Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD

Extraformational sediment recycling on Mars

International audienc

Clinical evaluation of the BioFire Global Fever Panel for the identification of malaria, leptospirosis, chikungunya, and dengue from whole blood: a prospective, multicentre, cross-sectional diagnostic accuracy study

BACKGROUND: Acute febrile illness is a common presentation for patients at hospitals globally. Assays that can diagnose a variety of common pathogens in blood could help to establish a diagnosis for targeted disease management. We aimed to evaluate the performance of the BioFire Global Fever Panel (GF Panel), a multiplex nucleic acid amplification test performed on whole blood specimens run on the BioFire FilmArray System, in the diagnosis of several pathogens that cause acute febrile illness. METHODS: We did a prospective, multicentre, cross-sectional diagnostic accuracy study to evaluate the GF Panel. Consenting adults and children older than 6 months presenting with fever in the previous 2 days were enrolled consecutively in sub-Saharan Africa (Ghana, Kenya, Tanzania, Uganda), southeast Asia (Cambodia, Thailand), central and South America (Honduras, Peru), and the USA (Washington, DC; St Louis, MO). We assessed the performance of six analytes (chikungunya virus, dengue virus [serotypes 1-4], Leptospira spp, Plasmodium spp, Plasmodium falciparum, and Plasmodium vivax or Plasmodium ovale) on the GF Panel. The performance of the GF Panel was assessed using comparator PCR assays with different primers followed by bidirectional sequencing on nucleic acid extracts from the same specimen. We calculated the positive percent agreement and negative percent agreement of the GF Panel with respect to the comparator assays. This study is registered with ClinicalTrials.gov, NCT02968355. FINDINGS: From March 26, 2018, to Sept 30, 2019, 1965 participants were enrolled at ten sites worldwide. Of the 1875 participants with analysable results, 980 (52·3%) were female and the median age was 22 years (range 0-100). At least one analyte was detected in 657 (35·0%) of 1875 specimens. The GF Panel had a positive percent agreement for the six analytes evaluated as follows: chikungunya virus 100% (95% CI 86·3-100), dengue virus 94·0% (90·6-96·5), Leptospira spp 93·8% (69·8-99·8), Plasmodium spp 98·3% (96·3-99·4), P falciparum 92·7% (88·8-95·6), and P vivax or P ovale 92·7% (86·7-96·6). The GF Panel had a negative percent agreement equal to or greater than 99·2% (98·6-99·6) for all analytes. INTERPRETATION: This 1 h sample-to-answer, molecular device can detect common causative agents of acute febrile illness with excellent positive percent agreement and negative percent agreement directly in whole blood. The targets of the assay are prevalent in tropical and subtropical regions globally, and the assay could help to provide both public health surveillance and individual diagnoses. FUNDING: BioFire Defense, Joint Project Manager for Medical Countermeasure Systems and US Army Medical Materiel Development Activity, and National Institute of Allergy and Infectious Diseases

THE AMAPARI MARKER BAND, GALE CRATER, MARS: METAL ENRICHMENTS AND POTENTIAL MECHANISMS OF FORMATION

International audienceThe Amapari Marker Band (AMB) is a unique resistant feature in the sulfate-rich Mirador formation (Mf), and is a feature that spans Mt Sharp, the central sedimentary mound within Gale crater, Mars [1]. From orbital observations, the AMB appears darker and retains craters, exhibits a high-Ca pyroxene signature, and varies in thickness [1]. The AMB was initially interpreted as a volcanic or more indurated sulfate deposit [1–2]. NASA Curiosity rover data has shown the AMB is a chemically and sedimentologically unique feature in the stratigraphy and only a thin interval in the Mount Sharp group (MSg) sequence [3–10]. The sedimentary textures and chemistry of the units above (Chenapau member) and below (Catrimani and Contigo members) the AMB are very similar but differ in mineralogy (Mg-sulfate in Catrimani [11] and siderite+Mg-sulfate in Chenapau [12])

THE AMAPARI MARKER BAND, GALE CRATER, MARS: METAL ENRICHMENTS AND POTENTIAL MECHANISMS OF FORMATION

International audienceThe Amapari Marker Band (AMB) is a unique resistant feature in the sulfate-rich Mirador formation (Mf), and is a feature that spans Mt Sharp, the central sedimentary mound within Gale crater, Mars [1]. From orbital observations, the AMB appears darker and retains craters, exhibits a high-Ca pyroxene signature, and varies in thickness [1]. The AMB was initially interpreted as a volcanic or more indurated sulfate deposit [1–2]. NASA Curiosity rover data has shown the AMB is a chemically and sedimentologically unique feature in the stratigraphy and only a thin interval in the Mount Sharp group (MSg) sequence [3–10]. The sedimentary textures and chemistry of the units above (Chenapau member) and below (Catrimani and Contigo members) the AMB are very similar but differ in mineralogy (Mg-sulfate in Catrimani [11] and siderite+Mg-sulfate in Chenapau [12])

THE AMAPARI MARKER BAND, GALE CRATER, MARS: METAL ENRICHMENTS AND POTENTIAL MECHANISMS OF FORMATION

International audienceThe Amapari Marker Band (AMB) is a unique resistant feature in the sulfate-rich Mirador formation (Mf), and is a feature that spans Mt Sharp, the central sedimentary mound within Gale crater, Mars [1]. From orbital observations, the AMB appears darker and retains craters, exhibits a high-Ca pyroxene signature, and varies in thickness [1]. The AMB was initially interpreted as a volcanic or more indurated sulfate deposit [1–2]. NASA Curiosity rover data has shown the AMB is a chemically and sedimentologically unique feature in the stratigraphy and only a thin interval in the Mount Sharp group (MSg) sequence [3–10]. The sedimentary textures and chemistry of the units above (Chenapau member) and below (Catrimani and Contigo members) the AMB are very similar but differ in mineralogy (Mg-sulfate in Catrimani [11] and siderite+Mg-sulfate in Chenapau [12])

THE AMAPARI MARKER BAND, GALE CRATER, MARS: METAL ENRICHMENTS AND POTENTIAL MECHANISMS OF FORMATION

International audienceThe Amapari Marker Band (AMB) is a unique resistant feature in the sulfate-rich Mirador formation (Mf), and is a feature that spans Mt Sharp, the central sedimentary mound within Gale crater, Mars [1]. From orbital observations, the AMB appears darker and retains craters, exhibits a high-Ca pyroxene signature, and varies in thickness [1]. The AMB was initially interpreted as a volcanic or more indurated sulfate deposit [1–2]. NASA Curiosity rover data has shown the AMB is a chemically and sedimentologically unique feature in the stratigraphy and only a thin interval in the Mount Sharp group (MSg) sequence [3–10]. The sedimentary textures and chemistry of the units above (Chenapau member) and below (Catrimani and Contigo members) the AMB are very similar but differ in mineralogy (Mg-sulfate in Catrimani [11] and siderite+Mg-sulfate in Chenapau [12])