Reversal of quantized Hall drifts at noninteracting and interacting topological boundaries.

The transport properties of gapless edge modes at boundaries between topologically distinct domains are of fundamental and technological importance. We experimentally studied long-distance quantized Hall drifts in a harmonically confined topological pump of ultracold fermionic atoms. We found that quantized drifts halt and reverse their direction when the atoms reach a critical slope of the confining potential, revealing the presence of a topological boundary. The drift reversal corresponded to a band transfer between a band with Chern number C = +1 and another with C = -1 through a gapless edge mode, in agreement with the bulk-edge correspondence for noninteracting particles. Nonzero repulsive Hubbard interactions led to the emergence of an additional edge in the system through a mechanism in which pairs of fermions are split.

Quantization and its breakdown in a Hubbard-Thouless pump.

Geometric properties of wave functions can explain the appearance of topological invariants in many condensed-matter and quantum systems1. For example, topological invariants describe the plateaux observed in the quantized Hall effect and the pumped charge in its dynamic analogue-the Thouless pump2-4. However, the presence of interparticle interactions can affect the topology of a material, invalidating the idealized formulation in terms of Bloch waves. Despite pioneering experiments in different platforms5-9, the study of topological matter under variations in interparticle interactions has proven challenging10. Here we experimentally realize a topological Thouless pump with fully tuneable Hubbard interactions in an optical lattice and observe regimes with robust pumping, as well as an interaction-induced breakdown. We confirm the pump's robustness against interactions that are smaller than the protecting gap for both repulsive and attractive interactions. Furthermore, we identify that bound pairs of fermions are responsible for quantized transport at strongly attractive interactions. However, for strong repulsive interactions, topological pumping breaks down, but we show how to reinstate it by modifying the pump trajectory. Our results will prove useful for further investigations of interacting topological matter10, including edge effects11 and interaction-induced topological phases12-15.

Topological Pumping in a Floquet-Bloch Band.

Constructing new topological materials is of vital interest for the development of robust quantum applications. However, engineering such materials often causes technological overhead, such as large magnetic fields, spin-orbit coupling, or dynamical superlattice potentials. Simplifying the experimental requirements has been addressed on a conceptual level-by proposing to combine simple lattice structures with Floquet engineering-but there has been no experimental implementation. Here, we demonstrate topological pumping in a Floquet-Bloch band using a plain sinusoidal lattice potential and two-tone driving with frequencies ω and 2ω. We adiabatically prepare a near-insulating Floquet band of ultracold fermions via a frequency chirp, which avoids gap closings en route from trivial to topological bands. Subsequently, we induce topological pumping by slowly cycling the amplitude and the phase of the 2ω drive. Our system is well described by an effective Shockley model, establishing a novel paradigm to engineer topological matter from simple underlying lattice geometries. This approach could enable the application of quantized pumping in metrology, following recent experimental advances on two-frequency driving in real materials.

Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study.

OBJECTIVES: To prospectively compare ultrasound (US) and whole-body MRI for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM). METHODS: Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z scores was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z scores was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or >3.5 (n = 1 muscle), or if ≥3 muscles showed abnormalities as described above for the other diagnostic methods. RESULTS: At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (P <0.01), and qualitative US (P <0.01). CONCLUSION: At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.

Type III cutaneous atypical meningioma of the scalp.

Meningiomas occur rarely in extracranial sites, including the skin, where they may pose a diagnostic challenge because of their histopathologic overlap with several other spindle-cell tumors. Cutaneous meningiomas are divided into type I (congenital), type II (ectopic), and type III (via direct extension) lesions. We present a rare case of atypical meningioma of the skin in a 71-year-old woman who presented with a painful and enlarging lesion on the left central frontal scalp. Biopsy showed bone and soft tissue with involvement of a spindle cell neoplasm, consisting of whorled nests with atypical features, including variably increased mitotic index, areas of hypercellularity, and sheeted architecture. The overall findings were consistent with an atypical meningioma (World Health Organization grade 2). Atypical meningiomas constitute only 5% to 15% of all meningiomas. Magnetic resonance imaging of the skull later demonstrated a left frontal tumor consistent with an atypical meningioma that had eroded through the skull. Dermatopathologists should consider cutaneous meningioma as a differential diagnosis of spindle-cell neoplasms of the skin and subcutaneous tissue in head and neck.

Assessment of disability in idiopathic inflammatory myopathy: a call for linearity.

OBJECTIVES: To evaluate the clinimetric properties of the Academic Medical Centre Disability Score (ALDS) in patients with idiopathic inflammatory myopathy (IIM). METHODS: We used prospectively collected data of IIM patients who completed a phase-2 study with first-line IVIG monotherapy. The ALDS is a patient-reported questionnaire which contains 25 items relevant for disability in myositis. ALDS and all core set measures (CSMs) for myositis [including HAQ-Disability Index (HAQ-DI)] were evaluated at baseline and 9 weeks follow-up. In addition, the 2016 ACR/EULAR myositis response criteria outcome called Total Improvement Score (TIS) was evaluated at 9 weeks. We examined floor/ceiling effects, reliability and construct validity of the ALDS. To examine known-group validity, ALDS change scores over time were compared with TIS and physician impression of clinical response. RESULTS: Nineteen patients with IIM [median age 59 years, 12 (63%) female] were enrolled. At baseline, ALDS showed a median score of 65.4 (IQR 58.2-73.5), good Cronbach's alpha (α = 0.84) and a small ceiling effect (11%). Construct validity was confirmed by moderate to strong correlations between ALDS and HAQ-DI [rs = -0.57 (baseline); -0.86 (follow-up)]. ALDS change score correlated with TIS (rs = 0.70), discriminated between responders and non-responders (TIS ≥ 40; P = 0.001), between groups based on physician impression of clinical response (P = 0.03), and detected deterioration. CONCLUSION: The ALDS showed promising clinimetric properties and detected relevant changes in disability in patients with myositis. These results warrant further investigations.

Functional constipation in infancy and early childhood: epidemiology, risk factors, and healthcare consultation.

BACKGROUND: Functional constipation (FC) is a pediatric problem that is seen frequently. However, its prevalence in Asia remains undetermined. In this study we attempted to determine the prevalence, risk factors and therapeutic modalities of FC in infants and toddlers in Sri Lanka. METHODS: Children aged 6.5 months to 4 years were selected from 14 well-baby and vaccination clinics in the Gampaha District of Sri Lanka. A questionnaire with questions regarding the socio-demographic characteristics, child's bowel habits, psycho-social risk factors and treatment modalities were filled by the mothers. FC was diagnosed according to ROME III criteria. RESULTS: A total of 1113 children were analyzed [(female n = 560 (50.3%) with a mean age of 20.7 months, standard deviation [SD] 11.2 months. FC was found in 89 (8.0%). FC was significantly and independently associated with underweight (14.3% vs 7.2%, p = 0.008. [OR and 95% CI: 2,3 (CI; 1.3-4.2)] and residence in an urban area (9.6% vs 5.6%, p = 0.013). [OR and 95% CI: 0.592 (CI; 0.396-0.95)]. Children subjected to violence showed a significantly higher prevalence of FC (20.0 vs 7.8%, p = 0.046). Children being overweight and children living with mothers subjected to violence showed a higher, though not statistically significant, tendency to develop FC. Children with FC visited healthcare clinics more frequently when compared to controls (19.6% vs 6.0%, p < 0.0001). However, only 24% of infants and toddlers with FC were treated specifically for the condition by a doctor. CONCLUSIONS: FC occurred in 8% of this cohort of Sri Lankan infants and toddlers. It is significantly associated with underweight and living in an urban area. Only a quarter of them received medical attention for their constipation. TRIAL REGISTRATION: SLCP/ERC/2014/12 , December 2014.

Hidradenitis Suppurativa After Radical Surgery-Long-Term Follow-up for Recurrences and Associated Factors.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating skin disease in inverse body areas. Wide excision is recommended in Hurley Stages II to III, but the rate and symptoms of recurrences in long-term follow-up remain unclear. OBJECTIVE: To analyze the allocation of recurrences regarding the operative field, the onset and quality of HS symptoms as well as factors associated with recurrences in long-term follow-up. MATERIAL AND METHODS: Forty-eight patients with Hurley Stage III disease who had undergone 91 wide excisions from 2010 to 2015 were clinically examined regarding postoperative complications and allocation and quality of recurrences. To determine the risk of recurrence, possible surgery, and lifestyle-related associated factors were investigated. RESULTS: Postoperative recurrences of HS were seen in 54.2%. Most recurrences (inflamed nodules) were detected in a <1-cm margin around the operative field (18.7%). Surgery under tumescence local anesthesia showed symptoms in 40.6% compared with 28.6% under general anesthesia. Increased alcohol consumption (p = .027) but not body mass index (p = .11) or smoking behavior (p = .45) had significant effect on relapse of HS. CONCLUSION: Caution must be given especially in surgery with local anesthesia only. Half of patients with HS showed long-term follow-up signs of recurrence after wide excision, most frequently nearby the operation field.

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.

Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

Migratory CD11b+ conventional dendritic cells induce T follicular helper cell-dependent antibody responses.

T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding which cDC instructs Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist because of the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different antigen formulations, we determined that CD11b+ migratory type 2 cDCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2, but not CD103+ cDC1, migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-dependent Tfh cell priming impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the subanatomic regions of the lymph node where Tfh cell priming occurs-the T-B border. This work identifies the DC subset responsible for Tfh cell-dependent antibody responses, particularly when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.

Antimicrobial stewardship: a qualitative study of the development of national guidelines for antibiotic use in hospitals.

BACKGROUND: As effective antibiotics are becoming a scarce resource, governmental regulation is needed to promote responsible use. Implementation of antibiotic stewardship and practice guidelines in health care facilities seems to be crucial to this effort. Empirical studies suggest, however, that guidelines have limited influence on health professionals' behavior and practice. Barriers and facilitators to guideline implementability are much studied, but little attention has been given to health professionals' perceptions of normative acceptability of guidelines as a condition for compliance. The aim of the present study was first, to examine if and how aspects potentially promoting acceptability and compliance among clinical target users were addressed during development of Norwegian national guidelines for antibiotic use in hospitals and second, to identify procedural characteristics of the development process that were perceived by target users to yield legitimate guidelines. METHODS: Qualitative deductive thematic analysis was used. A theoretical framework inspired by the AGREE II Instrument and the Accountability for reasonableness framework assisted data gathering and interpretation. Archival data was collected and used to detail the guideline development process. Semi-structured, in-depth interviews with eight clinicians with extensive knowledge of the guidelines were carried out. RESULTS: Guideline development was characterized by i) broad agreement about scope and purpose, ii) broad involvement of stakeholders in the development process, iii) use of systematic methods to search for and apply evidence, iv) easily identifiable and specific recommendations, v) provision of tools on how to put recommendations into practice, and vi) editorial independence. Several procedural characteristics were perceived by the interviewees as promoting guideline legitimacy; i) diverse perspectives systematically involved in the process, ii) accessibility and transparency of the rationales for decision making, iii) opportunities for appeals and reconsiderations, and iv) regulative authority. CONCLUSIONS: This study provides insights as to how guidelines that are intended to promote responsible use of antibiotics in hospitals can be carefully developed to facilitate perceptions of relevance, transparency, and authority by health professionals.

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling.

Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that LGALS1, which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.

Infection Programs Sustained Lymphoid Stromal Cell Responses and Shapes Lymph Node Remodeling upon Secondary Challenge.

Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.

Identification of CLK1 Inhibitors by a Fragment-linking Based Virtual Screening.

Alternative splicing plays an important role in the regulation of protein biosynthesis. CDC2-like kinases (CLKs) phosphorylate splicing factors rendering them a potential target for treating diseases caused by splicing dysregulation. As selective and potent inhibitors of CLK1 are still lacking, a fragment-linking based virtual screening campaign was successfully applied to identify new inhibitors showing activity on CLK1. These inhibitors exhibit a novel 2,4-substituted 1,3-thiazole scaffold that is suitable for further modification. A subsequently performed docking and protein structure based analysis revealed first hints for inhibitors showing preferred binding activity for CLK1 and DYRK2 over other splicing kinases.

The closely related CD103+ dendritic cells (DCs) and lymphoid-resident CD8+ DCs differ in their inflammatory functions.

Migratory CD103+ and lymphoid-resident CD8+ dendritic cells (DCs) share many attributes, such as dependence on the same transcription factors, cross-presenting ability and expression of certain surface molecules, such that it has been proposed they belong to a common sub-lineage. The functional diversity of the two DC types is nevertheless incompletely understood. Here we reveal that upon skin infection with herpes simplex virus, migratory CD103+ DCs from draining lymph nodes were more potent at inducing Th17 cytokine production by CD4+ T cells than CD8+ DCs. This superior capacity to drive Th17 responses was also evident in CD103+ DCs from uninfected mice. Their differential potency to induce Th17 differentiation was reflected by higher production of IL-1ß and IL-6 by CD103+ DCs compared with CD8+ DCs upon stimulation. The two types of DCs from isolated lymph nodes also differ in expression of certain pattern recognition receptors. Furthermore, elevated levels of GM-CSF, typical of those found in inflammation, substantially increased the pool size of CD103+ DCs in lymph nodes and skin. We argue that varied levels of GM-CSF may explain the contrasting reports regarding the positive role of GM-CSF in regulating development of CD103+ DCs. Together, we find that these two developmentally closely-related DC subsets display functional differences and that GM-CSF has differential effect on the two types of DCs.

Aldara activates TLR7-independent immune defence.

Aldara is a cream used for topical treatment of non-melanoma skin cancer, and is thought to act through stimulation of anti-tumour immunity. The active ingredient, imiquimod, has been shown to stimulate toll-like receptor 7. Aldara also induces psoriasis-like lesions when applied to naive murine skin, and as such is used as a mouse model for psoriasis. Here we find that in naive murine skin, Aldara induces inflammation largely independently of toll-like receptor 7. Surprisingly, inflammasome activation, keratinocyte death and interleukin 1 release also occur in response to the vehicle cream in the absence of imiquimod. We show that isostearic acid, a major component of the vehicle, promotes inflammasome activation in cultured keratinocytes, and so may contribute to the observed effects of Aldara on murine skin. Aldara therefore stimulates at least two immune pathways independently, and both imiquimod and vehicle are required for a full inflammatory response. Although it remains to be tested, it is possible that imiquimod-independent effects also contribute to the therapeutic efficacy of Aldara.

Hybridization detection of enzyme-labeled DNA at electrically heated electrodes.

In this report we describe an electrochemical DNA hybridization sensor approach, in which signal amplification is achieved using heated electrodes together with an enzyme as DNA-label. On the surface of the heatable low temperature co-fired ceramic (LTCC) gold electrode, an immobilized thiolated capture probe was hybridized with a biotinylated target using alkaline phosphatase (SA-ALP) as reporter molecule. The enzyme label converted the redox-inactive substrate 1-naphthyl phosphate (NAP) into the redox-active 1-naphthol voltammetrically determined at the modified gold LTCC electrode. During the measurement only the electrode was heated leaving the bulk solution at ambient temperature. Elevated temperature during detection led to increased enzyme activity and enhanced analytical signals for DNA hybridization detection. The limit of detection at 53 °C electrode temperature was 1.2 nmol/L.

CD24 Ala57Val polymorphism predicts pathologic complete response to sequential anthracycline- and taxane-based neoadjuvant chemotherapy for primary breast cancer.

Overexpression of CD24 is an independent prognostic factor for breast cancer. Recently, two polymorphisms in the CD24 gene were linked to disease risk and progression in autoimmune diseases. Here, we evaluated the clinical relevance of these polymorphisms with respect to their potential to predict a pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) for primary breast cancer (PBC), one of the strongest prognostic factors in this setting. A total of 257 patients were randomized to either doxorubicin/cyclophosphamide (AC) or doxorubicin/pemetrexed (AP), both followed by docetaxel (Doc) as NCT for T2-4 N0-2 M0 PBC as part of an international, multicenter, randomized phase II trial. CD24 polymorphisms were analyzed on germ line DNA and correlated with clinicopathologic variables and pCR. No significant associations were found between either of the polymorphisms and any of the clinicopathologic variables. In a multivariate analysis, CD24 Val/Val genotype was the only significant predictor of pCR (OR: 4.97; P = 0.003). The predictive potential was significant in both treatment arms and in the hormone receptor-positive subgroup. There was no correlation between CD24 3'UTR (TG/Del) genotype and pCR. We did not observe any association between CD24 genotype and CD24 protein expression or in vitro chemosensitivity, but there was a significant correlation between CD24 Val/Val and intratumoral lymphocyte aggregates. In conclusion, CD24 Ala/Val SNP is a strong and independent predictor of pCR after NCT for PBC and may affect immune functions rather than tumor characteristics. Further evaluation of the CD24 function and validation of its predictive potential are clearly warranted.