NfL and GFAP in serum are associated with microstructural brain damage in progressive multiple sclerosis.

BACKGROUND: The potential of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of disease activity and severity in progressive forms of multiple sclerosis (MS) is unclear. OBJECTIVE: To investigate the relationship between serum concentrations of NfL, GFAP, and magnetic resonance imaging (MRI) in progressive MS. METHODS: Serum concentrations of NfL and GFAP were measured in 32 healthy controls and 32 patients with progressive MS from whom clinical and MRI data including diffusion tensor imaging (DTI) were obtained during three years of follow-up. RESULTS: Serum concentrations of NfL and GFAP at follow-up were higher in progressive MS patients than in healthy controls and serum NfL correlated with the EDSS score. Decreasing fractional anisotropy (FA) in normal-appearing white matter (NAWM) correlated with worsening EDSS scores and higher serum NfL. Higher serum NfL and increasing T2 lesion volume correlated with worsening paced autitory serial addition test scores. In multivariable regression analyses with serum GFAP and NfL as independent factors and DTI measures of NAWM as dependent factors, we showed that high serum NfL at follow-up was independently associated with decreasing FA and increasing MD in NAWM. Moreover, we found that high serum GFAP was independently associated with decreasing MD in NAWM and with decreasing MD and increasing FA in cortical gray matter. CONCLUSION: Serum concentrations of NfL and GFAP are increased in progressive MS and are associated with distinct microstructural changes in NAWM and CGM.

Short wavelength operation of a 10 m perimeter ring laser gyroscope.

We report on the operation of a 10 m perimeter, helium-neon based ring laser gyroscope on the 3s 2→2p 6 (611.8 nm) and 3s 2→2p 10 (543.4 nm) transitions of neon. Cavity Q factors of 1.5×1012 and 3.8×1011 are obtained for 611.8 and 543.4 nm operation, inferred from measured ring-down times of 485 and 110 µs, respectively. For Sagnac frequencies, due to Earth rotation, of 205.14 and 230.96 Hz, minimum resolvable rotation rates of 80 and 226 prad/s are achieved for integration times of around 100 s. While environment limited performance is achieved for operation at 611.8 nm, it is found that a restrictive gas pressure regime must be utilized for the 543.4 nm lasing wavelength. As a consequence, the output photon count is low, which limits its intrinsic sensitivity for rotation rate measurements.

Gyroscopic performance and some seismic measurements made with a 10 meter perimeter ring laser gyro housed in the Ernest Rutherford building.

We describe the construction and operation of a large ring laser whose beam paths enclose an area of 6.25m2. The gyroscopic performance of this large laser interferometer was determined using laser operation at a wavelength of 632.8 nm. The laser cavity Q was inferred to be 1.1×1012 via a measured ring-down time of 375 µs, and the measured Sagnac frequency is 198.40 Hz due to Earth's rotation. The measured experimental sensitivity to rotation achieved is 7.9×10-12rad/s/Hz at an averaging interval of 512 s (being limited primarily by ambient building noise). The observation of microseismic activity in the 200 mHz region as well as local earthquakes is discussed.

The role of regional anaesthesia and multimodal analgesia in the prevention of chronic postoperative pain: a narrative review.

Effective prevention of chronic postoperative pain is an important clinical goal, informed by a growing body of studies. Peri-operative regional anaesthesia remains one of the most important tools in the multimodal analgesic toolbox, blocking injury-induced activation and sensitisation of both the peripheral and central nervous system. We review the definition and taxonomy of chronic postoperative pain, its mechanistic basis and the most recent evidence for the preventative potential of multimodal analgesia, with a special focus on regional anaesthesia. While regional anaesthesia targets several important aspects of the mechanistic pathway leading to chronic postoperative pain, evidence for its efficacy is still mixed, possibly owing to the heterogeneity of risk profiles within the surgical patient, but also to variation in techniques and medications reported in the literature.

Precision Angle Measurement Systems on the Basis of Ring Laser Gyro.

The main application of a ring laser gyroscope is navigation. It is currently the most widely used device for strapdown inertial navigation systems. However, it is also applicable for high-precision angle metrology systems. This paper discusses the properties of a laser dynamic goniometer (LDG) based on the ring laser gyroscope and designed for the calibration of optical polygons and digital angle converters, and for the measurement of angles between external mirrors (theodolite operating mode). We consider the main sources of uncertainty, such as the ring laser gyro bias due to an external magnetic field and the instability caused by the velocity of rotation along with applicable methods of their compensation. The reversal method providing separation of uncertainties of the LDG and the calibrated angle converter is analyzed in detail. The simplified cross-calibration method is also considered. The results of calibration of optical encoders of various designs-with and without their own rotors (on-axis and off-axis in Euramet terminology)-are presented. Some results of the dynamic goniometer for the measurement of angles between external mirrors are presented. It is shown that the LDG in this mode of operation demonstrates better accuracy than modern theodolites and total stations.

Pregnancy success rate and response to heparins and/or aspirin differ in women with antiphospholipid antibodies according to their Global AntiphosPholipid Syndrome Score.

BACKGROUND: The current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS. METHODS: One-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients' GAPSS into low risk (< 6), medium risk (6-11), and high risk (≥12). RESULTS: The live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late. Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS <6, n = 72), a medium risk group (GAPSS 6-11, n = 66) and a high risk group (GAPSS ≥12, n = 5). When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p < 0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p < 0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p < 0.001). CONCLUSIONS: GAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC.

Sensing Earth rotation with a helium-neon laser operating on three transitions in the visible region.

We demonstrate an active Sagnac ring interferometer that operates on the previously unexploited 3s2→2p6 (611.8 nm), 3s2→2p7 (604.6 nm), and 3s2→2p8 (593.9 nm) neon transitions, in a helium-neon gain medium. The cavity was constructed using state-of-the-art ion-beam sputtered, ultralow-loss supermirrors designed to yield greater transmission loss at lower optical frequency, which partially compensates for the gain differential across the three transitions. For an optimized cavity fill of 0.3 mbar partial pressure of neon (50% Ne20 and 50% Ne22) and a total gas pressure of 2 mbar, for laser operation at 611.8 nm, the cavity Q is 1.2×1011, having a cold cavity ringdown time of 38 µs. The laser yielded a stable Sagnac frequency of 117.4 Hz due to the Earth's rotation. The usable gyroscopic sensitivity is determined to be 8.8×10-9 rad/s for a measurement time of 128 s.

Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery.

Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.

Gyroscopic operation on the 3s2→2p10 543.3 nm transition of neon in a 2.56 m2 ring cavity.

We report the development and initial operation of a 6.4 meter perimeter laser gyroscope employing the 543.3 nm, 3s2→2p10 transition of neon. Employing fused silica based supermirrors yielding a cavity Q of 3.9×1011 and an inferred lock in threshold below 1 µHz, the gyroscope unlocked on the bias provided by Earth rotation alone with a measured Sagnac frequency of approximately 133 Hz, which is 16% larger than that of the 632.8 nm transition.

The Macek and Davis experiment revisited: a large ring laser interferometer operating on the 2s2 → 2p4 transition of neon.

We operate a large helium-neon-based ring laser interferometer with single-crystal GaAs/AlGaAs optical coatings on the 2s2→2p4 transition of neon at a wavelength of 1.152276 µm. For either single longitudinal- or phase-locked multi-mode operation, the preferable gas composition for gyroscopic operation is 0.2 and 0.3 mbar of 50:50 neon with total pressures between 6-12 mbar. The Earth rotation bias is sufficient to unlock the device, yielding a Sagnac frequency of approximately 60 Hz.

All-in-fiber SESAM based comb oscillator with an intra-cavity electro-optic modulator for coherent high bandwidth stabilization.

We demonstrate the stabilization of an all-in-fiber polarization maintaining semi-conductor saturable absorber mirror (SESAM) mode locked frequency comb oscillator with an intra-cavity waveguide electro-optic phase modulator (EOM) to a narrow linewidth HeNe laser over 46 hours. The high feedback bandwidth of the EOM allows a coherent optical lock with an in-loop integrated phase noise of 1.12 rad (integrated from 10 Hz to 3 MHz) from the carrier signal. No piezo fiber stretcher was required to guarantee long-term stabilization, preventing mechanical degradation of the optical fibers and enabling a long lifetime of the oscillator. As an application a hybrid stabilization scheme is presented, where a comb tooth is phase locked to a longitudinal mode of the large ring laser "G" located at the Geodatic Observatory Wettzell. The hybrid stabilization scheme describes the optical lock of the frequency comb to the G laser and the simultaneous compensation of the ring laser frequency drift by comparing the comb repetition rate against an active H-maser reference. In this context the ring laser reached a fractional Allan deviation of 5 · 10-16 at an integration time of 16384 s.

Abnormal vaginal bleeding in women of reproductive age treated with edoxaban or warfarin for venous thromboembolism: a post hoc analysis of the Hokusai-VTE study.

OBJECTIVE: To investigate the characteristics and outcome of abnormal vaginal bleeding in women receiving edoxaban or warfarin for treatment of venous thromboembolism (VTE). DESIGN AND SETTING: Post hoc analysis of the Hokusai-VTE study, a multicentre, randomised, double-blind trial comparing edoxaban with warfarin for acute symptomatic VTE. POPULATION: Women below 50 years receiving edoxaban or warfarin for treatment of VTE. METHODS: We collected data on diagnostic measures, treatment, and clinical outcome of abnormal vaginal bleeding events. MAIN OUTCOME MEASURES: Occurrence of major and clinically relevant nonmajor (CRNM) abnormal vaginal bleeding events. RESULTS: In all, 628 women aged under 50 years were treated with edoxaban and 665 with warfarin. The rate of abnormal vaginal bleeding was 15/100 person-years (py) (95% CI 11-19) in women receiving edoxaban and 9/100 py (95% CI 6-12) in the warfarin group (hazard ratio: 1.7, 95% CI 1.1-2.5). Major abnormal vaginal bleeding occurred in eight (1.3%) women on edoxaban and in three (0.9%) women receiving warfarin [odds ratio (OR) 2.8; 95% CI 0.8-10.8], and CRNM abnormal vaginal bleeding occurred in 53 (8.4%) women treated with edoxaban and in 37 (5.6%) on warfarin therapy (OR 1.6, 95% CI 1.0-2.4). Over 85% of all vaginal bleeds were characterised by heavy menstrual bleeding. Major bleeds frequently required treatment, and in more than 75% of patients anticoagulant therapy was adjusted. The severity of clinical presentation and course of major and CRNM bleeds was mild in most patients. CONCLUSIONS: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin. Reassuringly, most events could be managed conservatively and had a mild outcome. TWEETABLE ABSTRACT: Abnormal vaginal bleeding occurred more frequently in women treated with edoxaban than with warfarin.

Electron-electron interactions and the paired-to-nematic quantum phase transition in the second Landau level.

In spite of its ubiquity in strongly correlated systems, the competition of paired and nematic ground states remains poorly understood. Recently such a competition was reported in the two-dimensional electron gas at filling factor ν = 5/2. At this filling factor a pressure-induced quantum phase transition was observed from the paired fractional quantum Hall state to the quantum Hall nematic. Here we show that the pressure-induced paired-to-nematic transition also develops at ν = 7/2, demonstrating therefore this transition in both spin branches of the second orbital Landau level. However, we find that pressure is not the only parameter controlling this transition. Indeed, ground states consistent with those observed under pressure also develop in a sample measured at ambient pressure, but in which the electron-electron interaction was tuned close to its value at the quantum critical point. Our experiments suggest that electron-electron interactions play a critical role in driving the paired-to-nematic transition.

Disability in progressive MS is associated with T2 lesion changes.

BACKGROUND: Progressive multiple sclerosis (MS) is characterised by diffuse changes on brain magnetic resonance imaging (MRI), which complicates the use of MRI as a diagnostic and prognostic marker. The relationship between MRI measures (conventional and non-conventional) and clinical disability in progressive MS therefore warrants further investigation. OBJECTIVE: To investigate the relationship between clinical disability and MRI measures in patients with progressive MS. METHODS: Data from 93 primary and secondary progressive MS patients who had participated in 3 phase 2 clinical trials were included in this cross-sectional study. From 3T MRI baseline scans we calculated total T2 lesion volume and analysed magnetisation transfer ratio (MTR) and the diffusion tensor imaging indices fractional anisotropy (FA) and mean diffusivity (MD) in T2 lesions, normal-appearing white matter (NAWM) and cortical grey matter. Disability was assessed by the Expanded Disability Status Scale (EDSS) and the MS functional composite. RESULTS: T2 lesion volume was associated with impairment by all clinical measures. MD and MTR in T2 lesions were significantly related to disability, and lower FA values correlated with worse hand function in NAWM. In multivariable analyses, increasing clinical disability was independently correlated with increasing T2 lesion volumes and MTR in T2 lesions. CONCLUSION: In progressive MS, clinical disability is related to lesion volume and microstructure.

The risk of ischaemic stroke in primary antiphospholipid syndrome patients: a prospective study.

BACKGROUND AND PURPOSE: The most common neurological manifestation of antiphospholipid syndrome (APS) is ischaemic stroke. Identifying patients with APS at high risk for developing any thrombotic event remains a major challenge. In this study, the aim was to identify predictive factors of ischaemic stroke in a cohort of primary APS (PAPS) patients who presented with new onset symptoms suggestive of acute stroke. METHODS: This prospective multicentre study included 36 consecutive PAPS patients who presented with new onset symptoms suggestive of an acute stroke. Patients were prospectively followed up for 12 months. RESULTS: In 10 (28%) out of 36 PAPS patients [mean age 41 years (SD 13.4), 70% female], the suspicion of an acute stroke was confirmed by brain magnetic resonance imaging. Sixty per cent of these patients were <50 years old. Eight of the 10 patients had a history of previous venous thrombosis and were receiving vitamin K antagonist (VKA), with international normalized ratio target 2-3; one patient had a history of a previous arterial event receiving treatment with VKA target international normalized ratio 2-3 plus low dose aspirin; and one patient had a history of previous pregnancy morbidity receiving only low dose aspirin. Time in the therapeutic range for patients receiving VKA was 77.7% (SD 6.6%). Hypercholesterolaemia was significantly higher in patients with confirmed stroke compared to those without (P < 0.05). Similarly, a significantly higher rate of anti-ß2 glycoprotein-I (ß2GPI) antibodies (immunoglobulin G/immunoglobulin M; P < 0.05) and higher adjusted global APS score (aGAPSS) values were found in patients with a confirmed stroke [mean aGAPSS 8.9 (SD 4.7) vs. mean aGAPSS 6.4 (SD 2.5); P < 0.05]. CONCLUSIONS: Patients with PAPS, including young patients, have a high risk of recurrent thrombosis despite anticoagulation treatment. A careful risk assessment is mandatory to identify patients at risk for recurrence.

The adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for risk stratification in young APS patients with acute myocardial infarction.

BACKGROUND: Young adults with acute myocardial infarction are a critical group to examine for the purpose of risk factor stratification and modification. In this study we aimed to assess the clinical utility of the adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) for the risk stratification of acute myocardial infarction in a cohort of young patients with antiphospholipid syndrome (APS). METHODS: The analysis included 83 consecutive APS patients (≤50years old) who presented with arterial or venous thromboembolic events. Data on cardiovascular risk factors and antiphospholipid antibodies (aPL) positivity were retrospectively collected. The aGAPSS was calculated by adding the points corresponding to the risk factors, based on a linear transformation derived from the ß-regression coefficient as follows: 3 for hyperlipidaemia, 1 for arterial hypertension, 5 for aCL IgG/IgM, 4 for anti-b2 glycoprotein I IgG/IgM and 4 for LA. RESULTS: Higher aGAPSS values were observed in patients with acute myocardial infarction when compared to the others [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 9.2 (S.D. 5.1, range 1-17); T test: p<0.05]. Significantly higher aGAPSS values were also seen in patients with acute coronary syndrome compared to patients with a history of peripheral or cerebrovascular arterial thrombotic events [mean aGAPSS 11.9 (S.D. 4.15, range 4-18) Vs. mean aGAPSS 6.7 (S.D. 5.7, range 1-17); T test: P<0.005]. CONCLUSIONS: The aGAPSS is based upon a quantitative score and could aid risk stratifying APS patients younger than 50years for the likelihood of developing coronary thrombotic events and may guide pharmacological treatment for high-risk patients.

Oral contraception and menstrual bleeding during treatment of venous thromboembolism: Expert opinion versus current practice: Combined results of a systematic review, expert panel opinion and an international survey.

INTRODUCTION: The optimal management of oral contraception and menstrual bleeding during treatment of venous thromboembolism (VTE) is largely unknown. We aimed to elicit expert opinion and compare that to current practice as assessed by a world-wide international web-based survey among physicians. METHODS: 10 international thrombosis experts and 10 abnormal uterine bleeding experts independently completed a questionnaire containing three hypothetical patient cases each with four different scenarios, and additional queries covering different severities of VTE, patient circumstances, hormonal contraceptives and both thrombotic and bleeding complications. The consensus percentage was set a priori at ≥70%. The same questionnaire with randomized case scenarios was presented to international physicians via newsletters of the ISTH and national scientific communities. Differences between the expert groups and daily clinical care were assessed. RESULTS: Expert recommendations were divergent and differed in several important points from clinical practice. In contrast to common practice in which contraceptives are discontinued at the moment of a VTE diagnosis, the thrombosis experts agreed to continue oral contraception (OC) during the anticoagulation treatment period. Also, experts reached consensus on treating patients with anticoagulation-associated abnormal uterine bleeding with tranexamic acid, although this is not supported by strong evidence from the literature. No consensus was reached on the optimal anticoagulant drug class. CONCLUSIONS: International experts' opinions on handling of contraceptives and management of anticoagulant-associated abnormal uterine bleeding in female VTE patients are divergent and management in clinical practice is heterogeneous. There is a great need of further studies on these topics.