Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

BACKGROUND: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. OBJECTIVES: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. SEARCH METHODS: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. SELECTION CRITERIA: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. DATA COLLECTION AND ANALYSIS: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. MAIN RESULTS: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. AUTHORS' CONCLUSIONS: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

Comparative efficacy and acceptability of expressive writing treatments compared with psychotherapy, other writing treatments, and waiting list control for adult trauma survivors: a systematic review and network meta-analysis.

BACKGROUND: Expressive writing about a traumatic event is promising in treating posttraumatic stress disorder (PTSD) symptoms in adult trauma survivors. To date, the comparative efficacy and acceptability of this approach is uncertain. Therefore, we aimed to examine the comparative efficacy and acceptability of expressive writing treatments. METHODS: We included 44 RCTs with 7724 participants contributing 54 direct comparisons between expressive writing (EW), enhanced writing (i.e. including additional therapist contact or individualized writing assignments; EW+), PTSD psychotherapies (PT), neutral writing (NW), and waiting-list control (WL). RESULTS: EW, EW+, PT, and NW were statistically significantly more efficacious than WL at the longest available follow-up, with SMDs (95% CI) of -0.78 (-1.10 to -0.46) for PT, -0.81 (-1.02 to -0.61) for EW+ , -0.43 (-0.65 to -0.21) for EW, and -0.37 (-0.61 to -0.14) for NW. We found small to moderate differences between the active treatments. At baseline mean PTSD severity was significantly lower in EW+ compared with WL. We found considerable heterogeneity and inconsistency and we found elevated risk of bias in at least one of the bias dimensions in all studies. When EW+-WL comparisons were excluded from the analyses EW+ was no longer superior compared with EW. CONCLUSIONS: The summarized evidence confirms that writing treatments may contribute to improving PTSD symptoms in medium to long-term. Methodological issues in the available evidence hamper definite conclusions regarding the comparative efficacy and acceptability of writing treatments. Adequately sized comparative randomized controlled trials preferably including all four active treatment approaches, reporting long-term data, and including researchers with balanced preferences are needed.

Endoscopic negative pressure therapy as stand-alone treatment for perforated duodenal diverticulum: presentation of two cases.

BACKGROUND: Endoscopic negative pressure therapy is a novel and successful treatment method for a variety of gastrointestinal leaks. This therapy mode has been frequently described for rectal and esophageal leakages. Duodenal diverticular perforations are rare but life-threatening events. The early diagnosis of duodenal diverticular perforation is often complicated by inconclusive symptoms. This is the first report about endoscopic negative pressure therapy in patients with perforated duodenal diverticula. CASE PRESENTATION: We present two cases of duodenal diverticula perforations treated with endoscopic negative pressure therapy as stand-alone treatment. Start of symptoms varied from one to three days before hospital admission. Early sectional imaging led to the diagnosis of duodenal diverticular perforation. Both patients were treated with endoluminal endoscopic negative pressure therapy with simultaneous feeding option. Three respective changes of the suction device were performed. Both patients were treated with antibiotics and antimycotics during their hospital stay and be discharged from hospital after 20 days. CONCLUSIONS: This is the first description of successful stand-alone treatment by endoscopic negative pressure therapy in two patients with perforated duodenal diverticulum. We thus strongly recommend to attempt interventional therapy with endoluminal endoscopic negative pressure therapy in patients with duodenal diverticular perforations upfront to surgery.

Significance and clinical impact of routinely tested urinary ethyl glucuronide after liver transplantation - development of a risk score.

Alcohol abuse after liver transplantation can seriously impact graft and patient survival. However, to date, there is no defined standard procedure to identify patients consuming alcohol after liver transplantation. The aim of this study was to analyze the diagnostic value and clinical impact of routinely measured urinary ethyl glucuronide (uEtG) - a metabolite of ethanol - in patients after liver transplantation. Data of 362 consecutive patients after liver transplantation who visited the University Hospital of Tuebingen for outpatient follow-up were analyzed. Forty-eight patients (13%) displayed positive uEtG results. The uEtG positive group contained significantly more patients with pretransplant alcoholic liver disease. However, two thirds of the uEtG positive patients had no history of pretransplant alcoholic liver disease. Several clinical parameters were significantly associated with positive uEtG. In order to enable a more cost-effective application of uEtG in the future, a clinical risk score was developed (specificity 0.95). In conclusion, routine testing for uEtG reveals a considerable percentage of patients practicing alcohol intake after liver transplantation. Application of our proposed risk score could help focusing uEtG testing on patients at risk.

Health literacy and eHealth among adult asthma patients - results of a cross sectional survey.

Background: To investigate HL (health literacy) and eHealth literacy (eHL) among two groups of asthma outpatients, those with prior asthma education and those without. In addition, we aimed to compare two shortened versions of a HL measure instrument.Methods: A cross-sectional survey was conducted with a sample of adult asthma patients (n = 129). Half of them had received asthma patient education prior to the study (n = 64). The study collected demographic data, questions on HL (HLS-EU-Q16) and eHL (eHEALS).Results: In the main analysis respondents' mean HL values were almost identical in both groups, 11.9 (SD = 3.1) among trained and 11.8 (SD = 3.5) among untrained patients, demonstrating a problematic level of HL, according to the instrument. In the subdivision of sum scores, the HL level of trained patients was categorized more often as problematic (43%) than among untrained patients (20%). Bland-Altman plots of the 6-item and 16-item versions of the HLS-EU suggest only limited agreement between the versions. In terms of eHL, trained patients showed a mean of 3.0 (SD = 1.1) and untrained patients a mean of 3.2 (SD = 1.0). Analysis of HL and eHL showed no difference between groups.Conclusions: No consistent differences between groups were found, suggesting that trained patients did not benefit from asthma education regarding HL and eHL. The 6-item and 16-item versions of the HLS-EU were not easily interchangeable, limiting its use in a busy outpatient practice.AbbreviationseHEALSElectronic Health Literacy ScaleeHLElectronic Health Literacy HLS-EUEuropean Health Literacy Survey.

Impact of the COVID-19 pandemic on an interdisciplinary endoscopy unit in a German "hotspot" area: a single center experience.

BACKGROUND AND STUDY AIMS: Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19), has posed a pandemic threat to global health and has challenged health care system in all affected countries. PATIENTS AND METHODS: This is a combined study including a descriptive part about the changes in the daily work routine of an Interdisciplinary Endoscopic Unit (IEU) and a prospective analysis of patients tested positive for SARS-CoV-2 who required endoscopic interventions. Conclusively, we present the finding of a point-prevalence analysis in the staff of the IEU. RESULTS: We present effects of the COVID-19-related restructuring of processes in our interdisciplinary endoscopy unit (IEU) with respect to cancelation of examinations, relocation of staff to other departments, impact of SARS-CoV-2 on medical staff of the IEU, and supply of protective clothing. Additionally, we analyzed the cohort of COVID-19 patients: Sixteen endoscopic interventions were done in ten patients. In all patients with confirmed infection with SARS-CoV-2, emergency endoscopies were required for relevant bleeding situations. Re-endoscopies were required only in critically ill COVID-19 patients. CONCLUSIONS: The restructuring of processes in the IEU was feasible in short time, effective, and can also be applied broadly at least in developed countries [Garbe et al. in Gastroenterology 159:778-780, 2020; Repici A, Pace F, Gabbiadini R, Colombo M, Hassan C, Dinelli M, Group IG-CW, Maselli R, Spadaccini M, Mutignani M, Gabbrielli A, Signorelli C, Spada C, Leoni P, Fabbri C, Segato S, Gaffuri N, Mangiavillano B, Radaelli F, Salerno R, Bargiggia S, Maroni L, Benedetti A, Occhipinti P, De Grazia F, Ferraris L, Cengia G, Greco S, Alvisi C, Scarcelli A, De Luca L, Cereatti F, Testoni PA, Mingotto R, Aragona G, Manes G, Beretta P, Amvrosiadis G, Cennamo V, Lella F, Missale G, Lagoussis P, Triossi O, Giovanardi M, De Roberto G, Cantu P, Buscarini E, Anderloni A, Carrara S, Fugazza A, Galtieri PA, Pellegatta G, Antonelli G, Rosch T, Sharma P (2020) Endoscopy units and the COVID-19 Outbreak: a Multi-Center Experience from Italy. Gastroenterology;]. The endoscopy-related rate of SARS-CoV-2 infection of staff is low, but supply of protective equipment is crucial for this. Endoscopic procedures in COVID-19 patients were not directly related to SARS-CoV-2 infection, but to other underlying diseases or typical complications of long-term ICU treatment.

Pockels-effect-based adiabatic frequency conversion in ultrahigh-Q microresonators.

Adiabatic frequency conversion has some key advantages over nonlinear frequency conversion. No threshold and no phase-matching conditions need to be fulfilled. Moreover, it exhibits a conversion efficiency of 100 % down to the single-photon level. Adiabatic frequency conversion schemes in microresonators demonstrated so far suffer either from low quality factors of the employed resonators resulting in short photon lifetimes or small frequency shifts. Here, we present an adiabatic frequency conversion (AFC) scheme by employing the Pockels effect. We use a non-centrosymmetric ultrahigh-Q microresonator made out of lithium niobate. Frequency shifts of more than 5 GHz are achieved by applying just 20 V to a 70-µm-thick resonator. Furthermore, we demonstrate that with the same setup positive and negative frequency chirps can be generated. With this method, by controlling the voltage applied to the crystal, almost arbitrary frequency shifts can be realized. The general advances in on-chip fabrication of lithium-niobate-based devices make it feasible to transfer the current apparatus onto a chip suitable for mass production.

Endoscopic negative pressure therapy with open-pore film drainage and open-pore polyurethane sponge drainage for iatrogenic perforation of the esophagus.

BACKGROUND: Management of iatrogenic esophageal perforation (IEP) is challenging. Endoscopic negative pressure therapy (ENPT) is an emerging and effective tool for the treatment of gastrointestinal and anastomotic leaks. We have used ENPT as first-line therapy for IEP since 2017. The aim of this study was to present our results with this strategy in patients with IEP. METHODS: Nine patients were treated with ENPT for IEP between August 2017 and August 2019. Their treatment characteristics, including duration of therapy, strategy used, and outcomes, were analyzed. Treatment included ENPT with open-pore film drainage (OFD) and open-pore polyurethane foam drainage (OPD). RESULTS: Early diagnosis (< 24 hours) of IEP occurred in four patients. After a mean (standard deviation) of 19.0 (13.5) days of ENPT, 6.4 (3.4) endoscopies, and 38.1 (40.3) days of hospitalization, endoscopic treatment was effective and successful in all of the patients. Additional video-assisted thoracic surgery (VATS) was done in four patients. CONCLUSIONS: ENPT is an effective new method for the management of IEP. ENPT with OFD and OPD can be combined with minimally invasive operative methods for sepsis control in IEP.

Case report of a cystic parathyroidal adenoma with rapid growth induced by cinacalcet.

BACKGROUND: Primary hyperparathyroidism is a rare condition of disease which can seldomly present as giant retrotrhyroideal cysts, complicating the localization of the adenoma to resect. CASE PRESENTATION: A 56-year old female presented with hypercalcaemia of 3.38 mmol/L (2.2-2.65 mmol/L) and a history of breast cancer. A fast growing cystic parathyroidal adenoma was diagnosed by a multimodal approach including comprehensive diagnostic imaging (ultrasonography, scintigraphies, dynamic MRI) and cytopathological investigations after ultrasonography-guided puncture. The patient was cured by surgical extraction of the whole adenoma. In retrospect, the rapid growth was most likely induced by cinacalcet (initially 30 mg/d, later 60 mg/d) therapy which the patient received for few months only. Primary hyperparathyroidism was ascertained because surgical removal of the solitary adenoma cured the patient. Furthermore, there was no relevant renal insufficiency or history of prolonged calcium-level deregulation. CONCLUSIONS: This phenomenon of cystic degeneration of parathyroidal adenoma under therapy with cinacalcet has previously been described in secondary hyperparathyroidism, but not in primary hyperparathyroidism and should be considered in diagnostic approach.

Participation factors for asthma education programs - a cross sectional survey.

BACKGROUND: Although the impact of asthma education on important outcomes (e.g. emergency visits) has been well established, only an estimated quarter of asthma patients in Germany have received patient education yet. The aim of the study was to identify patient factors that could increase participation in asthma education programs. METHODS: This cross-sectional study investigated participation factors and differences between trained (n = 64) and untrained (n = 65) asthma patients from a large outpatient center in Germany. The survey included answers to asthma-related questions and open questions on patient education as well as such about knowledge of health literacy and eHealth. RESULTS: Mean age of participants was 55 ± 19 years and 61% were female. Trained patients were more likely to participate in disease management programs (odds ratio (OR) 6.85; 95%CI 2.17-21.59), were more frequently non-smokers (OR 0.07; 95%CI 0.01-0.85) and more often had an asthma action plan (OR 20.2; 1.55-263.41). Open questions' analysis of untrained asthma patients revealed that patients felt they were not adequately informed about asthma education (37%). About one-third of all patients (27%) showed openness to online asthma education. Analysis of HL and eHealth showed no difference between the groups. CONCLUSION: Untrained asthma patients should be informed even more intensively by their physicians about the importance and value of asthma education. Asthma education does not seem to benefit patients' health literacy. Online asthma education is of interest to approximately one-third of asthma patients. This should be motivation to develop and implement online asthma education concepts.

Quasi-phase-matched self-pumped optical parametric oscillation in a micro-resonator.

Lasing and self-pumped optical parametric oscillation (self-OPO) are achieved in a high-Q whispering-gallery-mode micro-resonator, made of neodymium-doped lithium niobate. A laser process providing 5 mW output power at 1.08 µm wavelength is sufficient to pump a self-OPO process within the same high-Q cavity. At 6 mW lasing output power, the sum of signal and idler output powers exceeds 1.2 mW. The wavelength of the generated light ranges from 1.5 to 3.8 µm. Phase matching is provided by a radial quasi-phase-matching structure, which is generated by a current-controlled calligraphic poling technique. To the best of our knowledge, this is the first demonstration of a quasi-phase-matched self-pumped nonlinear optical process in a micro-resonator, as well as the first self-OPO in a micro-resonator. The concept bears the potential for a highly integrated and wavelength-tunable coherent light source at low cost.

Control of mode anticrossings in whispering gallery microresonators.

Optical microresonators attract strong interest because of exciting effects and applications ranging from sensing of single atoms and molecules to quantum and nonlinear optics. For all this, control and tuning of the discrete resonances are vital. In resonators made of anisotropic materials that are beneficial for nonlinear-optical applications, anticrossings of ordinarily (o) and extraordinarily (e) polarized modes occur regularly. This effect is badly understood and harmful for mode control and tuning. We show that the anticrossings are inherent in the o- and e-modes because of the vectorial properties of Maxwell's equations. Within a novel pertubative approach employing a strong localization of the modes near the resonator rim, we have quantified the anticrossings. The values of avoidance gaps strongly exceeding the linewidths and selection rules for the interacting modes are predicted. The inferred values of the avoidance gaps are confirmed experimentally in resonators made of lithium niobate. Furthermore, based on theory, we have eliminated the anticrossings completely by spatially-controlled introduction of defects. This paves the way for unperturbed tuning of anisotropic microresonators.

Sulphite oxidase (SO) - a mitochondrial autoantigen as target for humoral and cellular immune reactions in primary sclerosing cholangitis.

BACKGROUND: In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail. METHODS: Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO-induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69. RESULTS: 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA-treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10). CONCLUSIONS: PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T-helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important.

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals.

Do general practice patients with and without appointment differ? Cross-sectional study.

BACKGROUND: Even in practices with a comprehensive appointment system a minority of patients walks in without prior notice, sometimes causing problems for practice service quality. We aimed to explore differences between patients consulting primary care practices with and without appointment. METHODS: Consecutive patients visiting five primary care practices without an appointment and following patients with an appointment were asked to fill in a four-page questionnaire addressing socio-demographic characteristics, the reason for encounter, urgency of seeing a physician, depressive, somatic and anxiety symptoms, personality traits, and satisfaction with the practice. Physicians also documented the reason for encounter and assessed the urgency. Data were analyzed using univariate and multivariate methods. RESULTS: Two hundred fifty-one patients without and 250 patients with appointment participated. Patients without appointment were significantly younger (mean age 44 vs. 50 years) and reported less often chronic diseases (29% vs. 45%). Also, reasons for encounter differed (e.g., 27% vs. 16% with a respiratory problem). Patients' ratings of urgency did not differ between groups (p = 0.46), but physicians rated urgency higher among patients without appointment (p < 0.001). In logistic regression analyses younger age, male gender, absence of chronic disease, positive screening for at least one mental disorder, low values on the personality trait openness for experience, a high urgency rating by the physician, and a respiratory or musculoskeletal problem as reason for encounter were significantly associated with a higher likelihood of being a patient without appointment. CONCLUSIONS: In this study, younger age and a high urgency rating by physicians were the variables most consistently associated with the likelihood of being a patient without appointment. Overall, differences between patients seeking general practices with a comprehensive appointment system without prior notice and patients with appointments were relatively minor.

Sequential Refined Partitioning for Probabilistic Dependence Assessment.

Modeling dependence probabilistically is crucial for many applications in risk assessment and decision making under uncertainty. Neglecting dependence between multivariate uncertainties can distort model output and prevent a proper understanding of the overall risk. Whenever relevant data for quantifying and modeling dependence between uncertain variables are lacking, expert judgment might be sought to assess a joint distribution. Key challenges for the use of expert judgment for dependence modeling are over- and underspecification. An expert can provide assessments that are infeasible, i.e., not consistent with any probability distribution (overspecification), and on the other hand, without making very restrictive parametric assumptions an expert cannot fully define a probability distribution (underspecification). The sequential refined partitioning method addresses over- and underspecification while allowing for flexibility about which part of a joint distribution is assessed and its level of detail. Potential overspecification is avoided by ensuring low cognitive complexity for experts through eliciting single conditioning sets and by offering feasible assessment ranges. The feasible range of any (sequential) assessment can be derived by solving a linear programming problem. Underspecification is addressed by modeling the density of directly and indirectly assessed distribution parts as minimally informative given their constraints. Hence, our method allows for modeling the whole distribution feasibly and in accordance with experts' information. A nonparametric way of assessing and modeling dependence flexibly in such detail has not been presented in the expert judgment literature for probabilistic dependence models so far. We provide an example of assessing terrorism risk in insurance underwriting.

Impact of the photorefractive and pyroelectric-electro-optic effect in lithium niobate on whispering-gallery modes.

Whispering-gallery resonators made of undoped and MgO-doped congruently grown lithium niobate are used to study electro-optic refractive index changes. Hereby, we focus on the volume photovoltaic and the pyroelectric effect, both providing an electric field driving the electro-optic effect. Our findings indicate that the light-induced photorefractive effect, combining the photovoltaic and electro-optic effect, is present only in the non-MgO-doped lithium niobate for exposure with light having wavelengths of up to 850 nm. This leads to strong resonance frequency shifts of the whispering-gallery modes. No photorefractive effect was observed in the MgO-doped material. One has to be aware that surface charges induced by the pyroelectric effect result in a similar phenomenon and are present in both materials.

Broadband infrared spectroscopy using optical parametric oscillation in a radially-poled whispering gallery resonator.

We demonstrate optical parametric oscillation in a millimeter-sized whispering gallery resonator suitable for broadband infrared spectroscopy. This nonlinear-optical process is quasi-phase-matched using a radial domain pattern with 30 µm period length, inscribed by calligraphic poling. The output wavelengths are selected in a controlled way over hundreds of nanometers. We achieve this by increasing the temperature of the resonator in steps such that the azimuthal mode number of the pump wave rises by one. As a proof-of-principle experiment, we measure a characteristic resonance of polystyrene in the spectral range of 2.25 - 2.45 µm.

Continuous-wave whispering-gallery optical parametric oscillator for high-resolution spectroscopy.

We achieve a continuous operation of a whispering gallery optical parametric oscillator by stabilizing the resonator temperature T on the mK level and simultaneously locking the pump frequency to a cavity resonance using the Pound-Drever-Hall technique. The millimeter-sized device converts several mW of a pump wave at 1040 nm wavelength to signal and idler waves around 2000 nm wavelength with more than 50% efficiency. Over 1 h, power and frequency of the signal wave vary by <±1% and by <±25 MHz, respectively. The latter can be tuned over 480 MHz without a mode hop by changing T over 120 mK. In order to prove the suitability for high-resolution spectroscopy, we scan the signal frequency across the resonance of a Fabry-Perot interferometer resolving nicely its 10 MHz linewidth.

First-generation protease inhibitor-triple therapy: SVR 24, safety, and predictors of response in a large single center cohort.

BACKGROUND/AIMS: Aim of this retrospective study was to analyze the efficacy, safety, and predictors of treatment success for first-generation-PI triple therapies, including either boceprevir or telaprevir, in a mono-centric "real-life" setting with respect to SVR 24. PATIENTS: 131 patients (102 patients telaprevir, 29 patients boceprevir) were treated. Of these, 33/131 patients were treatment naïve, 72/131 patients had been pretreated with PEG-IFN/RBV (PR) (thereof: 36 with non-response, 30 with relapse, 6 unknown), and 26/131 patients previously had received non-pegylated interferon. 96/131 patients were infected with HCV genotype 1b. 41/131 patients had liver cirrhosis. RESULTS: 95/131 (73%) patients achieved SVR 24. SVR rates for subgroups were: 26/33 (79%) for treatment naïve, 25/30 (83%) for PR-relapse, 20/36 (56%) for PR-non-response, 21/26 (81%) for non-PR pretreated patients, (26/41) 63% for patients with liver cirrhosis, 23/35 (66%) genotype 1a, 72/96 (75%) genotype 1b. Predictors of SVR 24 were eRVR and a negative viral load at PI-treatment week 4 (p < 0.0001), negative predictors were quantifiable HCV viral load at PI-treatment week 4 (p < 0.0001), baseline platelet count < 100/nl (p < 0.0001), and previous PR-non-response (p = 0.006). 33/131 (25%) patients discontinued treatment prematurely, of those 14/131 (11%) patients due to virological failure. Side effects were frequent (anemia 59/131 [45%], severe infections 6/131 [5%]). CONCLUSIONS: According to our SVR 24 results, efficacy of PI-based triple therapy in our "real-life" cohort is comparable to the large multi-centric clinical trials. Pronounced side effects are frequent during therapy and often need complex therapeutic interventions. Since new DAA are available, it is open to discussion, if first-generation PI-triple therapy is no longer indicated at all.