Observation of the effect of gravity on the motion of antimatter.

Einstein's general theory of relativity from 19151 remains the most successful description of gravitation. From the 1919 solar eclipse2 to the observation of gravitational waves3, the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory4 appeared in 1928; the positron was observed5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter7-10. In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP.

XUV frequency comb production with an astigmatism-compensated enhancement cavity.

We have developed an extreme ultraviolet (XUV) frequency comb for performing ultra-high precision spectroscopy on the many XUV transitions found in highly charged ions (HCI). Femtosecond pulses from a 100 MHz phase-stabilized near-infrared frequency comb are amplified and then fed into a femtosecond enhancement cavity (fsEC) inside an ultra-high vacuum chamber. The low-dispersion fsEC coherently superposes several hundred incident pulses and, with a single cylindrical optical element, fully compensates astigmatism at the w0 = 15 µm waist cavity focus. With a gas jet installed there, intensities reaching ∼ 1014 W/cm2 generate coherent high harmonics with a comb spectrum at 100 MHz rate. We couple out of the fsEC harmonics from the 7th up to the 35th (42 eV; 30 nm) to be used in upcoming experiments on HCI frequency metrology.

Short- and long-term haemodynamic consequences of transcatheter closure of atrial septal defect and patent foramen ovale.

BACKGROUND: Transcatheter atrial septal defect (ASD) and patent foramen ovale (PFO) closure might have opposite short- and long-term haemodynamic consequences compared with restricted interatrial shunt creation, which recently emerged as a potential treatment modality for patients with heart failure with preserved ejection fraction (HFpEF). Given the opposing approaches of ASD and PFO closure versus shunt creation, we investigated the early and sustained cardiac structural and functional changes following transcatheter ASD or PFO closure. METHODS: In this retrospective study, adult secundum-type ASD and PFO patients with complete echocardiography examinations at baseline and at 1­day and 1­year follow-up who also underwent transcatheter closure between 2013 and 2017 at the University Medical Centre Groningen, the Netherlands were included. RESULTS: Thirty-nine patients (mean age 48 ± standard deviation 16 years, 61.5% women) were included. Transcatheter ASD/PFO closure resulted in an early and persistent decrease in right ventricular systolic and diastolic function. Additionally, transcatheter ASD/PFO closure resulted in an early and sustained favourable response of left ventricular (LV) systolic function, but also in deterioration of LV diastolic function with an increase in LV filling pressure (LVFP), as assessed by echocardiography. Age (ß = 0.31, p = 0.009) and atrial fibrillation (AF; ß = 0.24, p = 0.03) were associated with a sustained increase in LVFP after transcatheter ASD/PFO closure estimated by mean E/e' ratio (i.e. ratio of mitral peak velocity of early filling to diastolic mitral annular velocity). In subgroup analysis, this was similar for ASD and PFO closure. CONCLUSION: Older patients and patients with AF were predisposed to sustained increases in left-sided filling pressures resembling HFpEF following ASD or PFO closure. Consequently, these findings support the current concept that creating a restricted interatrial shunt might be beneficial, particularly in elderly HFpEF patients with AF.

Improvement in left ventricular ejection fraction after pharmacological up-titration in new-onset heart failure with reduced ejection fraction.

OBJECTIVE: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. METHODS: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. RESULTS: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75-0.94, p = 0.002) for mortality and 0.85 (0.78-0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. CONCLUSIONS: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF.

100 MHz frequency comb for low-intensity multi-photon studies: intra-cavity velocity-map imaging of xenon.

We raise the power from a commercial 10 W frequency comb inside an enhancement cavity and perform multi-photon ionization of gas-phase atoms at 100 MHz for the first time, to the best of our knowledge. An intra-cavity velocity-map-imaging setup collects electron-energy spectra of xenon at rates several orders of magnitude higher than those of conventional laser systems. Consequently, we can use much lower intensities ${\sim}{{10}^{12}} \;{\rm W}/{{\rm cm}^2} $∼1012W/cm2 without increasing acquisition times above just a few seconds. The high rate and coherence of the stabilized femtosecond pulses are known to be transferred to the actively stabilized cavity and will allow studying purely perturbative multi-photon effects, paving the road towards a new field of precision tests in nonlinear physics.

Injuries in Dutch elite field hockey players: A prospective cohort study.

This study describes the prevalence, incidence density, severity, and nature of injuries in elite field hockey players over the Dutch 2015-2016 season. Eighty players answered a baseline questionnaire and were subsequently followed up every 2 weeks to report the hours spent on training/competition and experienced injuries, which were registered using the Oslo Sports Trauma Research Centre Questionnaire on Health Problems. Of the 74 players included in the analysis, 52 (70%) reported 112 injuries. Eighty-seven injuries (78%) received medical attention, and 56 (50%) led to training/competition time-loss. Thirty-four injuries (30%) hampered players' availability to train and compete. Most of the injuries (74%) were not caused by any contact. The mean prevalence of injury was 29% (95% confidence interval [CI] 3-55) for all, 9% (95% CI 0-20) for acute, and 14% (95% CI 0-36) for overuse injuries. Players sustained 3.5 (95% CI 2.5-4.5) new acute injuries per 1000 hours of training and 12.3 (95% CI 7.6-17.0) per 1000 hours of competition. The median of the severity score was 28 from 100 (25%-75% interquartile range [IQR] 16-42) for all, 35 (IQR 23-53) for acute, and 21 (IQR 16-31) for overuse injuries. On average, 1 in 4 elite field hockey players experiences an injury within a 2-week period during the season. Although acute injuries are common, overuse injuries pose a comparable problem in elite field hockey. As injuries are a burden on players' health and may hamper performance and availability to train and compete, prevention is of great importance.

Upper extremity injuries in Danish children aged 6-12, mechanisms, and risk factors.

Although injuries to the upper extremity are most costly, the picture of the upper extremity injury problem remains incomplete. This study is the first to describe the etiology and mechanisms of upper extremity injuries in Danish children. A 2.5-year observational prospective cohort study was conducted to record upper extremity injuries in 1048 children. Data were weekly collected by sending a text message. A total of 176 upper extremity injuries were reported (128 acute injuries). Of the acute upper extremity injuries, 55% were sprains, 47% occurred in the hand/wrist, and 53% of cases were caused by a fall. When corrected for exposure to physical activity, this resulted in an acute upper extremity injury incidence density of 0.18 per 1000 h of physical activity. The odds of sustaining an upper extremity injury was higher in the older children (HR: 1.84, 95% CI: 1.10-3.09), a tendency was found suggesting that girls are at increased acute upper extremity risk compared to boys (HR: 1.40 95% CI: 0.97-2.04). The findings that most injuries occur after a fall, that injury risk increases over age and that girls seem to be at increased injury risk provides essential information to guide future childhood injury prevention.

Double resonant absorption measurement of acetylene symmetric vibrational states probed with cavity ring down spectroscopy.

A novel mid-infrared/near-infrared double resonant absorption setup for studying infrared-inactive vibrational states is presented. A strong vibrational transition in the mid-infrared region is excited using an idler beam from a singly resonant continuous-wave optical parametric oscillator, to populate an intermediate vibrational state. High output power of the optical parametric oscillator and the strength of the mid-infrared transition result in efficient population transfer to the intermediate state, which allows measuring secondary transitions from this state with a high signal-to-noise ratio. A secondary, near-infrared transition from the intermediate state is probed using cavity ring-down spectroscopy, which provides high sensitivity in this wavelength region. Due to the narrow linewidths of the excitation sources, the rovibrational lines of the secondary transition are measured with sub-Doppler resolution. The setup is used to access a previously unreported symmetric vibrational state of acetylene, ν1+ν2+ν3+ν4 (1)+ν5 (-1) in the normal mode notation. Single-photon transitions to this state from the vibrational ground state are forbidden. Ten lines of the newly measured state are observed and fitted with the linear least-squares method to extract the band parameters. The vibrational term value was measured to be at 9775.0018(45) cm(-1), the rotational parameter B was 1.162 222(37) cm(-1), and the quartic centrifugal distortion parameter D was 3.998(62) × 10(-6) cm(-1), where the numbers in the parenthesis are one-standard errors in the least significant digits.

Promoting public playgrounds usage and children's physical activity with sports activities: A quasi-experimental study.

This study aimed to evaluate the children's usage and their physical activity levels at playgrounds with (N = 4) and without (N = 4) organized sports activities, following a quasi-experimental study design. Direct observations were used to assess the playground usage and estimate the playground users' age category, sex, and physical activity intensity level. The results indicated that playgrounds with sports activities were associated with 53% more users at the time of the activities. However, this increase was only seen in boys. Furthermore, playgrounds with sport activities were not associated with different physical activity levels in children as compared to children on regular playgrounds.

Closed-cycle noble gas recycling system for high-repetition rate high-harmonic generation.

We present a compact closed-loop recycling system for noble and inert gases. It has been developed for an extreme-ultraviolet (XUV) frequency comb based on high-harmonic generation at 100 MHz repetition rate. The system collects gas injected at several bars of backing pressure through a micrometer-sized nozzle into the laser-interaction region with a differential pumping system comprising turbomolecular pumps, and subsequently compresses the gas to a pressure of up to 200 bar. By drastically reducing the waste of expensive gases such as xenon and krypton, it enables the long operation times needed for spectroscopic measurements, as well as for continuous operation of the XUV frequency comb.

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on-line solid-phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva.

Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on-line solid-phase extraction LC-MS/MS. The method is linear for the three analytes over the range of 6-1400 nmol/L for serum and 2-450 nmol/L for ultrafiltrate and saliva. Within-run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time-concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva.

Photoelectron tomography with an intra-cavity velocity-map imaging spectrometer at 100 MHz repetition rate.

We present a compact velocity-map imaging (VMI) spectrometer for photoelectron imaging at 100 MHz repetition rate. Ultrashort pulses from a near-infrared frequency comb laser are amplified in a polarization-insensitive passive femtosecond enhancement cavity. In the focus, multi-photon ionization (MPI) of gas-phase atoms is studied tomographically by rotating the laser polarization. We demonstrate the functioning of the VMI spectrometer by reconstructing photoelectron angular momentum distributions from xenon MPI. Our intra-cavity VMI setup collects electron energy spectra at high rates, with the advantage of transferring the coherence of the cavity-stabilized femtosecond pulses to the electrons. In addition, the setup will allow studies of strong-field effects in nanometric tips.

An ultralow-noise superconducting radio-frequency ion trap for frequency metrology with highly charged ions.

We present a novel ultrastable superconducting radio-frequency (RF) ion trap realized as a combination of an RF cavity and a linear Paul trap. Its RF quadrupole mode at 34.52 MHz reaches a quality factor of Q ≈ 2.3 × 105 at a temperature of 4.1 K and is used to radially confine ions in an ultralow-noise pseudopotential. This concept is expected to strongly suppress motional heating rates and related frequency shifts that limit the ultimate accuracy achieved in advanced ion traps for frequency metrology. Running with its low-vibration cryogenic cooling system, electron-beam ion trap, and deceleration beamline supplying highly charged ions (HCIs), the superconducting trap offers ideal conditions for optical frequency metrology with ionic species. We report its proof-of-principle operation as a quadrupole-mass filter with HCIs and trapping of Doppler-cooled 9Be+ Coulomb crystals.

[A study of the efficacy and safety of a new modified-release betahistine formulation in the treatment of vestibular vertigo and Meniere's disease]. / Issledovanie effektivnosti i bezopasnosti novoi formy Betagistina s modifitsirovannym vysvobozhdeniem v lechenii vestibulyarnogo golovokruzheniya i bolezni Men'era.

OBJECTIVE: To evaluate the efficacy and safety of modified-release (MR) betahistine (48 mg once daily) versus betaserc (24 mg twice daily) in patients with Meniere's disease or vestibular vertigo. MATERIAL AND METHODS: A multicentre, double-blind, randomized clinical study in patients with an established diagnosis of Meniere's disease (35%) or vestibular vertigo (65%) was carried out. A total of 264 patients were randomized (132 in each group).The inclusion criteria were a Dizziness Handicap Inventory (DHI) total score of more than 30 points and at least 2 vertigo attacks within the previous 4 weeks. The primary efficacy variable was the change in the DHI total score from baseline to after 12 weeks of treatment. The predefined non-inferiority margin was set at 9 points for the DHI total score. RESULTS: After 12 weeks of treatment, the DHI total score was significantly (p<0.001) decreased compared with baseline, by 32.0±20.7 in the betahistine MR group and by 31.8±19.8 in the betaserc group. The adjusted difference in the change in the DHI total score with a one-sided 97.5% CI was 0.9 (--; 5.3) points, the upper confidence limit (+5.3) fell below the predefined margin of non-inferiority of 9 points, and the non-inferiority of betahistine MR to betaserc was established. The treatment groups were comparable in terms of reduced scores for the functional, emotional and physical subdomains of DHI; reduced frequency, intensity and duration of vertigo attacks; decreased proportion of patients with prolonged attacks and severe symptoms during attacks; and scores on the Clinical Global Impression - Improvement scale. The safety profile of betahistine MR was comparable to that of betaserc, the most frequently reported adverse event was headache in both treatment groups. CONCLUSION: Betahistine MR (48 mg once daily) is non-inferior to betaserc (24 mg twice daily) in patients with Meniere's disease or vestibular vertigo and has a comparable safety profile.

Exogenous insulin augments in healthy volunteers the cardiovascular reactivity to noradrenaline but not to angiotensin II.

Hyperinsulinemia has been implicated in the pathogenesis of the blood pressure elevation in patients with noninsulin-dependent diabetes mellitus, obesity, but also essential hypertension. In these conditions an increased cardiovascular reactivity to noradrenaline (NA) and angiotensin II (AII) can be observed. Using the euglycemic clamp technique, we determined the cardiovascular reactivity to graded infusions of NA and AII in nine healthy males before (Bas), and 1 and 6 h after infusion of insulin (50 mU/kg per h) was started. On separate days control experiments were carried out to control for any circadian variation. Insulin led to a decrease of the amount of circulating NA necessary to increase the diastolic blood pressure (DBP) 20 mmHg (actual experiment [mean +/- SEM]: Bas, 23.1 +/- 5.0; 1 h, 14.8 +/- 3.0; and 6 h, 12.3 +/- 3.1; and control experiment: Bas, 20.7 +/- 5.0; 1 h, 18.6 +/- 3.5; and 6 h, 17.3 +/- 3.3 nmol/liter; Bas vs. 1 and 6 h: P less than 0.05). Although the amount of NA infused to raise DBP 20 mmHg showed a similar decline after 1 h of insulin infusion, no such change from baseline could be observed at 6 h. This appeared to be due to an increase in NA clearance with more prolonged insulin infusion. Insulin exerted no effect on the amount of AII infused to increase DBP 20 mmHg (actual experiment: Bas, 27.6 +/- 6.4; 1 h, 28.8 +/- 10.0; and 6 h, 21.2 +/- 5.3; and control experiment: Bas, 33.6 +/- 5.7; 1 h, 34.2 +/- 6.1; and 6 h, 23.4 +/- 4.7 ng/kg/min; NS). We did observe a circadian variation in AII reactivity. Whether the increase in cardiovascular responsiveness to NA after administration of insulin contributes to the elevation in blood pressure frequently observed in patients with insulin resistance remains to be proven.

The pharmacodynamics and activity of intranasally administered insulin in healthy male volunteers.

The objective of the study was to assess the bioavailability and absorption dynamics of intranasal insulin (with di-decanoyl-alpha-phosphatidylcholine, DDPC, as absorption enhancer) in two potencies (U200 and U500). Toward this aim, the euglycemic clamp technique combined with somatostatin (100 micrograms/h) was used. Insulin was administered to 12 healthy males: 5 IU intravenously (20-min infusion); 10 IU subcutaneously; 50 IU (U200) and 50 IU, 100 IU, and 150 IU (U500) intranasally. Peak insulin levels (mean +/- SD) were reached at 17.9 +/- 2.6, 77.9 +/- 38.3, 23.3 +/- 5.4, 25.4 +/- 8.4, 26.2 +/- 8.3, and 27.5 +/- 5.8 min, respectively. For the 50 IU dose, peak glucose requirements during the clamp and time to peak were not significantly different for U200 and U500: 548.8 +/- 279.5 vs. 452.4 +/- 232.9 mg/min and 41.3 +/- 16.2 vs. 51.5 +/- 29.9 min, respectively. Compared with intravenous insulin, the bioavailability calculated from the total area under the insulin curve was 13.2% (95% confidence interval 7.9, 21.9) and 8.8% (95% confidence interval 5.6, 13.8), and compared with subcutaneous insulin, the bioavailability was 14.8% (95% confidence interval 8.7, 25.2) and 9.9% (95% confidence interval 6.4, 15.4) for the U200 and U500 preparations, respectively. An apparent nonlinear dose-dependent relation was found for the U500 potency. The within-subject variability of the areas under the curves of plasma insulin after the administration of 100 IU was 43.6% (range 20.7-85.7). In conclusion, this nasal insulin preparation has promising absorption and action profiles in both potencies, which makes it suitable for further exploration of clinical applications.

The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up.

Oral leukoplakia is an important premalignant lesion of the oral mucosa. We treat this lesion prophylactically with CO2 laser evaporation. In the period from 1976 to 2001, a group of 200 patients with 282 oral leukoplakias were treated by CO2 laser evaporation. In a follow up period of 1-219 months (mean 52), 251 treated leukoplakias (89.0%) did not show a recurrence. Twenty eight (9.9%) local recurrences were observed in 5 to 168 months after treatment. Three (1.1%) squamous cell carcinoma, occurred in the treated area respectively 7, 17 and 19 month after CO2 laser evaporation. This large study with a long follow up shows that laser treatment is a good prophylactic treatment for oral leukoplakia.

Fibroblast function and the maintenance of the aortic-valve matrix.

The long-term behaviour of the aortic-valve allograft seems to be dependent on the maintenance of its matrix. Protein and collagen synthesis was studied in rat aortic-valves. Quantitative and qualitative methods proved the production of at least two protein pools. One protein pool is localised intracellularily with a 'turn-over' time of about 2 weeks, and a second pool is localised extracellularly with a 'turn-over' time of at least 8 weeks. The latter protein pool mainly consists of collagen.

Cell survival in canine aortic heart valves stored in nutrient medium.

For transplantation of viable aortic valves a period of preservation will generally be needed. To maintain cell viability during this preservation period valves can be stored in nutrient medium after sterilisation in an antibiotic solution. To obtain quantitative data about the survival of aortic valve fibroblasts after preservation, we determined the number of viable fibroblasts in canine aortic valves after several weeks of preservation. The results shows that after storage of 1 week in nutrient medium cell survival is about 80%, after 2 weeks cell survival has declined substantially, while after 3 weeks survival is already unacceptably low. Storage for periods over 4 weeks results in almost completely non-viable aortic valves. These results show that only valves preserved for 1 to 2 weeks in nutrient medium can be considered as viable aortic valves.

Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock.

STUDY OBJECTIVE - The aim was to investigate whether heterogeneous coronary blood flow is maldistributed during endotoxin shock. DESIGN - Variables were studied before (t = 0) and at t = 90 and t = 120 min after bolus injection of saline (n = 6) or endotoxin (n = 6). SUBJECTS - 12 anaesthetised mongrel dogs, weight 20-27 kg, were used. MEASUREMENTS AND MAIN RESULTS - We studied myocardial blood flows in small tissue sections (of about 1 g in left and 2 g in right ventricle) with radioactive microspheres, together with haemodynamic variables and global myocardial metabolism. At t = 0 min in controls, regional flows per 100 g were heterogeneous and ranged from a factor 0.2 to 2.7 and 0.6 to 1.6 of mean flow per 100 g to the left and right ventricle respectively; heterogeneity was unchanged at t = 90 and t = 120 min. Between t = 0, t = 90, and t = 120 min regional flows correlated: r = 0.78(SD 0.14), n = 18, for left ventricle, and r = 0.70(0.17) for right ventricle. In the endotoxin group, cardiac output and mean arterial pressure decreased by 44(7) and 48(11)% respectively, and lactate increased by 3.2(0.6) mmol.litre-1 at t = 120 min. Global left ventricle blood flow and delivery and metabolism of O2 were unchanged; lactate extraction and external work fell. The ratio between global right ventricular O2 delivery and external work also rose. Regional blood flows ranged from a factor 0.2 to 2.7 and 0.1 to 1.8 of mean flow to left and right ventricles respectively; heterogeneity did not differ from controls and did not change with time. Flow correlations with time were reduced: 0.45(0.24) for left ventricle and 0.45(0.26) for right ventricle (both n = 18, p less than 0.005 v controls). The left ventricular endocardial to epicardial flow ratio fell; flow was redistributed to both layers. CONCLUSIONS - Heterogeneous blood flow is redistributed throughout the heart during canine endotoxin shock so that, at unchanged global blood flow and flow heterogeneity, flow decreases in some but increases in other areas. Flow maldistribution may be associated with focal ischaemia, which may be masked by a rise in O2 uptake for a given workload (contractile inefficiency) in overperfused areas, and may thereby contribute to a fall in global myocardial external work for a given O2 delivery.