Enhancing clinical decision support with genomic tools in breast cancer: A Scottish perspective.

INTRODUCTION: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. MATERIALS & METHODS: Pan-Scotland study between August 2018-August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. RESULTS: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. CONCLUSIONS: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland. It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Beat note stabilization in dual-polarization DFB fiber lasers by an optical phase-locked loop.

A fully fibered microwave-optical source at 1.5 µm is studied experimentally. It is shown that the beat note between two orthogonally polarized modes of a distributed-feedback fiber laser can be efficiently stabilized using an optical phase-locked loop. The pump-power-induced birefringence serves as the actuator. Beat notes at 1 GHz and 10 GHz are successfully stabilized to a reference synthesizer, passing from the 3 kHz free-running linewidth to a stabilized sub-Hz linewidth, with a phase noise as low as -75 dBc/Hz at 100 Hz offset from the carrier. Such dual-frequency stabilized lasers could provide compact integrated components for RF and microwave photonics applications.

Syndrome of inappropriate anti-diuresis induces volume-dependent hypercalciuria.

Hyponatremia is associated with bone demineralization. We hypothesized that, during hyponatremia, calciuria and calcium balance depend on volemic status. We evaluated calciuria in patients with hyponatremia, secondary to SIAD or hypovolemia. Patients with SIAD exhibited a volemic expansion that was associated with hypercalciuria. Calciuria was proportional to markers of volemia. INTRODUCTION: Chronic mild hyponatremia has been associated with bone demineralization of unknown mechanisms. During chronic hyponatremia, arginine-vasopressin secretion can result from hypovolemia or from syndrome of inappropriate anti-diuresis (SIAD) that leads to a slightly volemic expansion. Since volemia determines renal calcium excretion and balance, we evaluated calcium homeostasis in patients with chronic hyponatremia, related to SIAD or to hypovolemia. METHODS: We retrospectively included all patients referred to our Department between May 2006 and May 2014 for hyponatremia, resulting from SIAD or chronic hypovolemia. None had edema, cirrhosis, cardiac, or renal insufficiency. Exploration included estimation of volemia, extracellular fluid volume (ECFV) measurement with inulin, and calcium homeostasis. RESULTS: In total, the SIAD and hypovolemic groups included 22 and 7 patients, respectively. The SIAD group exhibited signs of increased volemia: higher glomerular filtration rate, higher fractional excretion of uric acid, and lower plasma renin. ECFV exceeded that of the hypovolemic group and was above usual values. There was no difference between the two groups regarding plasma calcium, PTH, and vitamin D. However, in the SIAD group, calciuria was higher than in the hypovolemic group, reaching levels of hypercalciuria. Furthermore, there was a positive correlation between calciuria and markers of volemia. CONCLUSIONS: Our results show that SIAD results in a volemic expansion tendency that is associated with a decrease in renal calcium reabsorption and thus hypercalciuria, whereas in the hypovolemic group, calciuria was not increased. Therefore, renal loss of calcium and bone demineralization in SIAD patients could be partly induced by volemic expansion.

Antiphase domain tailoring for combination of modal and 4¯ -quasi-phase matching in gallium phosphide microdisks.

We propose a novel phase-matching scheme in GaP whispering-gallery-mode microdisks grown on Si substrate combining modal and 4¯ -quasi-phase-matching for second-harmonic-generation. The technique consists in unlocking parity-forbidden processes by tailoring the antiphase domain distribution in the GaP layer. Our proposal can be used to overcome the limitations of form birefringence phase-matching and 4¯ -quasi-phase-matching using high order whispering-gallery-modes. The high frequency conversion efficiency of this new scheme demonstrates the competitiveness of nonlinear photonic devices monolithically integrated on silicon.

Optical fiber Sagnac interferometer for sensing scalar directional refraction: application to magnetochiral birefringence.

We present a setup dedicated to the measurement of the small scalar directional anisotropies associated to the magnetochiral interaction. The apparatus, based on a polarization-independent fiber Sagnac interferometer, is optimized to be insensitive to circular anisotropies and to residual absorption. It can thus characterize samples of biological interests, for which the two enantiomers are not available and/or which present poor transmission. The signal-to-noise ratio is shown to be limited only by the source intensity noise, leading to a detection limit of Δϕ = 500 nrad Hz(-1/2). It yields a limit on the magnetochiral index nMC < 4 × 10(-13) T(-1) at 1.55 µm for the organic molecules tested.

Measuring the universal synchronization properties of driven oscillators across a Hopf instability.

When a driven oscillator loses phase-locking to a master oscillator via a Hopf bifurcation, it enters a bounded-phase regime in which its average frequency is still equal to the master frequency, but its phase displays temporal oscillations. Here we characterize these two synchronization regimes in a laser experiment, by measuring the spectrum of the phase fluctuations across the bifurcation. We find experimentally, and confirm numerically, that the low frequency phase noise of the driven oscillator is strongly suppressed in both regimes in the same way. Thus the long-term phase stability of the master oscillator is transferred to the driven one, even in the absence of phase-locking. The numerical study of a generic, minimal model suggests that such behavior is universal for any periodically driven oscillator near a Hopf bifurcation point.

Lidar-radar velocimetry using a pulse-to-pulse coherent rf-modulated Q-switched laser.

An rf-modulated pulse train from a passively Q-switched Nd:YAG laser has been generated using an extra-cavity acousto-optic modulator. The rf modulation reproduces the spectral quality of the local oscillator. It leads to a high pulse-to-pulse phase coherence, i.e., phase memory, over thousands of pulses. The potentialities of this transmitter for lidar-radar are demonstrated by performing Doppler velocimetry on indoor moving targets. The experimental results are in good agreement with a model based on elementary signal processing theory. In particular, we show experimentally and theoretically that lidar-radar is a promising technique that allows discrimination between translation and rotation movements. Being independent of the laser internal dynamics, this scheme can be applied to any Q-switched laser.

Fístula arterio-venosa como tratamiento de EPOC grave / Arteriovenous fistula in the treatment of severe COPD

COPD patients have dyspnea limiting their exercise capacity due to different mechanisms. The origin of the arterial blood gases anomaly is an alteration of the ventilation/perfusion (V'/Q') ratio causing venous admixture which has not been addressed therapeutically so far. Theoretically an arteriovenous fistula (AVF) could increase venous content of O2 so that blood leaving the left ventricle has a higher than expected PaO2 .This, along with the associated increase in cardiac output leads to an increased delivery of O2 to tissues particularly skeletal muscle thus improving its performance. We present a patient with advanced COPD. Full conventional therapy failed to improve his dyspnea and hypoxemia which limits his exercise capacity. We made a peripheral arteriovenous fistula on him as a therapeutic intent. Spirometry showed an initial FEV1 of 0.74 L, a FVC of 1.97 L, he had hypoxemia (PaO2 :56.8 mmHg, oxyhemoglobin saturation (SaO2 ): 82.9 percent). A 6 min walking test with a distance of300 m corresponding to 61 percent of predetermined value that improved by 108 m providing O2 2 L/min. Echocardiography showed a pulmonary artery systolic pressure of 26 mm Hg and a 60 percent of left ventricle ejection fraction. The patient obtained 73.8 percent in Saint George's Respiratory Questionnaire (SGRQ), 38 points in COPD Assesment Test (CAT) and 6 points in BODE Index. After 4 weeks of AVF neither spirometric nor echocardiographic changes were observed, but there was an improvement in PaO2 to 68 mmHg and in SaO2 to 93 percent. The 6 min walking test showed an increase to 425 m. SGRQ improved to 3.88 points, BODE index improved to 3 points and CAT to 21 points. We conclude that in this patient an AVF determined an improvement in exercise capacity with a better control of disease that resulted in a better quality of life constituting an important non pharmacological aid in an advanced COPD patient who failed to improve with full medical therapy. In patients selection...

El paciente portador de EPOC tiene disnea que limita su capacidad de ejercicio por diferentes mecanismos entre los cuales está la incapacidad de la musculatura respiratoria para responder al aumento de las demandas, que puede ser secundaria a la disminución de la entrega de O2. La anomalía gasométrica propia de la enfermedad tiene como origen una alteración de la relación ventilación/ perfusión (V'/Q') que causa un aumento de la admisión venosa el cual no ha sido enfrentado terapéuticamente hasta el momento. Teóricamente una fístula arteriovenosa (FAV) podría aumentar el contenido venoso de O2 ,de modo que la sangre que sale del ventrículo izquierdo lo haga con una PaO2 mayor que la esperada. Esto, junto con el aumento del gasto cardíaco asociado llevaría a una mayor entrega de O2 a los tejidos mejorando de esa forma el desempeño de la musculatura esquelética. En un paciente con EPOC avanzada que con terapia máxima no logra mejorar la disnea ni la hipoxemia que limitan seriamente su capacidad de ejercicio, confeccionamos una fistula entre la vena safena interna y la arteria femoral superficial con intención terapéutica. La espirometría inicial mostró un VEF1de 0,74 L (26 por ciento del valor predeterminado) con CVF de 1,97 L (57 por ciento). Presentaba hipoxemia (PaO2 :56,8 mmHg y SaO2 :82,9 por ciento), un test de caminata de 6 min (TC6M) con un recorrido de 300 m que corresponde a un 61 por ciento del teórico que mejoraba al aportar O2 2 L/min a 408 m correspondiente a un 80 por ciento del teórico. El ecocardiograma detectó una presión sistólica de arteria pulmonar de 26 mmHg y una fracción de eyección del ventrículo izquierdo de 60 por ciento. En el cuestionario respiratorio de Saint George el paciente obtuvo 73,8 por ciento su CAT (COPD Assessment Test) fue de 38 puntos y su índice BODE (Body mass, Obstruction, Dyspnea, Exercise capacity) de 6 puntos. Al mes de realizada la FAVno hubo cambios espirométricos ni ecocardiográficos, pero la PaO2 mejoró a...

Dual-polarization mode-locked Nd:YAG laser.

A mode-locked solid-state laser containing a birefringent element is shown to emit synchronously two frequency combs associated to the two polarization eigenstates of the cavity. An analytical model predicts the polarization evolution of the pulse train, which is determined by the adjustable intracavity birefringence. Experiments realized with a Nd:YAG laser passively mode locked by a semiconductor saturable absorber mirror are in perfect agreement with the model. Locking between the two combs arises for particular values of their frequency difference, e.g., half the repetition rate, and the pulse train polarization sequence is then governed by the relative overall phase offset of the two combs.

Resonance assisted synchronization of coupled oscillators: frequency locking without phase locking.

Frequency locking without phase locking of two coupled nonlinear oscillators is experimentally demonstrated. This synchronization regime is found for two coupled laser modes, beyond the phase-locking range fixed by Adler's equation, because of a resonance mechanism. Specifically, we show that the amplitudes of the two modes exhibit strong fluctuations that produce average frequency synchronization, even if the instantaneous phases are unlocked. The experimental results are in good agreement with a theoretical model.

Non-linear optoelectronic phase-locked loop for stabilization of opto-millimeter waves: towards a narrow linewidth tunable THz source.

We propose an optoelectronic phase-locked loop concept which enables to stabilize optical beat notes at high frequencies in the mm-wave domain. It relies on the use of a nonlinear-response Mach-Zehnder modulator. This concept is demonstrated at 100 GHz using a two-axis dual-frequency laser turned into a voltage controlled oscillator by means of an intracavity electrooptic crystal. A relative frequency stability better than 10⁻¹¹ is reported. This approach of optoelectronic down conversion opens the way to the realization of continuously tunable ultra-narrow linewidth THz radiation.

Beat note stabilization of a 10-60 GHz dual-polarization microlaser through optical down conversion.

Down-conversion of a high-frequency beat note to an intermediate frequency is realized by a Mach-Zehnder intensity modulator. Optically-carried microwave signals in the 10-60 GHz range are synthesized by using a two-frequency solid-state microchip laser as a voltage-controlled oscillator inside a digital phase-locked loop. We report an in-loop relative frequency stability better than 2.5×10⁻¹¹. The principle is applicable to beat notes in the millimeter-wave range.

A dipole interaction model for magnetochiral birefringence.

We have developed a classical model to investigate the magnetochiral birefringence of an isotropic chiral medium submitted to a longitudinal magnetic field. This model, which is an extension of the atom dipole interaction model, yields direct calculations from the polarizabilities and positions of the atoms of the considered molecules. The numerical values obtained for the magnetochiral birefringence, as well as for the optical activity and Faraday rotation, are supported by the previously published experimental results on limonene, proline, and tartaric acid.

Intensity dependence of auditory-evoked cortical potentials in fibromyalgia patients: a test of the generalized hypervigilance hypothesis.

UNLABELLED: On the basis of recent evidence concerning the amplification of incoming stimulation in fibromyalgia (FM) patients, it has been proposed that a generalized hypervigilance of painful and nonpainful sensations may be at the root of this disorder. So far, research into this issue has been inconclusive, possibly owing to the lack of agreement as to the operational definition of "generalized hypervigilance" and to the lack of robust objective measures characterizing the sensory style of FM patients. In this study, we recorded auditory-evoked potentials (AEPs) elicited by tones of increasing intensity (60, 70, 80, 90, and 105 dB) in 27 female FM patients and 25 healthy controls. Fibromyalgia patients presented shorter N1 and P2 latencies and a stronger intensity dependence of their AEPs. Both results suggest that FM patients may be hypervigilant to sensory stimuli, especially when very loud tones are used. The most noteworthy difference between patients and control subjects is at the highest stimulus intensity, for which far more patients maintained increased N1-P2 amplitudes in relation to the 90-dB tones. The larger AEP amplitudes to the 105-dB tones suggest that defects in an inhibitory system protecting against overstimulation may be a crucial factor in the pathophysiology of FM. Because a stronger loudness dependence of AEPs has been related to weak serotonergic transmission, it is hypothesized that for many FM patients deficient inhibition of the response to noxious and intense auditory stimuli may be due to a serotonergic deficit. PERSPECTIVE: The study of auditory-evoked potentials in response to tones of increasing intensity in FM patients may help to clarify the pathophysiology of this disorder, especially regarding the role of inhibition deficits involving serotonergic dysfunction, and may be a useful tool to guide the pharmacologic treatment of FM patients.

[Surveillance of infections in chronic hemodialysis patients]. / Surveillance des infections chez les hémodialysés chroniques en centre.

OBJECTIVE: To confirm rates of infections from a previous survey in chronic hemodialysis patients; to get information about incidents and manipulations of vascular access-site, number and reasons of hospitalisation; to asses a relationship between the frequency of vascular access-site infections (VASI) and quality of care during the procedures of vascular access-site use. DESIGN: Prospective, multicenter survey performed from February 2000 to January 2001, including all patients underwent chronic hemodialysis in 5 participating centers. Standardized definitions used and different clinical and biological risk factors recorded. RESULTS: 429 patients for a total of 4273 dialysis months (DM) were enrolled. 245 infections in 164 infected patients were reported. The overall rate was 5.73 infections per 100 DM (18 VASI, 25 bacteraemia, 84 respiratory, 29 urinary tract, 1 endocarditis and 88 other infections). 50% of infections were microbiologically documented. 19 of 21 antibiotics resistant microorganisms were meticillin resistant Staphylococcus aureus. Compared to the incidence rate of fistula (0.05 per 1000 days of follow-up) or prosthesis related VASI (0.11), the incidence rate of catheter related VASI (0.65) was significantly higher. Poor hygiene and duration of catheter use were the significant risk factors for VASI showed by logistic analysis regression. VASI and bacteraemia occurred more frequently after incident or manipulation of the vascular access-site. The decrease of VASI between the 2 periods of survey was significantly higher in centers having reduced the catheter use and implemented written protocols. CONCLUSIONS: This second period of surveillance has confirmed the frequency of infections rate in chronic hemodialysis patients and particularly bacteraemia and VASI. This study has allowed to establish risk factors for infections and showed that VASI in hemodialysis are related to factors in part preventable.

Ferromagnetism in fcc twinned 2.4 nm size Pd nanoparticles.

The onset of ferromagnetism has been experimentally observed in small Pd particles of average diameter 2.4 nm. High-resolution studies reveal that a high percentage of the fcc particle exhibits single and multiple twinning boundaries. The spontaneous magnetization close to 0.02 emu/g seems to indicate that only a small fraction of atoms holds a permanent magnetic moment and contributes to ferromagnetism. The possible origin of ferromagnetism is briefly discussed according to different models recently reported.

Similar effect of family history of psychosis on Sylvian fissure size and auditory P200 amplitude in schizophrenic and bipolar subjects.

Several cerebral studies point to the non-specificity of structural and functional changes described in schizophrenia and bipolar disorders. Furthermore, the origin of these changes is still unclear. The present study investigated the effect of a family history (FH) of psychotic disorders in first-degree relatives on computed tomographic (CT) measures (ventricular, cerebral and Sylvian fissure size) and auditory event-related potentials (amplitudes and latencies of peak components in oddball paradigms) in 30 schizophrenic patients and 24 bipolar type I patients. We found a significant correlation between FH and the size of the right Sylvian fissure, and between FH and auditory P200 amplitude. More specifically, the schizophrenic and bipolar patients with negative FH (n=36) had larger right Sylvian fissures and smaller P200 amplitude than patients with positive FH (n=18). These findings were independent of the specific diagnosis, gender, and age of subjects. Our results suggest some underlying process common to schizophrenia and bipolar I disorder, and they provide support for the continuum view of the nosologic structure of psychotic illness.

The use of REE determination in a clinical setting applied to respiratory disease.

The determination of a patient's nutritional condition is an important moment of clinical evaluation in everyday experience. Quite often, it is important to identify symptoms, signs and objective parameters that may reveal a malnourished condition. To satisfy this request, clinicians recur to clinical examination and biochemical tests. It is also possible to use indirect calorimetry. Through the evaluation of oxygen consumption (VO2) and carbon dioxide production (VCO2), indirect calorimetry permits the respiratory quotient (RQ) to be calculated and the exact energy consumption during resting conditions to be determined. This technology, currently used in research departments and in hospital units, is more accurate for the estimation of resting energy expenditure (REE) than the Harris-Benedict equation, especially in the case of patients affected by respiratory diseases or other systemic conditions. The evaluation of REE through indirect calorimetry is a useful monitoring and prognostic index in acutely and chronically ill patients.

Existence of two coupling constants in microchip lasers.

We implemented two different experimental setups to probe directly the nonlinear coupling between modes in microchip lasers. We show that, remarkably, the results can be interpreted by use of Lamb's coupling constant. In an Er, Yb:glass microchip laser, we measured C(12) = 0.80 between longitudinal modes and C(xy) = 0.95 between orthogonally linearly polarized eigenstates. The high values obtained give some physical insight into the single-frequency operation of such lasers.