Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial.

The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.

Early experience with the ARTISENTIAL® articulated instruments in laparoscopic low anterior resection with TME.

BACKGROUND: The notion of articulation in surgery has been largely synonymous with robotics. The ARTISENTIAL® instruments aim at bringing advanced articulation to laparoscopy to overcome challenges in narrow anatomical spaces. In this paper, we present first single-center results of a series of low anterior resections, performed with ARTISENTIAL®. METHODS: Between September 2020 and August 2021, at the Department of Surgery, St. Marienkrankenhaus Siegen, Siegen, Germany, patients with cancer of the mid- and low rectum were prospectively enrolled in a pilot feasibility study to evaluate the ARTISENTIAL® articulated instruments in performing a laparoscopic low anterior resection. Perioperative and short-term postoperative data were analyzed. RESULTS: Seventeen patients (10 males/7 females) were enrolled in this study. The patients had a median age of 66 years (range 47-80 years) and a median body mass index of 28 kg/m2 (range 23-33 kg/m2). The median time to rectal transection was 155 min (range 118-280 min) and the median total operative time was 276 min (range 192-458 min). The median estimated blood loss was 30 ml (range 5-70 ml) and there were no conversions to laparotomy. The median number of harvested lymph nodes was 15 (range 12-28). Total mesorectal excision (TME) quality was 'good' in all patients with no cases of circumferential resection margin involvement (R0 = 100%). The median length of stay was 9 days (range 7-14 days). There were no anastomotic leaks and the overall complication rate was 17.6%. There was one unrelated readmission with no mortality. CONCLUSIONS: Low anterior resection with ARTISENTIAL® is feasible and safe. All patients had a successful TME procedure with a good oncological outcome. We will now seek to evaluate the benefits of ARTISENTIAL® in comparison with standard laparoscopic instruments through a larger study.

Search for a Variation of the Fine Structure Constant around the Supermassive Black Hole in Our Galactic Center.

Searching for space-time variations of the constants of Nature is a promising way to search for new physics beyond general relativity and the standard model motivated by unification theories and models of dark matter and dark energy. We propose a new way to search for a variation of the fine-structure constant using measurements of late-type evolved giant stars from the S star cluster orbiting the supermassive black hole in our Galactic Center. A measurement of the difference between distinct absorption lines (with different sensitivity to the fine structure constant) from a star leads to a direct estimate of a variation of the fine structure constant between the star's location and Earth. Using spectroscopic measurements of five stars, we obtain a constraint on the relative variation of the fine structure constant below 10^{-5}. This is the first time a varying constant of nature is searched for around a black hole and in a high gravitational potential. This analysis shows new ways the monitoring of stars in the Galactic Center can be used to probe fundamental physics.

Alzheimer's Disease Composite Score: A Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer's Disease.

As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.

Gravitational Redshift Test Using Eccentric Galileo Satellites.

We report on a new test of the gravitational redshift and thus of local position invariance, an integral part of the Einstein equivalence principle, which is the foundation of general relativity and all metric theories of gravitation. We use data spanning 1008 days from two satellites of Galileo, Europe's global satellite navigation system, which were launched in 2014, but accidentally delivered on elliptic rather than circular orbits. The resulting modulation of the gravitational redshift of the onboard atomic clocks allows the redshift determination with high accuracy. Additionally, specific laser ranging campaigns to the two satellites have enabled a good estimation of systematic effects related to orbit uncertainties. Together with a careful conservative modeling and control of other systematic effects we measure the fractional deviation of the gravitational redshift from the prediction by general relativity to be (0.19±2.48)×10^{-5} at 1 sigma, improving the best previous test by a factor 5.6. To our knowledge, this represents the first reported improvement on one of the longest standing results in experimental gravitation, the Gravity Probe A hydrogen maser rocket experiment back in 1976.

Lorentz Symmetry Violations from Matter-Gravity Couplings with Lunar Laser Ranging.

The standard-model extension (SME) is an effective field theory framework aiming at parametrizing any violation to the Lorentz symmetry (LS) in all sectors of physics. In this Letter, we report the first direct experimental measurement of SME coefficients performed simultaneously within two sectors of the SME framework using lunar laser ranging observations. We consider the pure gravitational sector and the classical point-mass limit in the matter sector of the minimal SME. We report no deviation from general relativity and put new realistic stringent constraints on LS violations improving up to 3 orders of magnitude previous estimations.

Testing General Relativity with Stellar Orbits around the Supermassive Black Hole in Our Galactic Center.

We demonstrate that short-period stars orbiting around the supermassive black hole in our Galactic center can successfully be used to probe the gravitational theory in a strong regime. We use 19 years of observations of the two best measured short-period stars orbiting our Galactic center to constrain a hypothetical fifth force that arises in various scenarios motivated by the development of a unification theory or in some models of dark matter and dark energy. No deviation from general relativity is reported and the fifth force strength is restricted to an upper 95% confidence limit of |α|<0.016 at a length scale of λ=150 astronomical units. We also derive a 95% confidence upper limit on a linear drift of the argument of periastron of the short-period star S0-2 of |ω[over ˙]_{S0-2}|<1.6×10^{-3} rad/yr, which can be used to constrain various gravitational and astrophysical theories. This analysis provides the first fully self-consistent test of the gravitational theory using orbital dynamic in a strong gravitational regime, that of a supermassive black hole. A sensitivity analysis for future measurements is also presented.

Testing Lorentz Symmetry with Lunar Laser Ranging.

Lorentz symmetry violations can be parametrized by an effective field theory framework that contains both general relativity and the standard model of particle physics called the standard-model extension (SME). We present new constraints on pure gravity SME coefficients obtained by analyzing lunar laser ranging (LLR) observations. We use a new numerical lunar ephemeris computed in the SME framework and we perform a LLR data analysis using a set of 20 721 normal points covering the period of August, 1969 to December, 2013. We emphasize that linear combination of SME coefficients to which LLR data are sensitive and not the same as those fitted in previous postfit residuals analysis using LLR observations and based on theoretical grounds. We found no evidence for Lorentz violation at the level of 10^{-8} for s[over ¯]^{TX}, 10^{-12} for s[over ¯]^{XY} and s[over ¯]^{XZ}, 10^{-11} for s[over ¯]^{XX}-s[over ¯]^{YY} and s[over ¯]^{XX}+s[over ¯]^{YY}-2s[over ¯]^{ZZ}-4.5s[over ¯]^{YZ}, and 10^{-9} for s[over ¯]^{TY}+0.43s[over ¯]^{TZ}. We improve previous constraints on SME coefficient by a factor up to 5 and 800 compared to postfit residuals analysis of respectively binary pulsars and LLR observations.

Searching for an Oscillating Massive Scalar Field as a Dark Matter Candidate Using Atomic Hyperfine Frequency Comparisons.

We use 6 yrs of accurate hyperfine frequency comparison data of the dual rubidium and caesium cold atom fountain FO2 at LNE-SYRTE to search for a massive scalar dark matter candidate. Such a scalar field can induce harmonic variations of the fine structure constant, of the mass of fermions, and of the quantum chromodynamic mass scale, which will directly impact the rubidium/caesium hyperfine transition frequency ratio. We find no signal consistent with a scalar dark matter candidate but provide improved constraints on the coupling of the putative scalar field to standard matter. Our limits are complementary to previous results that were only sensitive to the fine structure constant and improve them by more than an order of magnitude when only a coupling to electromagnetism is assumed.

A Period 2 genetic variant interacts with plasma SFA to modify plasma lipid concentrations in adults with metabolic syndrome.

Genetic variants of Period 2 (PER2), a circadian clock gene, have been linked to metabolic syndrome (MetS). However, it is still unknown whether these genetic variants interact with the various types of plasma fatty acids. This study investigated whether common single nucleotide polymorphisms (SNPs) in the PER2 locus (rs934945 and rs2304672) interact with various classes of plasma fatty acids to modulate plasma lipid metabolism in 381 participants with MetS in the European LIPGENE study. Interestingly, the rs2304672 SNP interacted with plasma total SFA concentrations to affect fasting plasma TG, TG-rich lipoprotein (TRL-TG), total cholesterol, apoC-II, apoB, and apoB-48 concentrations (P-interaction < 0.001-0.046). Carriers of the minor allele (GC+GG) with the highest SFA concentration (>median) had a higher plasma TG concentration (P = 0.001) and higher TRL-TG (P < 0.001) than the CC genotype. In addition, participants carrying the minor G allele for rs2304672 SNP and with a higher SFA concentration (>median) had higher plasma concentrations of apo C-II (P < 0.001), apo C-III (P = 0.009), and apoB-48 (P = 0.028) compared with the homozygotes for the major allele (CC). In summary, the rs2304672 polymorphism in the PER2 gene locus may influence lipid metabolism by interacting with the plasma total SFA concentration in participants with MetS. The understanding of these gene-nutrient interactions could help to provide a better knowledge of the pathogenesis in MetS.

Effects of dietary fat modification on skeletal muscle fatty acid handling in the metabolic syndrome.

OBJECTIVE: In the metabolic syndrome (MetS), increased fat storage in 'nonadipose' tissues such as skeletal muscle may be related to insulin resistance ('lipid overflow' hypothesis). The objective of this study was to examine the effects of dietary fat modification on the capacity of skeletal muscle to handle dietary and endogenous fatty acids (FAs). SUBJECTS AND METHODS: In total, 29 men with the MetS were randomly assigned to one of four diets for 12 weeks: a high-fat saturated fat diet (HSFA, n=6), a high-fat monounsaturated fat diet (HMUFA, n=7) and two low-fat high-complex carbohydrate diets supplemented with (LFHCCn-3, n=8) or without (LFHCC, n=8) 1.24 g per day docosahexaenoic and eicosapentaenoic acid. Fasting and postprandial skeletal muscle FA handling was examined by measuring arteriovenous concentration differences across the forearm muscle. [(2)H(2)]-palmitate was infused intravenously to label endogenous triacylglycerol (TAG) and free fatty acids in the circulation and subjects received a high-fat mixed meal (2.6 MJ, 61 energy% fat) containing [U-(13)C]-palmitate to label chylomicron-TAG. RESULTS: Postprandial circulating TAG concentrations were significantly lower after dietary intervention in the LFHCCn-3 group compared to the HSFA group (DeltaiAUC -139+/-67 vs 167+/-70 micromol l(-1) min(-1), P=0.009), together with decreased concentrations of [U-(13)C]-labeled TAG, representing dietary FA. Fasting TAG clearance across forearm muscle was decreased on the HSFA diet, whereas no differences were observed in postprandial forearm muscle FA handling between diets. CONCLUSION: Chronic manipulation of dietary fat quantity and quality did not affect forearm muscle FA handling in men with the MetS. Postprandial TAG concentrations decreased on the LFHCCn-3 diet, which could be (partly) explained by lower concentration of dietary FA in the circulation.

Effect of beta-adrenergic stimulation on whole-body and abdominal subcutaneous adipose tissue lipolysis in lean and obese men.

AIMS/HYPOTHESIS: Obesity is characterised by increased triacylglycerol storage in adipose tissue. There is in vitro evidence for a blunted beta-adrenergically mediated lipolytic response in abdominal subcutaneous adipose tissue (SAT) of obese individuals and evidence for this at the whole-body level in vivo. We hypothesised that the beta-adrenergically mediated effect on lipolysis in abdominal SAT is also impaired in vivo in obese humans. METHODS: We investigated whole-body and abdominal SAT glycerol metabolism in vivo during 3 h and 6 h [2H5]glycerol infusions. Arterio-venous concentration differences were measured in 13 lean and ten obese men after an overnight fast and during intravenous infusion of the non-selective beta-adrenergic agonist isoprenaline [20 ng (kg fat free mass)(-1) min(-1)]. RESULTS: Lean and obese participants showed comparable fasting glycerol uptake by SAT (9.7+/-3.4 vs 9.3+/-2.5% of total release, p=0.92). Furthermore, obese participants showed an increased whole-body beta-adrenergically mediated lipolytic response versus lean participants. However, their fasting lipolysis was blunted [glycerol rate of appearance: 7.3+/-0.6 vs 13.1+/-0.9 micromol (kg fat mass)(-1) min(-1), p<0.01], as was the beta-adrenergically mediated lipolytic response per unit SAT [Delta total glycerol release: 140+/-71 vs 394+/-112 nmol (100 g tissue)(-1) min(-1), p<0.05] compared with lean participants. Net triacylglycerol flux tended to increase in obese compared with lean participants during beta-adrenergic stimulation [Delta net triacylglycerol flux: 75+/-32 vs 16+/-11 nmol (100 g tissue)(-1) min(-1), p=0.06]. CONCLUSIONS/INTERPRETATION: We demonstrated in vivo that beta-adrenergically mediated lipolytic response is impaired systematically and in abdominal SAT of obese versus lean men. This may be important in the development or maintenance of increased triacylglycerol stores and obesity.

Medical abortion as an alternative to vacuum aspiration: first experiences with the 'abortion pill' in The Netherlands.

OBJECTIVE: To establish to what extent medical abortion is desired as a supplement to existing care provision in The Netherlands and to establish the (dis)advantages of medical abortion versus surgical vacuum aspiration. METHODS: The research project began in November 1999 and ended in September 2000. In two abortion clinics, the clients were asked to answer some questions about their expectations (before treatment) and their experiences with the treatment (at the post-treatment check-up). At the post-treatment check-up, the clients were also asked to fill out the Hopkin's Symptom Checklist (HSCL) which is an objective measure for the psychological and physical well-being of the clients during the previous week. RESULTS: One hundred and thirty-one clients who chose medical abortion and 131 clients who chose surgical vacuum aspiration participated in the study. The failure rate was 3.3% for medical abortion and 1.5% for surgical vacuum aspiration. Of the medical abortion clients, 80.2% reported they were satisfied with this treatment and 68.1% said they would choose the same treatment procedure in the future. For vacuum aspiration, these figures were 92.9% and 83.2%, respectively. The most reported advantage of medical abortion was the fact that it was a pill, and no surgical procedures were necessary. The most reported disadvantages of medical abortion were the amount of blood loss and insecurity concerning the time of abortion. CONCLUSIONS: Medical abortion seems to be a good supplement to the existing care provision in The Netherlands and should be offered in other clinics.