Characteristics of coexisting attractors and ghost orbiting in an optomechanical microresonator.

We explore the nonlinear interactions of an optomechanical microresonator driven by two external optical signals. Optical whispering-gallery waves are coupled to acoustic surface waves of a fused silica medium in the equatorial plane of a generic microresonator. The system exhibits coexisting attractors whose behaviors include limit cycles, steady states, tori, quasi-chaos, and fully developed chaos with ghost orbits of a known attractor. Bifurcation diagrams demonstrate the existence of self-similarity, periodic windows, and coexisting attractors and show high-density lines within chaos that suggests a potential ghost orbit. In addition, the Lyapunov spectral components as a function of control parameter illuminate the dynamic nature of attractors and periodic windows with symmetric and asymmetric formations, their domains of existence, their bifurcations, and other nonlinear effects. We show that the power-shift method can access accurately and efficiently attractors in the optomechanical system as it does in other nonlinear systems. To test whether the ghost orbit is the link between two attractors interrupted by chaos, we examine the elements of the bifurcation diagrams as a function of control parameter. We also use detuning as a second control parameter to avoid the chaotic region and clarify that the two attractors are one.

Enhancement of Dissipative Sensing in a Microresonator Using Multimode Input.

Optical whispering-gallery microresonators have proven to be especially useful as chemical sensors. Most applications involve dispersive sensing, such as the frequency shift of resonator modes in response to a change in the ambient index of refraction. However, the response to dissipative interaction can be even more sensitive than the dispersive response. Dissipative sensing is most often conducted via a change in the mode linewidth owing to absorption in the analyte, but the change in the throughput dip depth of a mode can provide better sensitivity. Dispersive sensing can be enhanced when the input to the microresonator consists of multiple fiber or waveguide modes. Here, we show that multimode input can enhance dip-depth dissipative sensing by an even greater factor. We demonstrate that the multimode-input response relative to single-mode-input response using the same fiber or waveguide can be enhanced by a factor of more than one thousand, independent of the mode linewidth, or quality factor (Q), of the mode. We also show that multimode input makes the dip-depth response nearly one hundred times more sensitive than the linewidth-change response. These enhancement factors are predicted by making only two measurements of dip depth in the absence of an analyte: one with the two input modes in phase with each other, and one with them out of phase.

Man against machine reloaded: performance of a market-approved convolutional neural network in classifying a broad spectrum of skin lesions in comparison with 96 dermatologists working under less artificial conditions.

BACKGROUND: Convolutional neural networks (CNNs) efficiently differentiate skin lesions by image analysis. Studies comparing a market-approved CNN in a broad range of diagnoses to dermatologists working under less artificial conditions are lacking. MATERIALS AND METHODS: One hundred cases of pigmented/non-pigmented skin cancers and benign lesions were used for a two-level reader study in 96 dermatologists (level I: dermoscopy only; level II: clinical close-up images, dermoscopy, and textual information). Additionally, dermoscopic images were classified by a CNN approved for the European market as a medical device (Moleanalyzer Pro, FotoFinder Systems, Bad Birnbach, Germany). Primary endpoints were the sensitivity and specificity of the CNN's dichotomous classification in comparison with the dermatologists' management decisions. Secondary endpoints included the dermatologists' diagnostic decisions, their performance according to their level of experience, and the CNN's area under the curve (AUC) of receiver operating characteristics (ROC). RESULTS: The CNN revealed a sensitivity, specificity, and ROC AUC with corresponding 95% confidence intervals (CI) of 95.0% (95% CI 83.5% to 98.6%), 76.7% (95% CI 64.6% to 85.6%), and 0.918 (95% CI 0.866-0.970), respectively. In level I, the dermatologists' management decisions showed a mean sensitivity and specificity of 89.0% (95% CI 87.4% to 90.6%) and 80.7% (95% CI 78.8% to 82.6%). With level II information, the sensitivity significantly improved to 94.1% (95% CI 93.1% to 95.1%; P < 0.001), while the specificity remained unchanged at 80.4% (95% CI 78.4% to 82.4%; P = 0.97). When fixing the CNN's specificity at the mean specificity of the dermatologists' management decision in level II (80.4%), the CNN's sensitivity was almost equal to that of human raters, at 95% (95% CI 83.5% to 98.6%) versus 94.1% (95% CI 93.1% to 95.1%); P = 0.1. In contrast, dermatologists were outperformed by the CNN in their level I management decisions and level I and II diagnostic decisions. More experienced dermatologists frequently surpassed the CNN's performance. CONCLUSIONS: Under less artificial conditions and in a broader spectrum of diagnoses, the CNN and most dermatologists performed on the same level. Dermatologists are trained to integrate information from a range of sources rendering comparative studies that are solely based on one single case image inadequate.

Diagnostic performance of a deep learning convolutional neural network in the differentiation of combined naevi and melanomas.

BACKGROUND: Deep learning convolutional neural networks (CNN) may assist physicians in the diagnosis of melanoma. The capacity of a CNN to differentiate melanomas from combined naevi, the latter representing well-known melanoma simulators, has not been investigated. OBJECTIVE: To assess the diagnostic performance of a CNN when used to differentiate melanomas from combined naevi in comparison with dermatologists. METHODS: In this study, a CNN with regulatory approval for the European market (Moleanalyzer-Pro, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used. We attained a dichotomous classification (benign, malignant) in dermoscopic images of 36 combined naevi and 36 melanomas with a mean Breslow thickness of 1.3 mm. Primary outcome measures were the CNN's sensitivity, specificity and the diagnostic odds ratio (DOR) in comparison with 11 dermatologists with different levels of experience. RESULTS: The CNN revealed a sensitivity, specificity and DOR of 97.1% (95% CI [82.7-99.6]), 78.8% (95% CI [62.8-89.1.3]) and 34 (95% CI [4.8-239]), respectively. Dermatologists showed a lower mean sensitivity, specificity and DOR of 90.6% (95% CI [84.1-94.7]; P = 0.092), 71.0% (95% CI [62.6-78.1]; P = 0.256) and 24 (95% CI [11.6-48.4]; P = 0.1114). Under the assumption that dermatologists use the CNN to verify their (initial) melanoma diagnosis, dermatologists achieve an increased specificity of 90.3% (95% CI [79.8-95.6]) at an almost unchanged sensitivity. The largest benefit was observed in 'beginners', who performed worst without CNN verification (DOR = 12) but best with CNN verification (DOR = 98). CONCLUSION: The tested CNN more accurately classified combined naevi and melanomas in comparison with trained dermatologists. Their diagnostic performance could be improved if the CNN was used to confirm/overrule an initial melanoma diagnosis. Application of a CNN may therefore be of benefit to clinicians.

Cross-polarization coupling of whispering-gallery modes due to the spin-orbit interaction of light.

Light can couple between two orthogonally polarized whispering-gallery modes of a microresonator; the effect is easily observable when those modes are frequency degenerate, and can result in coupled-mode induced transparency (CMIT). Experimental observations of CMIT show that the cross-polarization coupling (CPC) strength is typically 10-8-10-7 per round trip. It is shown in this Letter that polarization rotation resulting from optical spin-orbit interaction through the experimentally realistic asymmetry of a microresonator about its equator can produce CPC with strengths in the same range as observed in experiments.

pH sensing using whispering gallery modes of a silica hollow bottle resonator.

The limitations of electrochemical pH sensors have stimulated the development of optical pH sensing methods. In the method reported here, swellable pH-sensitive polymer particles are deposited on the interior surface of a silica hollow bottle resonator. As the pH of the buffer solution in contact with the particles increases, the refractive index of the particles decreases. As a result, whispering gallery modes with internal evanescent components shift in frequency as a function of pH. This shift is monitored by the throughput of tunable diode laser light coupled into the whispering gallery modes using a tapered fiber. Plots of selected mode frequencies vs. pH yielded sigmoid shaped titration curves similar to those obtained using turbidity to monitor refractive index changes of the particles as a function of pH. The response time of 10-15 s and best resolution of 0.06 pH unit represent improvements over previous optical pH sensing methods.

Changes in muscle cross-sectional area, muscle force, and jump performance during 6 weeks of progressive whole-body vibration combined with progressive, high intensity resistance training.

OBJECTIVES: We hypothesized that progressive whole-body vibration (WBV) superimposed to progressive high intensity resistance training has greater effects on muscle cross-sectional area (CSA), muscle force of leg muscles, and jump performance than progressive high intensity resistance training alone. METHODS: Two groups of healthy male subjects performed either 6 weeks of Resistive Vibration Exercise (RVE, squats and heel raises with WBV, n=13) or Resistive Exercise (RE, squats and heel raises without WBV, n=13). Squats under RVE required indispensable weight loading on the forefoot to damp harmful vibrations to the head. Time, intervention, and interaction effects were analyzed. RESULTS: After 6 weeks of training, knee extensor CSA, isometric knee extension force, and counter movement jump height increased equally in both groups (time effect, P⟨0.001, P≤0.02, and P≤0.03, respectively), whereas only in RVE ankle plantar flexor CSA and isometric ankle plantar flexion force reached significance or a tendency, respectively, (time effect, P=0.015 and P=0.069, respectively; intervention effect also for the latter, P=0.006). Drop jump contact time did significantly more improve in RVE (interaction effect, P=0.042). CONCLUSIONS: RVE showed better training effects than RE only in plantar flexor muscles. RVE seems to be suitable in professional sports with a special focus on calf muscles.

Melanoma thickness: the role of patients' characteristics, risk indicators and patterns of diagnosis.

BACKGROUND: Factors associated with early vs. late diagnosis of cutaneous melanoma remain poorly understood. OBJECTIVE: To identify factors with a significant impact on melanoma thickness. METHODS: Patients with previous melanoma (n = 347, median age at diagnosis: 56.5 years, 44.7% female, 55.3% male) were recruited for this monocentre, non-randomized, observational study between April 2012 and March 2013. All patients were assessed by means of a structured interview and systematic clinical and dermoscopic full-body examination. Melanoma thickness in association with patients' characteristics, risk indicators and patterns of diagnosis was submitted to statistical analyses. RESULTS: Univariate analyses revealed associations between a statistically significant lower Breslow thickness and participation in specialized dermoscopic screening programs, personal history of more than one previous melanoma, diagnostic examination with a dermatoscope, diagnostic examination by board certified dermatologist, high number of common and/or atypical nevi, younger age at time of diagnosis, higher level of education, or superficial spreading or lentigo maligna melanoma subtype (all P ≤ 0.01). In a multivariate regression analysis only three of these criteria: (i) participation in specialized screening programs (P < 0.0001); (ii) melanoma subtype (P < 0.0001); and (iii) diagnostic examination with a dermatoscope (P = 0.040) and one interaction term ('younger age' x 'female sex', P < 0.0001) showed an independent influence on a significantly lower melanoma thickness. CONCLUSIONS: The screening of patients in specialized surveillance programs resulted in melanoma detection at significantly earlier stages. The use of dermoscopy, SSM or LMM histotype and younger age in connection with female sex were also characteristics that were independently associated with significantly thinner melanomas in multivariate analyses.

[Incidence of Candidaemia Following Abdominal Surgery in German Hospitals]. / Inzidenz der Candidämie nach gastrointestinal-chirurgischen Eingriffen in deutschen Akutkrankenhäusern.

BACKGROUND: Invasive Candida infections following abdominal surgery represent a significant medical problem. This study initiates a benchmarking project to pinpoint the current role and epidemiology of candidemia in this patient group in German hospitals. MATERIAL AND METHODS: During the year 2010 data derived from 47 704 abdominal surgery cases in hospitals from Germany were analysed in order to determine benchmarking incidences for candidemia. RESULTS AND CONCLUSION: In 20.3 % of all recognised bloodstream infections Candida spp. were identified as the responsible organisms. If related to all abdominal surgery cases analysed in this study, a candidemia-benchmarking incidence of 0.15 % (95 % CI: 0.10-0.21 %) was determined. In patients who required intensive care after surgery the incidence of candidemia was found to be 0.89 % (95 % CI: 0.57-1.38 %). The incidence increased to 3.13 % (95 % CI: 2.09-4.66 %) in patients who received blood culture diagnosis. The German National Reference Centre of Systemic Mycosis provides hospital specific data for participants of this study to enable benchmarking and infection control (www.nrz-mykosen.de/gastrointestinalchirurgie).

Randomized controlled study on resistive vibration exercise (EVE study): protocol, implementation and feasibility.

OBJECTIVES: A training intervention comparing resistance exercise with or without whole-body vibration (WBV) was conducted to compare acute and chronic effects on functional and molecular parameters. METHODS: A six-week training intervention was performed including 26 healthy males (26 years, SD=4). Two groups were analyzed in a parallel design performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training with weekly increasing vibration frequencies (20-40Hz). Resting and exercising blood pressure and heart rate were measured before and after the 6-week intervention. RESULTS: Both training interventions decreased resting systolic blood pressure (P=0.003). Resting diastolic blood pressure was significantly decreased only in the RVE group (P=0.01). Exercising diastolic blood pressure was significantly decreased during the final training (P<0.001) with no additional effect of superimposed vibrations. Resistance exercise with superimposed vibrations evoked back pain to a higher degree than resistance exercise alone when training at frequencies above 30Hz (P<0.01). CONCLUSIONS: These data suggest positive effects of resistance exercise upon cardiovascular health and vascular responsiveness and a further beneficial effect of superimposed vibrations in decreasing resting diastolic blood pressure. Finally, development of back pain may be fostered by superimposed vibrations to high training loads, particularly at higher frequencies.

Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families.

Many studies have evaluated the performance of risk assessment models for BRCA1/2 mutation carrier probabilities in different populations, but to our knowledge very few studies have been conducted in the German population so far. In the recent study, we validated the performance of three risk calculation models by names BRCAPRO, Myriad and BOADICEA in 183 German families who had undergone molecular testing of mutations in BRCA1 and BRCA2 with an indication based on clinical criteria regarding their family history of cancer. The sensitivity and specificity at the conventional threshold of 10% as well as for a threshold of 20% were evaluated. The ability to discriminate between carriers and non-carriers was judged by the area under the receiver operating characteristics curve. We further focused on the performance characteristic of these models in patients carrying large genomic rearrangements as a subtype of mutations which is currently gaining increasing importance. BRCAPRO and BOADICEA performed almost equally well in our patient population, but we found a lack of agreement to Myriad. The results obtained from this study were consistent with previously published results from other population and racial/ethnic groups. We suggest using model specific decision thresholds instead of the recommended universal value of 10%. We further suggest integrating the CaGene5 software package, which includes BRCAPRO and Myriad, in the genetic counselling of German families with suspected inherited breast and ovarian cancer because of the good performance of BRCAPRO and the substantial ease of use of this software.

Optical method for measuring thermal accommodation coefficients using a whispering-gallery microresonator.

A novel optical method has been developed for the measurement of thermal accommodation coefficients in the temperature-jump regime. The temperature dependence of the resonant frequency of a fused-silica microresonator's whispering-gallery mode is used to measure the rate at which the microresonator comes into thermal equilibrium with the ambient gas. The thermal relaxation time is related to the thermal conductivity of the gas under some simplifying assumptions and measuring this time as a function of gas pressure determines the thermal accommodation coefficient. Using a low-power tunable diode laser of wavelength around 1570 nm to probe a microsphere's whispering-gallery mode through tapered-fiber coupling, we have measured the accommodation coefficients of air, helium, and nitrogen on fused silica at room temperature. In addition, by applying thin-film coatings to the microsphere's surface, we have demonstrated that accommodation coefficients can be measured for various gases on a wide range of modified surfaces using this method.

Thrombophilia in patients with chronic venous leg ulcers-a study on patients with or without post-thrombotic syndrome.

BACKGROUND: Chronic venous leg ulcers (CVU) cause considerable burden of disease for the patients as well as enormous costs for health care systems. The pathophysiology of CVU is complex and not entirely understood. So far reliable pathogenic and/or prognostic parameters have not been identified. OBJECTIVES: We studied the role of thrombophilia in patients referred to a University dermatology department for treatment of CVU. PATIENTS AND METHODS: A cohort of 310 patients with active chronic venous leg ulcers (CEAP 6) was stratified into two comparably large groups according to the presence or absence of post-thrombotic syndrome (PTS+; PTS-) as determined using duplex scan and/or phlebography. In addition, several thrombophilia parameters were assessed. RESULTS: The prevalence of protein S deficiency and factor V Leiden mutation was significantly higher in PTS+ patients compared with the PTS- group. However, patients in both subgroups revealed high prevalences of thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance, factor V mutation or elevated homocysteine). CONCLUSION: Based on these data, it is conceivable that thrombophilia contributes to the pathogenesis of CVU, possibly through induction of microcirculatory dysregulations.

Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and comprises two major histological subtypes: alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS). Seventy-five percent of ARMS harbor reciprocal chromosomal translocations leading to fusion genes of the forkhead transcription factor FOXO1 and PAX3 or PAX7. The hedgehog (Hh) pathway has been implied in tumor formation and progression of various cancers including RMS. However, whether Hh pathway activation presents a general feature of RMS or whether it is restricted to specific subgroups has not yet been addressed. Here, we report that marker genes of active Hh signaling, that is, Patched1 (Ptch1), Gli1, Gli3 and Myf5, are expressed at significantly higher levels in ERMS and fusion gene-negative ARMS compared with fusion gene-positive ARMS in two distinct cohorts of RMS patients. Consistently, Gli1 expression correlates with Ptch1 expression in ERMS and fusion gene-negative ARMS, but not in fusion gene-positive ARMS. In addition, expression levels of MyoD1 are significantly lower in ERMS and fusion gene-negative ARMS, pointing to an inverse association of Hh activation and early muscle differentiation. Moreover, Myf5 is identified as a novel excellent class predictor for RMS by receiver operating characteristic analysis. Importantly, high expression of Ptch1 or low MyoD1 expression significantly correlate with reduced cumulative survival in fusion gene-negative RMS underscoring the clinical relevance of these findings. By showing that Hh signaling is preferentially activated in specific subgroups of RMS, our study has important implications for molecular targeted therapies, such as small molecule Hh inhibitors, in RMS.

Prospective study of digital radiographs versus conventional screen films in Small Bowel Follow-Through examination.

PURPOSE: To prospectively compare subjective radiological quality, radiation dose and effect on workflow using digital radiography (DR) vs. conventional screen film (SF) radiography in the Small Bowel Follow-Through (SBFT) examination. METHODS: Five attending and four resident radiologists compared hard-copy images from 11 SBFT examinations, for which every patient had a defined pair of SF and DR images taken 20-30 min apart. SF and DR were performed with equivalent exposure data. Overall image quality, intestinal mucosa definition and bone visualization were graded on a 5-point scale, with 5 being the highest value. Thus, 11 patients had three criteria judged by nine observers in two modalities for a total of 594 observations of image quality. The radiation doses and effect on workflow were also compared. Statistical analysis was performed with the Mann-Whitney U test. RESULTS: The mean scores on DR and SF for overall image quality, intestinal mucosa definition and bone visualization were 4.49 vs. 3.17, 4.38 vs. 3.4, and 4.5 vs. 2.4, respectively (p<0.001 in all cases). The average radiation dose with DR was 0.93+/-0.54 cGy, and -1.58+/-0.63 cGy with SF (p=0.016), reflecting a 41% dose reduction. Production of a DR image by technicians took 3.5+/-1.3 min vs. 5.5+/-1.5 min for SF (p=0.002). CONCLUSION: Subjective image quality of hard-copy digital radiographs of the small bowel through examination is superior to images obtained with conventional radiographs, with an associated reduction of 41% in radiation dose and increased efficiency.

Broadband optical absorbance spectroscopy using a whispering gallery mode microsphere resonator.

We demonstrate the ability to excite and monitor many whispering gallery modes (WGMs) of a microsphere resonator simultaneously in order to make broadband optical absorbance measurements. The 340 microm diameter microsphere is placed in a microfluidic channel. A hemispherical prism is used for coupling the WGMs into and out of the microsphere. The flat surface of the prism seals the microfluidic channel. The slight nonsphericity in the microsphere results in coupling to precessed modes whose emission is spatially separated from the reflected excitation light. The evanescent fields of the light trapped in WGMs interact with the surrounding environment. The change in transmission observed in the precessed modes is used to determine the absorbance of the surrounding environment. In contrast to our broadband optical absorbance measurements, previous WGM sensors have used only a single narrow mode to measure properties such as refractive index. With the microfluidic cell, we have measured the absorbance of solutions of dyes (lissamine green B, sunset yellow, orange G, and methylene blue), aromatic molecules (benzylamine and benzoic acid), and biological molecules (tryptophan, phenylalanine, tyrosine, and o-phospho-L-tyrosine) at visible and ultraviolet wavelengths. The microsphere surface was reacted with organosilane molecules to attach octadecyl groups, amino groups, and fluorogroups to the surface. Both electrostatic and hydrophobic interactions were observed between the analytes and the microsphere surface, as indicated by changes in the measured effective pathlength with different organosilanes. For a given analyte and coated microsphere, the pathlength measurement was repeatable within a few percent. Methylene blue dye had a very strong interaction with the surface and pathlengths of several centimeters were measured. Choosing an appropriate surface coating to interact with a specific analyte should result in the highest sensitivity detection.

Analysis of whispering-gallery microcavity-enhanced chemical absorption sensors.

A theoretical analysis of the operation of a chemical sensor based on cavity-enhanced optical absorption is given for a system in which the cavity is a dielectric whispering-gallery microresonator. Continuous-wave input is assumed, and the detection sensitivity is characterized in terms of an effective absorption path length. In the case of tunable single-frequency input, it is shown that monitoring analyte-induced changes in the throughput dip depth enables detection with relative sensitivity greater than that of frequency-shift and cavity-ringdown methods. In addition, for the case of broadband input and drop-port output, an analysis applicable to microcavity-enhanced absorbance spectroscopy experiments is given.

Cavity-enhanced laser absorption spectroscopy using microresonator whispering-gallery modes.

Tunable diode laser absorption spectroscopy using microresonator whispering-gallery modes (WGMs) is demonstrated. WGMs are excited around the circumference of a cylindrical cavity 125 mum in diameter using an adiabatically tapered fiber. The microresonator is very conveniently tuned by stretching, enabling the locking of an individual WGM to the laser. As the laser is scanned in frequency over an atmospheric trace-gas absorption line, changes in the fiber throughput are recorded. The experimental results of cavity-enhanced detection using such a microresonator are centimeter effective absorption pathlengths in a volume of only a few hundred microns cubed. The measured effective absorption pathlengths are in good agreement with theory.

Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study.

BACKGROUND: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND. METHODS: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry. RESULTS: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD. CONCLUSION: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.