Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene.

Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.

Use of the Ferroelectric Ceramic Bismuth Titanate as an Ultrasonic Transducer for High Temperatures and Nuclear Radiation.

Ultrasonic transducers are often used in the nuclear industry as sensors to monitor the health and process status of systems or the components. Some of the after-effects of the Fukushima Daiichi earthquake could have been eased if sensors had been in place inside the four reactors and sensed the overheating causing meltdown and steam explosions. The key element of ultrasonic sensors is the piezoelectric wafer, which is usually derived from lead-zirconate-titanate (Pb(Zr, Ti)O3, PZT). This material loses its piezoelectrical properties at a temperature of about 200 °C. It also undergoes nuclear transmutation. Bismuth titanate (Bi4Ti3O12, BiTi) has been considered as a potential candidate for replacing PZT at the middle of this temperature range, with many possible applications, since it has a Curie-Weiss temperature of about 650 °C. The aim of this article is to describe experimental details for operation in gamma and nuclear radiation concomitant with elevated temperatures and details of the performance of a BiTi sensor during and after irradiation testing. In these experiments, bismuth titanate has been demonstrated to operate up to a fast neutron fluence of 5 × 1020 n/cm2 and gamma radiation of 7.23 × 1021 (gamma/cm2). The results offer a perspective on the state-of the-art for a possible sensor for harsh environments of high temperature, Gamma radiation, and nuclear fluence.

Odderon Exchange from Elastic Scattering Differences between pp and pp[over ¯] Data at 1.96 TeV and from pp Forward Scattering Measurements.

We describe an analysis comparing the pp[over ¯] elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeV using a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of sqrt[s]=1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4σ level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4σ and 4.6σ. The combined significance is larger than 5σ and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.

Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease.

OBJECTIVE: In patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping. METHODS: Incident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068). RESULTS: During randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin. CONCLUSION: Discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess. TRIAL REGISTRATION NUMBER: NCT01776424.

Influence of Meteorological Conditions on the Incidence of Chronic Subdural Haematoma, Subarachnoid and Intracerebral Haemorrhages - the "Bleeding Weather Hypothesis".

AIM: To elucidate possible causal relationships on climate change and intracranial haematomas. MATERIAL AND METHODS: In a retrospective study we examined all patients (N=1169) treated for subarachnoid haemorrhage (SAH; n=484), intracerebral haemorrhage (ICH; n=417) or chronic subdural haematoma (CSDH; n=268) in our department over a 7-yearperiod between 1st June 2005 until 31th May 2012. The date of admission was correlated with the corresponding meteorological parameters which included; mean daily temperature (°C), relative humidity (%), vapor pressure (hPa), barometric pressure (hPa), cloud amount (/8), and wind speed (m/s). RESULTS: Incidence of SAH tended to increase in April, ICH in January and CSDH in July, respectively, but ?² test did not reveal any statistical significance in seasonality for the three bleeding pathologies. Comparing the arithmetic average of meteorological key parameters of uneventful and eventful days by using student?s t-test within the three groups (SAH, ICH, CSDH) we could not demonstrate any statistical significance (p > 0.05). For SAH, logistic regression analyses revealed an increased risk associated with a decrease of barometric pressure (p=0.021). CONCLUSION: Although our data suggest seasonal variabilities of SAH, ICH and CSDH, the single weather parameters do not demonstrate causal relationships with the incidence of cerebrovascular events. However, incidence of SAH tended to increase with changes of barometric pressure which confirms previously published results and might indicate a possible underlying relationship.

Low colonization rates with Multidrug-resistant Gram-negative bacteria in a German hospital-affiliated hemodialysis center.

BACKGROUND: Multidrug-resistant Gram-negative bacteria (MDRGN) are found with rising prevalence in non-hemodialysis risk populations as well as hemodialysis (HD) cohorts in Asia, Europe and North America. At the same time, colonization and consecutive infections with such pathogens may increase mortality and morbidity of affected individuals. We aimed to monitor intestinal MDRGN colonization in a yet not investigated German HD population. METHODS: We performed cross-sectional point-prevalence testing with 12 months follow-up and selected testing of relatives in an out-patient HD cohort of n = 77 patients by using microbiological cultures from fresh stool samples, combined with Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS) and antimicrobial susceptibility testing. RESULTS: We detected MDRGN in 8 out of 77 patients (10.4%) and 1 out of 22 relatives (4.5%), indicating only colonization and no infections. At follow-up, 2 patients showed phenotypic persistence of MDRGN colonization, and in 6 other patients de-novo MDRGN colonization could be demonstrated. Pathogens included Escherichia coli and Klebsiella pneumoniae (with extended-spectrum beta-lactamase [ESBL]-production as well as fluoroquinolone resistance), Stenotrophomonas maltophilia and Enterobacter cloacae. CONCLUSIONS: In a single-center study, MDRGN colonization rates were below those found in non-HD high-risk populations and HD units in the US, respectively. Reasons for this could be high hygiene standards and a strict antibiotic stewardship policy with evidence of low consumption of fluoroquinolones and carbapenems in our HD unit and the affiliated hospital.

State-of-the-Art and Practical Guide to Ultrasonic Transducers for Harsh Environments Including Temperatures above 2120 °F (1000 °C) and Neutron Flux above 1013 n/cm2.

In field applications currently used for health monitoring and nondestructive testing, ultrasonic transducers primarily employ PZT5-H as the piezoelectric element for ultrasound transmission and detection. This material has a Curie-Weiss temperature that limits its use to about 210 °C. Some industrial applications require much higher temperatures, i.e., 1000-1200 °C and possible nuclear radiation up to 1020 n/cm2 when performance is required in a reactor environment. The goal of this paper is the survey and review of piezoelectric elements for use in harsh environments for the ultimate purpose for structural health monitoring (SHM), non-destructive evaluation (NDE) and material characterization (NDMC). The survey comprises the following categories: 1. High-temperature applications with single crystals, thick-film ceramics, and composite ceramics, 2. Radiation-tolerant materials, and 3. Spray-on transducers for harsh-environment applications. In each category the known characteristics are listed, and examples are given of performance in harsh environments. Highlighting some examples, the performance of single-crystal lithium niobate wafers is demonstrated up to 1100 °C. The wafers with the C-direction normal to the wafer plane were mounted on steel cylinders with high-temperature Sauereisen and silver paste wire mountings and tested in air. In another example, the practical use in harsh radiation environments aluminum nitride (AlN) was found to be a good candidate operating well in two different nuclear reactors. The radiation hardness of AlN was evident from the unaltered piezoelectric coefficient after a fast and thermal neutron exposure in a nuclear reactor core (thermal flux = 2.12 × 1013 ncm-2; fast flux 2 (>1.0 MeV) = 4.05 × 1013 ncm-2; gamma dose rate: 1 × 109 r/h; temperature: 400-500 °C). Additionally, some of the high-temperature transducers are shown to be capable of mounting without requiring coupling material. Pulse-echo signal amplitudes (peak-to-peak) for the first two reflections as a function of the temperature for lithium niobate thick-film, spray-on transducers were observed to temperatures of about 900 °C. Guided-wave send-and-receive operation in the 2-4 MHz range was demonstrated on 2-3 mm thick Aluminum (6061) structures for possible field deployable applications where standard ultrasonic coupling media do not survive because of the harsh environment. This approach would benefit steam generators and steam pipes where temperatures are above 210 °C. In summary, there are several promising approaches to ultrasonic transducers for harsh environments and this paper presents a survey based on literature searches and in-house laboratory observations.

Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.

The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.

Measurement of the Effective Weak Mixing Angle in pp[over ¯]→Z/γ

We present a measurement of the effective weak mixing angle parameter sin^{2}θ_{eff}^{ℓ} in pp[over ¯]→Z/γ^{*}→µ^{+}µ^{-} events at a center-of-mass energy of 1.96 TeV, collected by the D0 detector at the Fermilab Tevatron Collider and corresponding to 8.6 fb^{-1} of integrated luminosity. The measured value of sin^{2}θ_{eff}^{ℓ}[µµ]=0.23016±0.00064 is further combined with the result from the D0 measurement in pp[over ¯]→Z/γ^{*}→e^{+}e^{-} events, resulting in sin^{2}θ_{eff}^{ℓ}[comb]=0.23095±0.00040. This combined result is the most precise measurement from a single experiment at a hadron collider and is the most precise determination using the coupling of the Z/γ^{*} to light quarks.

Detection and characterization of early plaque formations by Raman probe spectroscopy and optical coherence tomography: an in vivo study on a rabbit model.

Intravascular imaging techniques provide detailed specification about plaque appearance and morphology, but cannot deliver information about the biochemical composition of atherosclerotic plaques. As the biochemical composition is related to the plaque type, important aspects such as the risk of a plaque rupture and treatment are still difficult to assess. Currently, various spectroscopic techniques are tested for potential applications for the chemical analysis of plaque depositions. Here, we employ Raman spectroscopy in combination with optical coherence tomography (OCT) for the characterization of plaques on rabbits in vivo. Experiments were carried out on New Zealand white rabbits treated with a fat- and cholesterol-enriched diet, using a Raman probe setup with a 785-nm multimode laser as an excitation source. Subsequently, OCT images were acquired with a swept source at 1305±55 nm at 22.6 mW. Raman spectra were recorded from normal regions and regions with early plaque formations. The probe positioning was monitored by x-ray angiography. The spectral information identified plaque depositions consisting of lipids, with triglycerides as the major component. Afterward, OCT images of the spectroscopically investigated areas were obtained. The spectral information correlates well with the observed intravascular morphology and is in good agreement with histology. Raman spectroscopy can provide detailed biochemical specification of atherosclerotic plaques.

Evidence for a B_{s}

We report evidence for a narrow structure, X(5568), in the decay sequence X(5568)→B_{s}^{0}π^{±}, B_{s}^{0}→J/ψϕ, J/ψ→µ^{+}µ^{-}, ϕ→K^{+}K^{-}. This is evidence for the first instance of a hadronic state with valence quarks of four different flavors. The mass and natural width of this state are measured to be m=5567.8±2.9(stat)_{-1.9}^{+0.9}(syst) MeV/c^{2} and Γ=21.9±6.4(stat)_{-2.5}^{+5.0}(syst) MeV/c^{2}. If the decay is X(5568)→B_{s}^{*}π^{±}→B_{s}^{0}γπ^{±} with an unseen γ, m(X(5568)) will be shifted up by m(B_{s}^{*})-m(B_{s}^{0})∼49 MeV/c^{2}. This measurement is based on 10.4 fb^{-1} of pp[over ¯] collision data at sqrt[s]=1.96 TeV collected by the D0 experiment at the Fermilab Tevatron collider.

Evidence for Simultaneous Production of J/ψ and ϒ Mesons.

We report evidence for the simultaneous production of J/ψ and ϒ mesons in 8.1 fb^{-1} of data collected at sqrt[s]=1.96 TeV by the D0 experiment at the Fermilab pp[over ¯] Tevatron Collider. Events with these characteristics are expected to be produced predominantly by gluon-gluon interactions. In this analysis, we extract the effective cross section characterizing the initial parton spatial distribution, σ_{eff}=2.2±0.7(stat)±0.9(syst) mb.

Inclusive Production of the X(4140) State in pp[over ¯] Collisions at D0.

We present a study of the inclusive production of the X(4140) state with the decay to the J/ψϕ final state in hadronic collisions. Based on 10.4 fb^{-1} of pp[over ¯] collision data collected by the D0 experiment at the Fermilab Tevatron collider, we report the first evidence for the prompt production of an X(4140) state and find the fraction of X(4140) events originating from b hadrons to be f_{b}=0.39±0.07(stat)±0.10(syst). The ratio of the nonprompt X(4140) production rate to the B_{s}^{0} yield in the same channel is R=0.19±0.05(stat)±0.07(syst). The values of the mass M=4152.5±1.7(stat)_{-5.4}^{+6.2}(syst) MeV and width Γ=16.3±5.6(stat)±11.4(syst) MeV are consistent with previous measurements.

Search for Violation of CPT and Lorentz Invariance in Bs(0) Meson Oscillations.

We present the first search for CPT-violating effects in the mixing of Bs(0) mesons using the full Run II data set with an integrated luminosity of 10.4 fb(-1) of proton-antiproton collisions collected using the D0 detector at the Fermilab Tevatron Collider. We measure the CPT-violating asymmetry in the decay Bs(0)→µ(±)Ds(±) as a function of celestial direction and sidereal phase. We find no evidence for CPT-violating effects and place limits on the direction and magnitude of flavor-dependent CPT- and Lorentz-invariance violating coupling coefficients. We find 95% confidence intervals of Δa⊥<1.2×10(-12) GeV and (-0.8<ΔaT-0.396ΔaZ<3.9)×10(-13) GeV.

Measurement of the Effective Weak Mixing Angle in pp[over ¯]→Z/γ

We present a measurement of the fundamental parameter of the standard model, the weak mixing angle sin^{2}θ_{eff}^{ℓ} which determines the relative strength of weak and electromagnetic interactions, in pp[over ¯]→Z/γ^{*}→e^{+}e^{-} events at a center of mass energy of 1.96 TeV, using data corresponding to 9.7 fb^{-1} of integrated luminosity collected by the D0 detector at the Fermilab Tevatron. The effective weak mixing angle is extracted from the forward-backward charge asymmetry as a function of the invariant mass around the Z boson pole. The measured value of sin^{2}θ_{eff}^{ℓ}=0.23147±0.00047 is the most precise measurement from light quark interactions to date, with a precision close to the best LEP and SLD results.

Non-linear imaging and characterization of atherosclerotic arterial tissue using combined SHG and FLIM microscopy.

Atherosclerosis is one of the leading causes of death in the Western World and its characterization is extremely interesting from the diagnostic point of view. Here, we employed combined SHG-FLIM microscopy to characterize arterial tissue with atherosclerosis. The shorter mean fluorescence lifetime measured within plaque depositions (1260 ± 80 ps) with respect to normal arterial wall (1480 ± 100 ps) allowed discriminating collagen from lipids. SHG measurements and image analysis demonstrated that the normal arterial wall has a more anisotropic Aspect Ratio (0.37 ± 0.02) with respect to plaque depositions (0.61 ± 0.02) and that the correlation length can be used for discriminating collagen fibre bundles (2.0 ± 0.6 µm) from cholesterol depositions (4.1 ± 0.6 µm). The presented method has the potential to find place in a clinical setting as well as to be applied in vivo in the near future. Graphic composition of SHG and FLIM images representing normal arterial wall and plaque depositions.

Measurement of the B(s)(0) lifetime in the flavor-specific decay channel B(s)(0)→D(s)(-)µ(+)νX.

We present an updated measurement of the B(s)(0) lifetime using the semileptonic decays B(s)(0)→D(s)(-)µ(+)νX, with D(s)(-)→ϕπ(-) and ϕ→K(+)K(-) (and the charge conjugate process). This measurement uses the full Tevatron Run II sample of proton-antiproton collisions at √[s]=1.96 TeV, comprising an integrated luminosity of 10.4 fb(-1). We find a flavor-specific lifetime τ(fs)(B(s)(0))=1.479±0.010(stat)±0.021(syst) ps. This technique is also used to determine the B(0) lifetime using the analogous B(0)→D(-)µ(+)νX decay with D(-)→ϕπ(-) and ϕ→K(+)K(-), yielding τ(B(0))=1.534±0.019(stat)±0.021(syst) ps. Both measurements are consistent with the current world averages, and the B(s)(0) lifetime measurement is one of the most precise to date. Taking advantage of the cancellation of systematic uncertainties, we determine the lifetime ratio τ(fs)(B(s)(0))/τ(B(0))=0.964±0.013(stat)±0.007(syst).

Measurement of the forward-backward asymmetry in the production of B(±) mesons in pp̄ collisions at √s=1.96 TeV.

We present a measurement of the forward-backward asymmetry in the production of B(±) mesons, A(FB)(B(±)), using B(±)→J/ψK(±) decays in 10.4 fb(-1) of pp̄ collisions at sqrt[s]=1.96 TeV collected by the D0 experiment during Run II of the Tevatron collider. A nonzero asymmetry would indicate a preference for a particular flavor, i.e., b quark or ̄b antiquark, to be produced in the direction of the proton beam. We extract A(FB)(B(±)) from a maximum likelihood fit to the difference between the numbers of forward- and backward-produced B(±) mesons. We measure an asymmetry consistent with zero: A(FB)(B(±))=[-0.24±0.41 (stat)±0.19 (syst)]%.

Constraints on models for the Higgs boson with exotic spin and parity in VH → Vbb final states.

We present constraints on models containing non-standard-model values for the spin J and parity P of the Higgs boson H in up to 9.7 fb(-1) of pp collisions at sqrt[s] = 1.96 TeV collected with the D0 detector at the Fermilab Tevatron Collider. These are the first studies of Higgs boson J(P) with fermions in the final state. In the ZH → ℓℓbb, WH → ℓνbb, and ZH → ννbb final states, we compare the standard model (SM) Higgs boson prediction, J(P) = 0(+), with two alternative hypotheses, J(P) = 0(-) and J(P) = 2(+). We use a likelihood ratio to quantify the degree to which our data are incompatible with non-SM J(P) predictions for a range of possible production rates. Assuming that the production rate in the signal models considered is equal to the SM prediction, we reject the J(P) = 0(-) and J(P) = 2(+) hypotheses at the 97.6% CL and at the 99.0% CL, respectively. The expected exclusion sensitivity for a J(P) = 0(-) (J(P) = 2(+)) state is at the 99.86% (99.94%) CL. Under the hypothesis that our data are the result of a combination of the SM-like Higgs boson and either a J(P) = 0(-) or a J(P) = 2(+) signal, we exclude a J(P) = 0(-) fraction above 0.80 and a J(P) = 2(+) fraction above 0.67 at the 95% CL. The expected exclusion covers J(P) = 0(-) (J(P) = 2(+)) fractions above 0.54 (0.47).