Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

High levels of short-chain fatty acids secreted by Candida albicans hyphae induce neutrophil chemotaxis via free fatty acid receptor 2

Candida albicans belongs to our commensal mucosal flora and in immune-competent individuals in the absence of epithelial damage, this fungus is well tolerated and controlled by our immune defense. However, C. albicans is an opportunistic microorganism that can cause different forms of infections, ranging from superficial to life-threatening systemic infections. C. albicans is polymorphic and switches between different phenotypes (e.g. from yeast form to hyphal form). C. albicans hyphae are invasive and can grow into tissues to eventually reach circulation. During fungal infections, neutrophils in particular play a critical role for the defense, but how neutrophils are directed toward the invasive forms of fungi is less well understood. We set out to investigate possible neutrophil chemoattractants released by C. albicans into culture supernatants. We found that cell-free culture supernatants from the hyphal form of C. albicans induced both neutrophil chemotaxis and concomitant intracellular calcium transients. Size separation and hydrophobic sorting of supernatants indicated small hydrophilic factors as responsible for the activity. Further analysis showed that the culture supernatants contained high levels of short-chain fatty acids with higher levels from hyphae as compared to yeast. Short-chain fatty acids are known neutrophil chemoattractants acting via the neutrophil free fatty acid receptor 2. In line with this, the calcium signaling in neutrophils induced by hyphae culture supernatants was blocked by a free fatty acid receptor 2 antagonist and potently increased in the presence of a positive allosteric modulator. Our data imply that short-chain fatty acids may act as a recruitment signal whereby neutrophils can detect C. albicans hyphae

Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFa inhibition

We describe a female patient suffering from severe chronic non-bacterial osteomyelitis (CNO) with systemic inflammation and advanced malnutrition and complete deficiency of myeloperoxidase (MPO). CNO is a rare autoinflammatory bone disorder associated with dysregulation of the innate immune system. MPO deficiency is a genetic disorder with partial or complete absence of the phagocyte peroxidase MPO. MPO deficiency has no established clinical phenotype but reports indicate increased susceptibility to infection and chronic inflammation. The patients symptoms began at 10 years of age with pain in the thighs, systemic inflammation and malnutrition. She was diagnosed with CNO at 14 years of age. Treatment with nonsteroidal anti-inflammatory drugs, corticosteroids, bisphosphonates or IL1-receptor antagonists (anakinra) did not relieve the symptoms. However, the patient responded instantly and recovered from her clinical symptoms when treated with TNF alpha blockade (adalimumab). Three years after treatment initiation adalimumab was withdrawn, resulting in rapid symptom recurrence. When reintroducing adalimumab, the patient promptly responded and went into remission. In addition to clinical and laboratory profiles, neutrophil functions (reactive oxygen species, ROS; neutrophil extracellular traps, NETs; degranulation; apoptosis; elastase activity) were investigated both in a highly inflammatory state (without treatment) and in remission (on treatment). At diagnosis, neither IL1 beta, IL6, nor TNF alpha was significantly elevated in serum, but since TNF alpha blockade terminated the inflammatory symptoms, the disease was likely TNF alpha-driven. All neutrophil parameters were normal both during treatment and treatment withdrawal, except for MPO-dependent intracellular ROS- and NET formation. The role of total MPO deficiency for disease etiology and severity is discussed.Funding Agencies|This research received financial support from the Swedish Research Council - Medicine (2018-03077, 2019-01123), the King Gustaf V Memorial Foundation (2015-0165, 2017-0368, 2021-0804, 2022-0873), the Swedish state under the ALF agreement (ALFGBG-726801), t [2018-03077, 2019-01123]; Swedish Research Council - Medicine [2015-0165, 2017-0368, 2021-0804, 2022-0873]; King Gustaf V Memorial Foundation [ALFGBG-726801]; Swedish state under the ALF agreement [2018-2344, 2019-3102]; Wilhelm and Martina Lundgrens Scientific Foundation [2018-02579, 2021-04110]; Magnus Bergwall foundation; Alfred Ahlqvists foundation - Swedish pharmacy Society [VGFOUREG-858661, VGFOUREG-981130]; Ingabritt and Arne Lundberg Foundation</p

Operational Experience and Performance of the Belle II Pixel Detector

The Belle II experiment at the super KEK B factory (SuperKEKB) started its physics operation with the full detector setup in March 2019, and it aims at collecting 50 ab$^{−1}$ of $e^+e^−$ collision data. The vertex detector (VXD) of Belle II contains a 4-layer silicon vertex detector (SVD) using double sided silicon strips and an inner 2-layer pixel detector (PXD) that is based on the depleted P-channel Field Effect Transistor (DEPFET) technology. The signal generation and amplification are combined in pixels with a minimum pitch of 55 × 50 µm$^2$. The sensors are thinned down to 75 µm, and each module has interconnects and ASICs integrated on the sensor with silicon frames for mechanical support. This approach led to a material budget of around 0.21% X$_0$ per layer including the cooling structure in the acceptance region. The PXD has an integration time of around 20 µs, a signal-to-noise ratio of around 50 and a detecting efficiency of better than 99%. Its two layers are arranged at the radii of 14 and 22 mm around the interaction point, and an impact parameter resolution of better than 15 µm has been achieved. Due to its close proximity to the beam line and its sensitivity to few-keV photons, the PXD also plays an important role in background studies

DEPFET pixel detector in the Belle II experiment

The Belle II experiment will run with a reduced beam asymmetry and a factor of 40 higher instantaneous luminosity compared to the Belle experiment. To cope with this and to be able to perform high precision vertex measurements for charge conjugation parity violating processes, a pixel detector based on DEPFET technology will be installed in the center of Belle II. Its basic properties and the DAQ chain are presented in this article

The Belle II vertex detector integration

The Belle II experiment comes with a substantial upgrade of the Belle detector and will operate at the SuperKEKB energy-asymmetric collider with energies tuned to (4 ) resonance sqrt() = 10.588 GeV. The accelerator has successfully completed the first phase of commissioning in 2016 and the first electron\u2013positron collisions in Belle II took place in April 2018. Belle II features a newly designed silicon vertex detector based on DEPFET pixel and double-sided strip layers. Currently, a subset of the vertex detector is installed (Phase 2 of the experiment). Installation of the full detector (Phase 3) will be completed by the end of 2018. This paper describes the Phase 2 arrangement of the Belle II silicon vertex detector, with focus on the interconnection of detectors and their integration with the software framework of Belle II. Alignment issues are discussed based on detector simulations and first acquired data