Performance and Hypothetical Impact on Joint Infection Management of the BioFire Joint Infection Panel: a Retrospective Analysis.

Pathogen identification is key in septic arthritis. Culture-based techniques are challenging, especially when patients have been pretreated with antibiotics or when difficult-to-culture bacteria are encountered. The BioFire joint infection assay (BJA) is a multiplex PCR panel which detects 31 of the most prevalent bacterial and fungal pathogens causing septic arthritis. Here, 123 cryoconserved contemporary synovial fluid samples from 120 patients underwent BJA analysis. Results were compared to those of culture-based diagnostics (standard of care [SOC]). Clinical data were collected, and the possible impact of the molecular diagnostic application on patient management was evaluated. Fifteen of 123 synovial fluid cultures grew bacterial pathogens. All on-panel pathogens (9/15) were correctly identified by the BJA. The BJA identified four additional bacterial pathogens in four SOC-negative cases. BJA sensitivity and specificity were 100% (95% confidence interval [CI], 69.2% to 100%) and 100% (95% CI, 96.8% to 100%), respectively. Compared to the SOC, the BJA would have resulted in faster provision of species identification and molecular susceptibility data by 49 h and 99 h, respectively. Clinical data analysis indicates that in BJA-positive cases, faster species ID could have led to timelier optimization of antibiotic therapy. This retrospective study demonstrates high sensitivity and specificity of the BJA to detect on-panel organisms in bacterial arthritis. The usefulness of the BJA in prosthetic-joint infections is limited, as important pathogens (i.e., coagulase negative staphylococci and Cutibacterium acnes) are not covered. Evidence from patient data analysis suggests that the assay might prove valuable for optimizing patient management in acute arthritis related to fastidious organisms or for patients who received antibiotics prior to specimen collection.

Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis.

BACKGROUND: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. METHODS: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. RESULTS: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. CONCLUSION: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.

Retinal detachment after post-operative endophthalmitis: clinical characteristics, outcomes and risk factors.

PURPOSE: To describe clinical characteristics, risk factors, and outcomes of rhegmatogenous retinal detachment (RRD) following treatment of postoperative endophthalmitis (PE). METHODS: Analysis of cross-referenced data from two service reviews of patients with RRD and bacterial PE treated between 01/01/2013 and 01/07/2020. The main outcome measure was final best-corrected visual acuity (BCVA). Secondary measures include proportion of patients with BCVA of ≤ 0.3 logMAR and ≥ 1.0 logMAR, rate of phthsis, and rate of eye removal. RESULTS: Ninety-four cases of PE were analysed finding 21 cases of RRD (22%). Seven (35%) experienced recurrent RRD. Seven eyes (35%) were left with permanent silicone oil fill. All RRD cases had vitrectomy. After PE with RRD the median BCVA was 1.1 logMAR, compared with 0.4 logMAR for PE without RRD (p < 0.04). Fifty-seven percent (12/21) of RRD eyes attained BCVA of ≥ 1.0 logMAR vs. 29% (21/73) of PE without RRD (p = 0.01). Nineteen percent (4/21) of eyes with RRD attained BCVA of ≤ 0.3 logMAR, whereas those without RRD did so in 43% (31/73) of cases (p = 0.02). Five eyes with RRD (24%) and 2 eyes without RRD (3%) developed phthisis (p < 0.01). Three non-RRD cases required removal of the eye (4%, p = 0.46). Higher bacterial virulence was associated with worse final BCVA (2.1 logMAR vs. 0.3 logMAR; p < 0.01). RRD rate did not differ by bacterial virulence (OR 1.9; CI95: 0.6-6.9; p = 0.24). CONCLUSIONS: RRD following PE leads to worse clinical outcomes. Eyes which developed RRD were more likely to have undergone vitrectomy. Final BCVA was worse in cases with more virulent micro-organisms.

Enzyme replacement therapy in mice lacking arylsulfatase B targets bone-remodeling cells, but not chondrocytes.

Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal growth. In the present study, we treated them by weekly injection of recombinant human ARSB (rhARSB) to analyze the impact of enzyme replacement therapy (ERT) on skeletal growth and bone remodeling. We found that all bone-remodeling abnormalities of Arsb-deficient mice were prevented by ERT, whereas chondrocyte defects were not. Likewise, histologic analysis of the surgically removed femoral head from an ERT-treated MPS-VI patient revealed that only chondrocytes were pathologically affected. Remarkably, a side-by-side comparison with other cell types demonstrated that chondrocytes have substantially reduced capacity to endocytose rhARSB, together with low expression of the mannose receptor. We finally took advantage of Arsb-deficient mice to establish quantification of chondroitin sulfation for treatment monitoring. Our data demonstrate that bone-remodeling cell types are accessible to systemically delivered rhARSB, whereas the uptake into chondrocytes is inefficient.

Dissolution Rate of Nanomaterials Determined by Ions and Particle Size under Lysosomal Conditions: Contributions to Standardization of Simulant Fluids and Analytical Methods.

Dissolution of inhaled engineered nanomaterials (ENM) under physiological conditions is essential to predict the clearance of the ENM from the lungs and to assess their biodurability and the potential effects of released ions. Alveolar macrophage (AM) lysosomes contain a pH 4.5 saline brine with enzymes and other components. Different types of artificial phagolysosomal simulant fluids (PSFs) have been developed for dissolution testing, but the consequence of using different media is not known. In this study, we tested to which extent six fundamentally different PSFs affected the ENM dissolution kinetics and particle size as determined by a validated transmission electron microscopy (TEM) image analysis. Three lysosomal simulant media were consistent with each other and with in vivo clearance. These media predict the quick dissolution of ZnO, the partial dissolution of SiO2, and the very slow dissolution of TiO2. The valid media use either a mix of organic acids (with the total concentration below 0.5 g/L, thereof citric acid below 0.15 g/L) or another organic acid (KH phthalate). For several ENM, including ZnO, BaSO4, and CeO2, all these differences induce only minor modulation of the dissolution rates. Only for TiO2 and SiO2, the interaction with specific organic acids is highly sensitive, probably due to sequestration of the ions, and can lead to wrong predictions when compared to the in vivo behavior. The media that fail on TiO2 and SiO2 dissolution use citric acid at concentrations above 5 g/L (up to 28 g/L). In the present selection of ENM, fluids, and methods, the different lysosomal simulant fluids did not induce changes of particle morphology, except for small changes in SiO2 and BaSO4 particles most likely due to ion dissolution, reprecipitation, and coalescence between neighboring particles. Based on the current evidence, the particle size by TEM analysis is not a sufficiently sensitive analytical method to deduce the rate of ENM dissolution in physiological media. In summary, we recommend the standardization of ENM dissolution testing by one of the three valid lysosomal simulant fluids with determination of the dissolution rate and halftime by the quantification of ions. This recommendation was established for a continuous flow system but may be relevant as well for static (batch) solubility testing.

Systemic calcitonin gene-related peptide receptor antagonism decreases survival in a porcine model of polymicrobial sepsis: blinded randomised controlled trial.

BACKGROUND: Calcitonin gene-related peptide (CGRP) and procalcitonin, which are overexpressed in sepsis, exert distinct immunomodulatory effects mediated through the CGRP receptor. The CGRP receptor antagonist olcegepant improves survival in murine sepsis. This study evaluated whether CGRP receptor antagonism is similarly beneficial in a porcine model of polymicrobial sepsis. METHODS: We conducted a prospective randomised, controlled, investigator-blinded trial in adult pigs of either sex, that were anaesthetised and ventilated before sepsis was induced by polymicrobial (autologous) faecal peritonitis. After the onset of early septic shock (systolic blood pressure <90 mm Hg or >10% decline from baseline MAP), pigs were resuscitated (i.v. fluid/antibiotics/vasopressors) and randomised to receive either i.v. olcegepant (n=8) or vehicle control (n=8). The primary outcome was time to death, euthanasia required up to 72 h after surgery (according to predefined severe cardiorespiratory failure), or both. Secondary outcomes included haemodynamic changes, and systemic as well as organ inflammation (mRNA expression). RESULTS: Septic shock developed 8.7 h (inter-quartile range, 5.8-11.1 h) after the onset of faecal peritonitis. Olcegepant worsened survival, with 6/8 pigs randomised to the control group surviving 72.0 h (50.9-72.0 h), compared with 3/8 pigs receiving olcegepant surviving 51.3 h (12.5-72.0 h; P=0.01). At 48 h, lower MAP and higher cardiac output occurred in pigs receiving olcegepant. Cardiac, hepatic, and renal injury was not different between pigs randomised to receive olcegepant or vehicle. Olcegepant reduced mRNA expression of several inflammation-related cytokines and CD68+ macrophages in liver but not in lung tissue. CONCLUSIONS: CGRP receptor antagonism with olcegepant was not beneficial in this porcine model of polymicrobial sepsis, which closely mimics human sepsis.

The Use of Nanomaterial In Vivo Organ Burden Data for In Vitro Dose Setting.

Effects of nanomaterials are usually observed at higher concentrations in vitro compared to animal studies. This is pointing to differences between in vivo situations and generally less complex in vitro models. These differences concern toxicodynamics and the internal exposure (at the target cells of the in vitro and in vivo test system). The latter can be minimized by appropriate in vivo to in vitro dose extrapolations (IVIVE). An IVIVE six-step procedure is proposed here: 1) determine in vivo exposure; 2) identify in vivo organ burden at lowest observed adverse effect concentration; 3) extrapolate in vivo organ burden to in vitro effective dose; 4) extrapolate in vitro effective dose to nominal concentration; 5) set dose ranges to establish dose-response relationships; and 6) consider uncertainties and specificities of in vitro test system. Assessing the results of in vitro studies needs careful consideration of discrepancies between in vitro and in vivo models: apart from different endpoints (usually cellular responses in vitro and adverse effects on organs or organisms in vivo), nanomaterials can also have a different potency in relatively simple in vitro models and the more complex corresponding organ in vivo. IVIVE can, nonetheless, reduce the differences in exposures.

Simulating Nanomaterial Transformation in Cascaded Biological Compartments to Enhance the Physiological Relevance of In Vitro Dosing Regimes: Optional or Required?

Would an engineered nanomaterial (ENM) still have the same identity once it reaches a secondary target tissue after a journey through several physiological compartments? Probably not. Does it matter? ENM pre-treatments may enhance the physiological relevance of in vitro testing via controlled transformation of the ENM identity. The implications of material transformation upon reactivity, cytotoxicity, inflammatory, and genotoxic potential of Ag and SiO2 ENM on advanced gastro-intestinal tract cell cultures and 3D liver spheroids are demonstrated. Pre-treatments are recommended for certain ENM only.

Procalcitonin Exerts a Mediator Role in Septic Shock Through the Calcitonin Gene-Related Peptide Receptor.

OBJECTIVES: Clinically, procalcitonin represents the most widely used biomarker of sepsis worldwide with unclear pathophysiologic significance to date. Pharmacologically, procalcitonin was shown to signal through both calcitonin receptor and calcitonin gene-related peptide receptor in vitro, yet the identity of its biologically relevant receptor remains unknown. DESIGN: Prospective randomized animal investigations and in vitro human blood studies. SETTING: Research laboratory of a university hospital. SUBJECTS: C57BL/6J mice and patients with post-traumatic sepsis. INTERVENTIONS: Procalcitonin-deficient mice were used to decipher a potential mediator role in experimental septic shock and identify the relevant receptor for procalcitonin. Cecal ligation and puncture and endotoxemia models were employed to investigate septic shock. Disease progression was evaluated through survival analysis, histology, proteome profiling, gene expression, and flow cytometry. Mechanistic studies were performed with cultured macrophages, dendritic cells, and gamma delta T cells. Main findings were confirmed in serum samples of patients with post-traumatic sepsis. MEASUREMENTS AND MAIN RESULTS: Procalcitonin-deficient mice are protected from septic shock and show decreased pulmonary inflammation. Mechanistically, procalcitonin potentiates proinflammatory cytokine expression in innate immune cells, required for interleukin-17A expression in gamma delta T cells. In patients with post-traumatic sepsis, procalcitonin positively correlates with systemic interleukin-17A levels. In mice with endotoxemia, immunoneutralization of interleukin-17A inhibits the deleterious effect of procalcitonin on disease outcome. Although calcitonin receptor expression is irrelevant for disease progression, the nonpeptide calcitonin gene-related peptide receptor antagonist olcegepant, a prototype of currently introduced antimigraine drugs, inhibits procalcitonin signaling and increases survival time in septic shock. CONCLUSIONS: Our experimental data suggest that procalcitonin exerts a moderate but harmful effect on disease progression in experimental septic shock. In addition, the study points towards the calcitonin gene-related peptide receptor as relevant for procalcitonin signaling and suggests a potential therapeutic application for calcitonin gene-related peptide receptor inhibitors in sepsis, which warrants further clinical investigation.

Proinflammatory and bone protective role of calcitonin gene-related peptide alpha in collagen antibody-induced arthritis.

OBJECTIVES: Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling. METHODS: Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT. RESULTS: CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1ß, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time. CONCLUSION: This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.

Understanding the impact of more realistic low-dose, prolonged engineered nanomaterial exposure on genotoxicity using 3D models of the human liver.

BACKGROUND: With the continued integration of engineered nanomaterials (ENMs) into everyday applications, it is important to understand their potential for inducing adverse human health effects. However, standard in vitro hazard characterisation approaches suffer limitations for evaluating ENM and so it is imperative to determine these potential hazards under more physiologically relevant and realistic exposure scenarios in target organ systems, to minimise the necessity for in vivo testing. The aim of this study was to determine if acute (24 h) and prolonged (120 h) exposures to five ENMs (TiO2, ZnO, Ag, BaSO4 and CeO2) would have a significantly different toxicological outcome (cytotoxicity, (pro-)inflammatory and genotoxic response) upon 3D human HepG2 liver spheroids. In addition, this study evaluated whether a more realistic, prolonged fractionated and repeated ENM dosing regime induces a significantly different toxicity outcome in liver spheroids as compared to a single, bolus prolonged exposure. RESULTS: Whilst it was found that the five ENMs did not impede liver functionality (e.g. albumin and urea production), induce cytotoxicity or an IL-8 (pro-)inflammatory response, all were found to cause significant genotoxicity following acute exposure. Most statistically significant genotoxic responses were not dose-dependent, with the exception of TiO2. Interestingly, the DNA damage effects observed following acute exposures, were not mirrored in the prolonged exposures, where only 0.2-5.0 µg/mL of ZnO ENMs were found to elicit significant (p ≤ 0.05) genotoxicity. When fractionated, repeated exposure regimes were performed with the test ENMs, no significant (p ≥ 0.05) difference was observed when compared to the single, bolus exposure regime. There was < 5.0% cytotoxicity observed across all exposures, and the mean difference in IL-8 cytokine release and genotoxicity between exposure regimes was 3.425 pg/mL and 0.181%, respectively. CONCLUSION: In conclusion, whilst there was no difference between a single, bolus or fractionated, repeated ENM prolonged exposure regimes upon the toxicological output of 3D HepG2 liver spheroids, there was a difference between acute and prolonged exposures. This study highlights the importance of evaluating more realistic ENM exposures, thereby providing a future in vitro approach to better support ENM hazard assessment in a routine and easily accessible manner.

Comparison of Perfluorodecalin and Silicone Oil as Initial Tamponade for Giant Retinal Tear-Associated Retinal Detachment.

INTRODUCTION: To compare visual outcomes and complication rates of giant retinal tear-associated retinal detachment (GRT-RD) cases treated with short-term perfluorodecalin (PFD) tamponade versus silicone oil (SiO). METHODS: Database analysis of patients with GRT-RD operated on in the period from 1 January 2014 to 31 December 2019. RESULTS: Forty-five patients were operated for GRT-RD using PFD or SiO during this period. Two children, 7 patients receiving gas tamponade, and 2 lost to follow-up were excluded. Eighteen eyes (40%) received PFD and 27 (60%) received SiO. There were 15/18 (83%) macula-sparing cases in the PFD group and 18/27 (67%) in the SiO group (p = 0.13). The mean duration of oil tamponade was 91 days for SiO and 7.6 days for PFD (p < 0.0001). The mean length of follow-up was 274.5 days for PFD and 668.9 days for SiO. The mean BCVA was 6/18 (63.4 ± 26.0 ETDRS letters) for SiO and 6/12 (72.9 ± 12.7 ETDRS letters) for PFD (p = 0.42). Analysing macula-sparing pseudophakic eyes, the BCVA was 6/12 (67.4 ± 25.9 letters, n = 18) for SiO eyes and 6/9 (76.8 ± 9.9 letters, n = 11) for PFD eyes (p = 0.54). The recurrence rate was 22% (6/27) for SiO and 6% (1/18) for PFD (p = 0.12). The rate of cystoid macular oedema (CMO) was 22% for SiO and 22% for PFD. Epiretinal membrane (ERM) was found in 26% of SiO cases and 22% of PFD cases. Loss of vision after oil removal was not observed. Seven eyes (26%) receiving SiO and none receiving PFD developed chronic ocular hypertension (OHT) (p = 0.02). CONCLUSIONS: Short-term tamponade with PFD for GRT-RD appears similar to tamponade with SiO in terms of the visual outcomes and complication rates.

Inducing empathy affects cardiovascular reactivity reflected in changes in high-frequency heart rate variability.

Empathy represents an emotional trigger of prosocial emotions and social engagement behaviour as previous research demonstrates. Departing from literature indicating that parasympathetic mechanisms are associated with the preparation of social engagement behaviour, the present research investigates how feeling with another person affects empathising individuals' cardiovascular reactivity reflecting influences of parasympathetic mechanisms. Specifically, individuals' high-frequency heart rate variability (HF-HRV) while being instructed to feel with a target person in need reacting with a specific emotional response to a need-causing event (with anger or sadness) was investigated. Results of one experiment (N = 124) revealed that inducing empathy with needy target persons results in increases of HF-HRV - irrespective of their emotional reaction. No relation between cardiovascular indices and self-reported prosocial behaviour was found. Accordingly, these findings indicate that inducing empathy affects phasic vagal activity implied by parasympathetic mechanisms whereas the association of cardiovascular reactivity and social engagement behaviour needs further investigation.

Tranexamic Acid Promotes Murine Bone Marrow-Derived Osteoblast Proliferation and Inhibits Osteoclast Formation In Vitro.

Despite modern surgical trauma care, bleeding contributes to one-third of trauma-related death. A significant improvement was obtained through the introduction of tranexamic acid (TXA), which today is widely used in emergency and elective orthopedic surgery to control bleeding. However, concerns remain regarding potential adverse effects on bone turnover and regeneration. Therefore, we employed standardized cell culture systems including primary osteoblasts, osteoclasts, and macrophages to evaluate potential effects of TXA on murine bone cells. While osteoblasts derived from calvarial digestion were not affected, TXA increased cell proliferation and matrix mineralization in bone marrow-derived osteoblasts. Short-term TXA treatment (6 h) failed to alter the expression of osteoblast markers; however, long-term TXA stimulation (10 days) was associated with the increased expression of genes involved in osteoblast differentiation and extracellular matrix synthesis. Similarly, whereas short-term TXA treatment did not affect gene expression in terminally differentiated osteoclasts, long-term TXA stimulation resulted in the potent inhibition of osteoclastogenesis. Finally, in bone marrow-derived macrophages activated with LPS, simultaneous TXA treatment led to a reduced expression of inflammatory cytokines and chemokines. Collectively, our study demonstrates a differential action of TXA on bone cells including osteoanabolic, anti-resorptive, and anti-inflammatory effects in vitro which suggests novel treatment applications.

Glucose Metabolism in Osteoblasts in Healthy and Pathophysiological Conditions.

Bone tissue in vertebrates is essential to performing movements, to protecting internal organs and to regulating calcium homeostasis. Moreover, bone has also been suggested to contribute to whole-body physiology as an endocrine organ, affecting male fertility; brain development and cognition; and glucose metabolism. A main determinant of bone quality is the constant remodeling carried out by osteoblasts and osteoclasts, a process consuming vast amounts of energy. In turn, clinical conditions associated with impaired glucose metabolism, including type I and type II diabetes and anorexia nervosa, are associated with impaired bone turnover. As osteoblasts are required for collagen synthesis and matrix mineralization, they represent one of the most important targets for pharmacological augmentation of bone mass. To fulfill their function, osteoblasts primarily utilize glucose through aerobic glycolysis, a process which is regulated by various molecular switches and generates adenosine triphosphate rapidly. In this regard, researchers have been investigating the complex processes of energy utilization in osteoblasts in recent years, not only to improve bone turnover in metabolic disease, but also to identify novel treatment options for primary bone diseases. This review focuses on the metabolism of glucose in osteoblasts in physiological and pathophysiological conditions.

Relevance of Notch Signaling for Bone Metabolism and Regeneration.

Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/ß-catenin, BMP and RANKL/OPG, are outlined.

Using a Telegram chatbot as cost-effective software infrastructure for ambulatory assessment studies with iOS and Android devices.

In this work, we present an innovative and cost-effective approach to run ambulatory assessment (AA) studies on participants' smartphones via Telegram Messenger. Our approach works both for Android and iOS devices. The population of potential participants in a given country or region consists of all individuals who (a) are in possession of a smartphone, (b) are willing to install Telegram Messenger, and (c) live in an environment providing constant connection to the Internet. In our new approach to AA, participants are asked to subscribe to a Telegram chatbot that provides them with links to brief surveys at specified points in time in their everyday lives via short notifications. We developed a user-friendly Python script that allows for the flexible editing of the chatbot's settings, e.g., the number of surveys per day. All common survey software designed for mobile devices can be used to present surveys to participants. This means that data collection takes place exclusively via the selected survey software, not via Telegram. With our approach, AA studies can be carried out among iOS and Android users cost-effectively and reliably while data security is ensured. Initial data from a pilot study show that studies of this kind are feasible, and the procedure is accepted by participants. Our Python script is licensed under General Public License (GPLv3) and therefore freely available and editable: https://github.com/Raze97/Telegram-Survey-Bot.

[Robotic Assisted Proctocolectomy with Ileal Pouch-Anal Anastomosis in a Case of Suspected Hereditary Polyposis]. / Roboterassistierte Proktokolektomie mit ileopouchanaler Anastomose bei Verdacht auf hereditäre Polyposis.

BACKGROUND: Various forms of hereditary polyposis have been described in the literature. Classical familial adenomatous polyposis (FAP) is a rare, autosomal dominantly inherited disease which is caused by a germline mutation in the adenomatous polyposis coli gene (APC). Patients with this diagnosis successively develop multiple polyps of the colon. Left untreated, FAP almost inevitably leads to malignant transformation. INDICATION: We present the case of a 37-year-old patient with histologically confirmed, stenotic adenocarcinoma of the descending colon and an initially suspected hereditary polyposis due to multiple polyps in the descending and sigmoid colon. METHODS: The video describes the preoperative imaging as well as endoscopic findings and demonstrates the technique of a two-stage, robotically assisted proctocolectomy with ileal pouch-anal anastomosis (IPAA) and the creation of a temporary loop ileostomy. CONCLUSIONS: With respect to the surgical treatment of classic FAP, restorative proctocolectomy (RPC) with ileal J-pouch construction can be regarded as an established standard procedure, despite controversy regarding various technical aspects. Minimally invasive strategies should be considered as an equivalent option compared to conventional techniques.

Crosstalk of Brain and Bone-Clinical Observations and Their Molecular Bases.

As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain 'efferent', signaling from brain to bone, this review emphasizes the emergence of bone as a crucial 'afferent' regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

Self-Contempt as a Predictor of Suicidality: A Longitudinal Study.

People with mental illness can internalize public prejudice and negative emotional reactions to their group, leading to self-contempt. This study examined self-contempt related to having a mental illness as predictor of suicidality among 77 people with mental illness in Southern Germany. Self-contempt, depressive symptoms, hopelessness, and suicidality were assessed at baseline; suicidality was measured again 3 months later. High self-contempt at baseline predicted increased suicidality at follow-up, adjusting for baseline suicidality, symptoms, diagnosis, age, sex, and hopelessness. These results suggest that self-contempt may be a risk factor for suicidality and call for specific interventions targeting self-stigma and its emotional consequences.