Booster-free anti-retroviral therapy for persons living with HIV and multidrug resistance (B-Free): protocol for a multicentre, multistage, randomised, controlled, non-inferiority trial.

Introduction: Anti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART.

Impact of the SGLT2 inhibitor empagliflozin on urinary supersaturations in kidney stone formers (SWEETSTONE trial): protocol for a randomised, double-blind, placebo-controlled cross-over trial.

Introduction: Kidney stones are a global healthcare problem. Given high recurrence rates and the morbidity associated with symptomatic stone disease, effective medical prophylaxis is clearly an unmet need. Explanatory analyses of randomised controlled trials with sodium/glucose cotransporter isoform 2 inhibitors indicated a 30%-50% reduced rate of stone events in patients with diabetes.

Implementation of the Symptom Navi © Programme for cancer patients in the Swiss outpatient setting: a study protocol for a cluster randomised pilot study (Symptom Navi© Pilot Study).

Introduction: Self-management interventions show promising results on symptom outcomes and self-management behaviours. The Symptom Navi© Programme (SN©P) is a nurse-led intervention supporting patients' symptom self-management during anticancer treatment. It consists of written patient information (Symptom Navi© Flyers (SN©Flyers)), semistructured consultations and a training manual for nurses.

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.

Background: Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women.

Data management of clinical trials during an outbreak of Ebola virus disease.

Introduction: Clinical trial data management (DM) conducted during outbreaks like that of Ebola virus disease (EVD) in West Africa, 2014-2016, has to adapt to specific, unique circumstances. CTU Bern was asked to set up a safe data capture/management system that could be launched within a few weeks and cover two different vaccine trials. This article describes some of the challenges we faced and our solutions during the two different trials.

Bunched, the Drosophila homolog of the mammalian tumor suppressor TSC-22, promotes cellular growth.

Background: Transforming Growth Factor-beta1 stimulated clone-22 (TSC-22) is assumed to act as a negative growth regulator and tumor suppressor. TSC-22 belongs to a family of putative transcription factors encoded by four distinct loci in mammals. Possible redundancy among the members of the TSC-22/Dip/Bun protein family complicates a genetic analysis.

Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.

Mice lacking both the p110gamma and p110delta isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110gamma-/-/p110delta(D910A/D910A) (p110gamma(KO)delta(D910A)) mice where the p110delta isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110gammadelta deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses.

Overgrowth caused by misexpression of a microRNA with dispensable wild-type function.

MicroRNAs (miRNAs) represent an abundant class of non-coding RNAs that negatively regulate gene expression, primarily at the post-transcriptional level. miRNA genes are frequently located in proximity to fragile chromosomal sites associated with cancers and amplification of a miRNA cluster has been correlated with the etiology of lymphomas and solid tumors. The oncogenic potential of a miRNA polycistron has recently been demonstrated in vivo.

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.

Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg).

Chemokine inhibition--why, when, where, which and how?

Chemokines are small chemoattractant cytokines that control a wide variety of biological and pathological processes, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Genetic and pharmacological studies have shown that chemokines are responsible for the excessive recruitment of leucocytes to inflammatory sites and damaged tissue. In the present paper, we discuss the rationale behind interfering with the chemokine system and introduce various points for therapeutic intervention using either protein-based or small-molecule inhibitors.

The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.

Background: Forkhead transcription factors belonging to the FOXO subfamily are negatively regulated by protein kinase B (PKB) in response to signaling by insulin and insulin-like growth factor in Caenorhabditis elegans and mammals. In Drosophila, the insulin-signaling pathway regulates the size of cells, organs, and the entire body in response to nutrient availability, by controlling both cell size and cell number. In this study, we present a genetic characterization of dFOXO, the only Drosophila FOXO ortholog.

The Drosophila dual-specificity ERK phosphatase DMKP3 cooperates with the ERK tyrosine phosphatase PTP-ER.

ERK MAP kinase plays a key role in relaying extracellular signals to transcriptional regulation. As different activity levels or the different duration of ERK activity can elicit distinct responses in one and the same cell, ERK has to be under strict positive and negative control. Although numerous genes acting positively in the ERK signaling pathway have been recovered in genetic screens, mutations in genes encoding negative ERK regulators appear underrepresented.

dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1.

Genetic studies in Drosophila melanogaster underscore the importance of the insulin-signalling pathway in controlling cell, organ and animal size. Effectors of this pathway include Chico (the insulin receptor substrate homologue), dPI(3)K, dPKB, dPTEN, and dS6K. Mutations in any of these components have a striking effect on cell size and number, with the exception of dS6K.

PDK1 regulates growth through Akt and S6K in Drosophila.

The insulin/insulin-like growth factor-1 signaling pathway promotes growth in invertebrates and vertebrates by increasing the levels of phosphatidylinositol 3,4,5-triphosphate through the activation of p110 phosphatidylinositol 3-kinase. Two key effectors of this pathway are the phosphoinositide-dependent protein kinase 1 (PDK1) and Akt/PKB. Although genetic analysis in Caenorhabditis elegans has implicated Akt as the only relevant PDK1 substrate, cell culture studies have suggested that PDK1 has additional targets.

An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control.

Background: Size regulation is fundamental in developing multicellular organisms and occurs through the control of cell number and cell size. Studies in Drosophila have identified an evolutionarily conserved signaling pathway that regulates organismal size and that includes the Drosophila insulin receptor substrate homolog Chico, the lipid kinase PI(3)K (Dp110), DAkt1/dPKB, and dS6K.

Results: We demonstrate that varying the activity of the Drosophila insulin receptor homolog (DInr) during development regulates organ size by changing cell size and cell number in a cell-autonomous manner.

[75th annual session of the Swiss Ophthalmological Society; on its founding and its founders].

The Swiss Ophthalmological Society (SOS) was founded in Bern on 26 April 1908. An important prelude to the foundation of the Society was the tenth international congress of ophthalmology in Lucerne in 1904, at which Marc Dufour presided. Among the 50 Swiss ophthalmologists who organized and attended this congress were the founders of the Swiss Ophthalmological Society.