High prevalence of hidradenitis suppurativa in patients with perianal fistula

Abstract Background Perianal fistula is an abnormal communication between the anal canal and perianal skin. Hidradenitis suppurativa (HS) is a chronic, auto-inflammatory skin disease in the intertriginous body areas, presenting with recurring abscesses, inflammatory nodules, and sinus tracts. The aim of this study was to determine the prevalence of HS in patients with a perianal fistula. Methods All patients with perianal fistula visiting a specialized proctology clinic between July and September 2017 were included and asked a validated diagnostic question for HS. Subsequently, physical examination was performed to objectively assess the diagnosis and relevant patient characteristics. Results In 6.6% (8/122) of patients, HS was diagnosed outside the perianal region. Four of these patients were newly diagnosed. The fistulas in HS patients were classified as a superficial fistula (three), a blind ending fistula (two), and a transsphincteric fistula (two). One patient had more than one type of fistula. Conclusion The prevalence of HS in patients with a perianal fistula is at least 6.6%. This is higher than the prevalence reported in the general European population (1%) suggesting an association between perianal fistulas and HS. We stress the importance to screen for HS in patients with perianal fistulas in order to start appropriate anti-inflammatory treatment to reduce symptoms and disease progression

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

Time-integrated luminosity recorded by the BABAR detector at the PEP-II e+e- collider

This article is the Preprint version of the final published artcile which can be accessed at the link below.We describe a measurement of the time-integrated luminosity of the data collected by the BABAR experiment at the PEP-II asymmetric-energy e+e- collider at the ϒ(4S), ϒ(3S), and ϒ(2S) resonances and in a continuum region below each resonance. We measure the time-integrated luminosity by counting e+e-→e+e- and (for the ϒ(4S) only) e+e-→μ+μ- candidate events, allowing additional photons in the final state. We use data-corrected simulation to determine the cross-sections and reconstruction efficiencies for these processes, as well as the major backgrounds. Due to the large cross-sections of e+e-→e+e- and e+e-→μ+μ-, the statistical uncertainties of the measurement are substantially smaller than the systematic uncertainties. The dominant systematic uncertainties are due to observed differences between data and simulation, as well as uncertainties on the cross-sections. For data collected on the ϒ(3S) and ϒ(2S) resonances, an additional uncertainty arises due to ϒ→e+e-X background. For data collected off the ϒ resonances, we estimate an additional uncertainty due to time dependent efficiency variations, which can affect the short off-resonance runs. The relative uncertainties on the luminosities of the on-resonance (off-resonance) samples are 0.43% (0.43%) for the ϒ(4S), 0.58% (0.72%) for the ϒ(3S), and 0.68% (0.88%) for the ϒ(2S).This work is supported by the US Department of Energy and National Science Foundation, the Natural Sciences and Engineering Research Council (Canada), the Commissariat à l’Energie Atomique and Institut National de Physique Nucléaire et de Physiquedes Particules (France), the Bundesministerium für Bildung und Forschung and Deutsche Forschungsgemeinschaft (Germany), the Istituto Nazionale di Fisica Nucleare (Italy), the Foundation for Fundamental Research on Matter (The Netherlands), the Research Council of Norway, the Ministry of Education and Science of the Russian Federation, Ministerio de Ciencia e Innovación (Spain), and the Science and Technology Facilities Council (United Kingdom). Individuals have received support from the Marie-Curie IEF program (European Union) and the A.P. Sloan Foundation (USA)

Guidelines and considerations for designing field experiments simulating precipitation extremes in forest ecosystems

1. Precipitation regimes are changing in response to climate change, yet understanding of how forest ecosystems respond to extreme droughts and pluvials remains incomplete. As future precipitation extremes will likely fall outside the range of historical variability, precipitation manipulation experiments (PMEs) are critical to advancing knowledge about potential ecosystem responses. However, few PMEs have been conducted in forests compared to short‐statured ecosystems, and forest PMEs have unique design requirements and constraints. Moreover, past forest PMEs have lacked coordination, limiting cross‐site comparisons. Here, we review and synthesize approaches, challenges, and opportunities for conducting PMEs in forests, with the goal of guiding design decisions, while maximizing the potential for coordination. 2. We reviewed 63 forest PMEs at 70 sites world‐wide. Workshops, meetings, and communications with experimentalists were used to generate and build consensus around approaches for addressing the key challenges and enhancing coordination. 3. Past forest PMEs employed a variety of study designs related to treatment level, replication, plot and infrastructure characteristics, and measurement approaches. Important considerations for establishing new forest PMEs include: selecting appropriate treatment levels to reach ecological thresholds; balancing cost, logistical complexity, and effectiveness in infrastructure design; and preventing unintended water subsidies. Response variables in forest PMEs were organized into three broad tiers reflecting increasing complexity and resource intensiveness, with the first tier representing a recommended core set of common measurements. 4. Differences in site conditions combined with unique research questions of experimentalists necessitate careful adaptation of guidelines for forest PMEs to balance local objectives with coordination among experiments. We advocate adoption of a common framework for coordinating forest PME design to enhance cross‐site comparability and advance fundamental knowledge about the response and sensitivity of diverse forest ecosystems to precipitation extremes.New Hampshire Agricultural Experiment Station, Grant/Award Number: NH00071-M; Northern States Research Cooperative, Grant/Award Number: 14-DG-11242307- 142; National Science Foundation Long-Term Ecological Research, Grant/Award Number: 1637685; USDA Forest Service; University of New Hampshire; NASA, Grant/Award Number: NNX14AD31G; USDA National Institute of Food and Agriculture McIntire- Stennis Project, Grant/Award Number: NH00071-M; U.S. Department of Energy; Office of Science’s Terrestrial Ecosystem Science program; Pacific Northwest National Labs’ LDRD program; MSCA-IF 2015; EU-Horizon2020 program; NSF’s Research Coordination Network Progra

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

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 search for the decay B+→K+ννˉB^+ \to K^+ \nu \bar{\nu}

We search for the rare flavor-changing neutral-current decay $B^+ \to K^+ \nu \bar{\nu}$ in a data sample of 82 fb$^{-1}$ collected with the {\sl BABAR} detector at the PEP-II B-factory. Signal events are selected by examining the properties of the system recoiling against either a reconstructed hadronic or semileptonic charged-B decay. Using these two independent samples we obtain a combined limit of ${\mathcal B}(B^+ \to K^+ \nu \bar{\nu})<5.2 \times 10^{-5}$ at the 90% confidence level. In addition, by selecting for pions rather than kaons, we obtain a limit of ${\mathcal B}(B^+ \to \pi^+ \nu \bar{\nu})<1.0 \times 10^{-4}$ using only the hadronic B reconstruction method.Comment: 7 pages, 8 postscript figures, submitted to Phys. Rev. Let