Measurement of aggregate risk with copulas

Summary When aggregating financial risk on a portfolio level, the specification of the dependence structure between the risk factors plays an important role. Promising parametric models are often based on a so-called copula approach. Case studies of market crashes suggest the application of concepts allowing for extremal dependence. We present a transformed copula as a new model that both fits the data and allows for exact prediction in the tails. It turns out that the new model improves benchmark models like the t- or Clayton copula with respect to risk measures like VaR or Expected Shortfall. By performing different goodness-of-fit tests, the quality of the estimation is examined.     

Prävention von CMV-Infektionen bei Frühgeborenen (<28 + 0 SSW oder einem Geburtsgewicht <1000 g) durch Muttermilch – Update 2018

Monatsschrift Kinderheilkunde - Das Zytomegalievirus (CMV) kann während der Laktation reaktiviert und über Muttermilch übertragen werden. Diese Übertragung ist für reife...     

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows.     

Functional modulation of PTH1R activation and signaling by RAMP2

Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein–coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signaling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique preactivated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modeling, we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signaling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.

G protein–coupled receptors(GPCRs) represent the largest class of membrane-bound proteins and are involved in a multitude of biological processes (1). They are characterized by a seven-transmembrane helix structure, which undergoes a characteristic rearrangement upon binding of agonists. Agonist binding to its cognate receptor induces conformational changes in the transmembrane helices, which are transmitted to the cytosolic face of the receptors and ultimately result in receptor activation, which represents the key step of signal transduction. The combination of crystallographic and cryogenic electron microscopy studies and the employment of optical biosensors to study the reorganization of the seven transmembrane domains has allowed a detailed understanding of the general mechanisms of GPCR activation (2–5).Earlier structural studies suggest that GPCRs undergo similar conformational changes upon activation, including, most prominently, an outward movement of the transmembrane helix 6 at the cytosolic face, thereby creating a pocket to which the G protein α-subunit can couple (5). More recent studies, however, have revealed that the exact type of changes may depend on the receptor class and the specific receptor (6–8). Class- and receptor-specific differences may also exist in the interaction of receptors not only with downstream G proteins and β-arrestins but also with accessory and modulatory proteins (9).Studies of the kinetic steps that govern the structural rearrangements which underlie receptor activation (10) showed that its speed might depend on the receptor class and the specific receptor. For example, when exposed to saturating agonist concentrations, most class A GPCRs switch into the active state within tens of milliseconds. The same process takes 1 to 2 ms for a class C GPCR and may take up to a second for class B receptors (11–15). Little is known whether the activation kinetics of GPCRs can be modulated by their cellular context and whether proteins other than the receptors themselves might play a role in shaping signaling kinetics and specificity.Here, we study the parathyroid hormone 1 receptor (PTH1R), a prototypical member of class B GPCRs characterized by a large N-terminal domain that binds a major part of their cognate peptide agonists (16, 17). Compared to class A GPCRs, PTH1R activation is relatively slow and occurs in a two-step process: The initial N-terminal binding step has a time constant of ∼140 ms, followed by an interaction of the ligand with the transmembrane core, which changes into its active conformation with a time constant of ∼1 s (11, 14). Pleiotropic in its downstream coupling, PTH1R signals primarily via G_s but can also couple to G_q (18), G_12/13 (19), and G_i (20) and interacts with and signals via β-arrestins (21, 22). The two endogenous agonists, parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), trigger PTH1R activation with similar kinetics and specificity for the various intracellular pathways (23–25). However, PTH can induce prolonged signaling from intracellular sites, while PTHrP signals exclusively from the cell surface (26).PTH1R has been reported to interact with modulatory proteins of the receptor-activity-modifying protein (RAMP) family (27–29). RAMPs constitute a family of single transmembrane helix proteins with three members: RAMP1, RAMP2, and RAMP3.It is controversial whether PTH1R interacts only or preferentially with RAMP2 (28) or all three RAMPs (28, 29). In RAMP2 knock-out mice, PTH1R function is deregulated, and placental dysfunction is observed (30), suggesting a major physiological role of the PTH1R/RAMP2 interaction. Yet, the molecular mechanisms of how RAMPs may modulate the activation dynamics of PTH1R and their signaling properties remain to be elucidated.To address these questions, we develop and employ biosensors for PTH1R activation and investigate an array of downstream signaling pathways to assess the effects of RAMPs on the activation dynamics and signaling properties of PTH1R in response to its two endogenous ligands, PTH and PTHrP. We observe that RAMP2 specifically interacts with PTH1R and modulates its activation kinetics as well as signaling dynamics in an agonist-dependent manner.     

Occult lung infarction may induce false interpretation of 18F-FDG PET in primary staging of pulmonary malignancies

Purpose The aim of the present report is to describe abnormal ¹⁸F-fluorodeoxyglucose (FDG) accumulation patterns in the pleura and lung parenchyma in a group of lung cancer patients in whom lung infarction was present at the time of positron emission tomography (PET).Methods Between November 2002 and December 2003, a total of 145 patients (102 males, 43 females; age range 38–85 years) were subjected to whole-body FDG PET for initial staging (n=117) or restaging (n=11) of lung cancer or for evaluation of solitary pulmonary nodules (n=17). Of these patients, 24 displayed abnormal FDG accumulation in the lung parenchyma that was not consistent with the primary lesion under investigation (ipsilateral n=12, contralateral n=9 or bilateral n=3). Without correlative imaging, this additional FDG uptake would have been considered indeterminate in differential diagnosis.Results Of the 24 patients who were identified as having such lesions, six harboured secondary tumour nodules diagnosed as metastases, while in three the diagnosis of a synchronous second primary lung tumour was established. Additionally, nine patients were identified as having post-stenotic pneumonia and/or atelectasis (n=6) or granulomatous lung disease (n=3). In the remaining six (4% of all patients), a diagnosis of recent pulmonary embolism that topographically matched the additional FDG accumulation (SUV_max range 1.4–8.6, mean 3.9) was made. Four of these six patients were known to have pulmonary embolism, and hence false positive interpretation was avoided by correlating the PET findings with those of the pre-existing diagnostic work-up. The remaining two patients were harbouring small occult infarctions that mimicked satellite nodules in the lung periphery. Based on histopathological results, the abnormal FDG accumulation in these two patients was attributed to the inflammatory reaction and tissue repair associated with the pathological cascade of pulmonary embolism.Conclusion In patients with pulmonary malignancies, synchronous lung infarction may induce pathological FDG accumulation that can mimic active tumour manifestations. Identifying this potential pitfall may allow avoidance of false positive FDG PET interpretation.     

Antibacterial and Biodegradable Polysaccharide-Based Films for Food Packaging Applications: Comparative Study

One of the major objectives of food industry is to develop low-cost biodegradable food packaging films with optimal physicochemical properties, allowing for their large-scale production and providing a variety of applications. To meet the expectations of food industry, we have fabricated a series of solution-cast films based on common biodegradable polysaccharides (starch, chitosan and alginate) to be used in food packaging applications. Selected biopolymers were modified by the addition of glycerol and oxidized sucrose (starch), glycerol (chitosan), and glycerol and calcium chloride (alginate), as well as being used to form blends (starch/chitosan and starch/alginate, respectively). A chestnut extract was used to provide antibacterial properties to the preformed materials. The results of our studies showed that each modification reduced the hydrophilic nature of the polymers, making them more suitable for food packaging applications. In addition, all films exhibited much higher barrier properties to oxygen and carbon dioxide than commercially available films, such as polylactic acid, as well as exhibiting antimicrobial properties against model Gram-negative and Gram-positive bacteria (Escherichia coli and Staphylococcus epidermidis, respectively), as well as yeast (Candida albicans).     

Infrainguinal atherectomy: a retrospective review of a single-center experience

By decreasing plaque burden, atherectomy provides an alternative to angioplasty and stenting as a means of revascularizing patients with peripheral arterial disease. A new atherectomy device (SilverHawk) has recently been approved by the Food and Drug Administration, but the results with its use are unclear. We analyzed a series of consecutive patients undergoing atherectomy. We retrospectively reviewed the charts of 35 patients undergoing infrainguinal (IF) atherectomy in 38 limbs. The Trans-Atlantic Inter-Society Consensus (TASC) classification and Society of Vascular Surgery runoff scores were calculated. Time to event analysis was performed using Kaplan-Meier estimates. Risk factors affecting patency were analyzed with a multivariate Cox model. Mean patient age was 70 +/- 9.6 years. Indications for intervention were claudication (26%), rest pain (21%), and tissue loss (53%). Femoropopliteal (FP) atherectomy was performed in 68% and tibial atherectomy in 32%. For FP lesions, the TASC distribution was A, 42%; B, 23%; C, 4%; and D, 15%. The average lesion treatment length was 9.4 +/- 10.6 cm (range 1-40), and the runoff score was 5.1 +/- 3.5. For tibial lesions, the TASC distribution was A, 0%; B, 17%; C, 8%; and D, 75%. The average lesion treatment length was 9.2 +/- 6.0 cm (range 2-20), with a runoff score of 5.4 +/- 2.4. A total of 39% of patients had prior IF interventions. Adjunctive angioplasty of the atherectomized lesion was performed in 55% of cases, stenting in 0%, and adjunctive therapy for tandem lesions in 39%. The postoperative ankle-brachial index increased by 0.30 +/- 0.14 and toe pressures increased by 40 +/- 32.4 mm Hg. Mean follow-up was 10 +/- 8 months (range 0.3-23). During the studied period, seven patients required major limb amputation and five open surgical revascularization. Total primary and secondary patency rates were 66% and 70% at 1 year, respectively. Primary and secondary patency rates for FP atherectomy were 68% and 73% at 1 year, respectively. The limb salvage rate was 74% at 6 months. Patients with prior interventions in the atherectomized segment had an almost 10-fold decrease in primary patency. Atherectomy produces acceptable results, similar to those in reported series of conventional balloon angioplasty/stenting. Patients with prior IF interventions had a nearly 10-fold decrease in primary patency. A greater than sixfold decrease in patency rates was noted in patients who underwent simultaneous inflow or outflow procedures, but this finding did not reach statistical significance (p = 0.082). Future studies should focus on cost comparisons with other treatments such as angioplasty and stenting, and prospective randomized trials should be performed to compare these treatment alternatives.     

Real-Time Sonoelastography of Salivary Glands for Diagnosis and Functional Assessment of Primary Sjögren’s Syndrome

The purpose of this study was to investigate the value of real-time sonoelastography (RTS) of salivary glands for the diagnosis and assessment of glandular damage in primary Sjögren’s syndrome (pSS). After institutional review board approval, 45 pSS patients, 24 sicca patients and 11 healthy controls were investigated prospectively. Questionnaires were completed and Saxon and Schirmer tests and routine blood tests carried out in all patients. All patients underwent B-mode ultrasonography and RTS of parotid and submandibular glands. Abnormal findings were graded from 0 to 48 and from 0 to 16, respectively. Sialoscintigraphy was done according to a routine protocol; scoring ranged from 0 to 12. Statistical analysis comprised receiver operating characteristic curve and multivariate regression analysis. Patients with pSS had higher B-mode (median score = 25 [range: 2–44] vs. 9 [1–20], p < 0.001) and RTS (6.5 [2–13] versus 4 [1–9], p < 0.001) scores than controls with sicca syndrome, yielding areas under the curve of 0.83 and 0.85 (p < 0.05 each), respectively for pSS diagnosis. In cases with an inconclusive B-mode ultrasonography result, RTS (cutoff score: ≥6) led to a sensitive (66.7%) and specific (85.7%) classification of patients and sicca controls. In multivariate regression analysis, RTS (regression coefficient = –0.48, p = 0.005), but not B-mode ultrasonography, reflected impaired salivary gland function according to the Saxon test, whereas none of the subjective measures of dryness or discomfort were related to ultrasonography results. B-mode and RTS results were both associated with sialoscintigraphy scores (regression coefficient = 0.66, p < 0.001, and regression coefficient = 0.55, p = 0.001, respectively). Reproducibility of B-mode ultrasonography and RTS was good, with intra-class correlation coefficients of 0.93 (95% confidence interval: 0.57–0.98) and 0.93 (95% confidence interval: 0.79–0.98), respectively. In summary, RTS might be a useful adjunct to B-mode ultrasonography for diagnosis and assessment of salivary gland impairment in primary Sjögren’s syndrome.     

Rolle der Diabetesberatung im digitalen Zeitalter

Digitization has long since taken hold in the diabetes sector. Digital support including pumps, rtCGM (CGM: continuous glucose monitoring, rtCGM: real time CGM), iscCGM (intermittent scanning CGM), apps as well as measuring devices with pattern recognition and a reminder function has become commonplace in many areas. Training to become a diabetes advisor provides diabetes professionals with appropriate basic knowledge to advise the patient in self-management with technical support. Continuous medical training to empower and support patients in health literacy, data protection and the use of telemedicine is imperative.