 were HBsAg negative and 16/17 had undetectable HBV-DNA. RESULTS: After mean follow-up of 2 years 16/17 patients were alive, one died due to urosepsis. All 16 with undetectable HBV-DNA remained HBV-DNA negative. From 15 HBsAg negative patients at start, in one seroconversion to positive HBsAg occurred, without detectable HBV-DNA. Liver biochemistry remained within the normal ranges. There were no cases of drug discontinuation. No major side effects were reported. TDF/FTC use saves €16,262/year over standard-of-care (HBIG+LAM). This prospective follow-up study shows that in liver transplantation for chronic hepatitis B, after initial treatment including HBIG for at least 6 months combined with or followed by (dual) nucleos(t)ide analog therapy, TDF/FTC provides adequate prophylaxis against recurrent HBV infection without major side effects and leads to substantial cost savings over a regimen with HBIG. CONCLUSION: Combined prophylaxis with TDF/ETV nucleoside plus nucleotide analogs and cessation of immunoglobulin after liver transplantation in chronic hepatitis B is safe and effective.