Impact of polygenic risk score for triglyceride trajectory and diabetic complications in subjects with type 2 diabetes based on large electronic medical record data from Taiwan: a case control study.

BACKGROUND: The prevalence of diabetic dyslipidemia has gradually increased worldwide and individuals with hypertriglyceridemia often have a high polygenic burden of triglyceride (TG)-increasing variants. However, the contribution of genetic variants to dyslipidemia in patients with type 2 diabetes (T2D) remains limited. Therefore, in this study, we aimed to investigate the genetic characteristics of longitudinal changes in TG levels among patients with T2D and summarize the genetic effects of polygenic risk score (PRS) on TG trajectory and risk of diabetic complications. METHODS: We conducted a case-control study. A total of 11,312 patients with T2D with longitudinal TG and genetic data were identified from a large hospital database in Taiwan. We then performed a genome-wide association study and calculated the relative PRS. RESULTS: In total, 21 single-nucleotide polymorphisms (SNPs) related to TG trajectory were identified and yielded an area under the receiver operating characteristic curve (ROC) of 0.712 for high TG trajectory risk among Taiwanese patients with T2D. A cumulative genetic effect was observed for high TG trajectory, even when considering the adherence of a lipid-lowering agent in stratified analysis. An increased PRS increases high TG trajectory risk in a logistic regression model (odds ratio = 1.55; 95% confidence interval [CI] = 1.31-1.83 in the validation cohort). The TG-specific PRS was associated with the risk of diabetic microvascular complications, including diabetic retinopathy and nephropathy (with hazard ratios of 1.11 [95% CI = 1.01-1.21, P = 0.027] and 1.05 [95% CI = 1.01-1.1, P = 0.018], respectively). CONCLUSIONS: This study may contribute to the identification of patients with T2D who are at risk of abnormal TG levels and diabetic microvascular complications using polygenic information.

Cavity ring-down spectroscopy based on a comb-locked optical parametric oscillator source.

Spectroscopy of molecules in the mid-infrared (MIR) region has important applications in various fields, such as astronomical observation, environmental detection, and fundamental physics. However, compared to that in the near-infrared, precision spectroscopy in the MIR is often limited by the light source and has not shown full potential in sensitivity. Here we report a cavity ring-down spectroscopy system using a tunable narrow-linewidth optical parametric oscillator, which fulfills the requirement of high sensitivity and high precision in the MIR region. The Lamb-dip spectrum of the N2O molecule at 2.7 µm was measured as a demonstration of spectroscopy in the MIR with kilohertz accuracy.

Seeded optical parametric oscillator light source for precision spectroscopy.

Precision spectroscopy of fundamental bands of molecules in the mid-infrared (MIR) region is of great interest in applications of trace detection and testing fundamental physics, where high-power and narrow-linewidth MIR lasers are needed. By using a frequency-stabilized near-infrared laser as a seed of the signal light of a continuous-wave optical parametric oscillator, we established a broadly tunable MIR light source that has an output power of several hundred milliwatts and a linewidth of a few tens of kilohertz. The MIR laser frequency drift was reduced to below 1 kHz by using an optical frequency comb to stabilize the frequency of the 1064 nm pumping laser. The performance of the light source was investigated and tested by measuring the saturated absorption spectroscopy of a few molecular transitions at 3.3 µm.

Comb-locked cavity ring-down spectroscopy with variable temperature.

Temperature dependence of molecular absorption line shape is important information for spectroscopic studies and applications. In this work, we report a comb-locked cavity ring-down spectrometer employing a cryogenic cooler to perform absorption spectroscopy measurements at temperatures between 40 K and 300 K. As a demonstration, we recorded the spectrum of the R(0) line in the (2-0) band of HD at 46 K. The temperature was also confirmed by the Doppler width of the HD line. Spectra of CH4 near 1.394 µm were also recorded in a wide temperature range of 70-300 K. Lower-state energies of methane lines were analyzed by fitting these spectra, which can be directly compared with the HITRAN and TheoReTS databases. Considerable deviations were observed, indicating the need to investigate the assignments of the methane lines in this region.

Determination of the Interval between the Ground States of Para- and Ortho-H_{2}.

Nuclear-spin-symmetry conservation makes the observation of transitions between quantum states of ortho- and para-H_{2} extremely challenging. Consequently, the energy-level structure of H_{2} derived from experiment consists of two disjoint sets of level energies, one for para-H_{2} and the other for ortho-H_{2}. We use a new measurement of the ionization energy of para-H_{2} [E_{I}(H_{2})/(hc)=124 417.491 098(31) cm^{-1}] to determine the energy separation [118.486 770(50) cm^{-1}] between the ground states of para- and ortho-H_{2} and thus link the energy-level structure of the two nuclear-spin isomers of this fundamental molecule. Comparison with recent theoretical results [M. Puchalski et al., Phys. Rev. Lett. 122, 103003 (2019)PRLTAO0031-900710.1103/PhysRevLett.122.103003] enables the derivation of an upper bound of 1.5 MHz for a hypothetical global shift of the energy-level structure of ortho-H_{2} with respect to that of para-H_{2}.

Prednisolone dose during treatment of tuberculosis might be a risk factor for mortality in patients with systemic lupus erythematosus: a hospital-based cohort study.

Patients with systemic lupus erythematosus (SLE) are at high risk of tuberculosis (TB) because of their immunocompromised status and the use of immunosuppressive drugs. In endemic regions, TB complicates the diagnosis and treatment of SLE, but the risk factors of mortality in these patients have not been investigated. In this study, we reviewed medical records during 2006-2016. Patients who fulfilled the 1997 American College of Rheumatology SLE criteria and presented with definite TB were enrolled. The primary outcome was mortality during TB treatment. There were 5388 SLE patients screened, and 30 patients were enrolled. Seven patients died during follow-up. Compared with the survival group, patients in the mortality group had significantly more central nervous system involvement of TB, higher Systemic Lupus Erythematosus Disease Activity Index-2000 scores and more cyclophosphamide use before TB, and higher prednisolone dose before and during TB treatment. Cox regression showed that prednisolone dose during TB treatment was an independent risk factor for mortality (per 10 mg/day increase, hazard ratio (HR) 1.61, p = .019). For SLE patients, prednisolone dose during TB treatment is an independent risk factor for mortality. Keeping prednisolone dose at less than 25 mg per day during TB treatment might be a reasonable strategy in these patients.

Dissociation Energy of the Hydrogen Molecule at 10

The ionization energy of ortho-H_{2} has been determined to be E_{I}^{o}(H_{2})/(hc)=124 357.238 062(25) cm^{-1} from measurements of the GK(1,1)-X(0,1) interval by Doppler-free, two-photon spectroscopy using a narrow band 179-nm laser source and the ionization energy of the GK(1,1) state by continuous-wave, near-infrared laser spectroscopy. E_{I}^{o}(H_{2}) was used to derive the dissociation energy of H_{2}, D_{0}^{N=1}(H_{2}), at 35 999.582 894(25) cm^{-1} with a precision that is more than one order of magnitude better than all previous results. The new result challenges calculations of this quantity and represents a benchmark value for future relativistic and QED calculations of molecular energies.

Multichannel continuous-wave fiber cavity ringdown gas sensing utilizing frequency-shifted interferometry.

We present a multichannel continuous-wave (CW) fiber cavity ringdown (FCRD) gas sensing method based on frequency-shifted interferometry (FSI). This scheme detects gas concentration by measuring the intensity decay rates of continuous light from different ringdown cavities in the spatial domain, unlike conventional FCRD techniques, which measure the decay rates of pulse light in the time domain. This method shares one CW light source, one slow detector, and one slow data collector. In order to illustrate the theory, acetylene gas concentration measurement in a two-channel FSI-FCRD system was experimentally conducted in the range of 0%-1%. A linear relation was established between concentration and absorption loss, which is proportional to the intensity decay rate, and the measurement resolutions of 3.871%/dB and 3.658%/dB were achieved, respectively. The results reveal that the proposed system has the advantages of low cost, high sensitivity, high precision, and good stability in multichannel gas detection.

Identification and characterization of a late gene encoded by grouper iridovirus 2L (GIV-2L).

Grouper iridovirus (GIV) belongs to the Ranavirus genus and is one of the most important viral pathogens in grouper, particularly at the fry and fingerling stages. In this study, we identified and characterized the GIV-2L gene, which encodes a protein of unknown function. GIV-2L is 1242 bp in length, with a predicted protein mass of 46.2 kDa. It displayed significant identity only with members of the Ranavirus and Iridovirus genera. We produced mouse monoclonal antibodies against the GIV-2L protein by immunizing mice with GIV-2L-His-tag recombinant protein. By inhibiting de novo protein and DNA synthesis in GIV-infected cells, we showed that GIV-2L was a late gene during the viral replication. Finally, immunofluorescence microscopy revealed that GIV-2L protein accumulated in both the nucleus and cytoplasm of infected cells. These results offer important insights into the pathogenesis of GIV.

CTGF is a therapeutic target for metastatic melanoma.

Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.

Analysis of 85Kr: a comparison at the 10 -14 level using micro-liter samples.

The isotopic abundance of (85)Kr in the atmosphere, currently at the level of 10(-11), has increased by orders of magnitude since the dawn of nuclear age. With a half-life of 10.76 years, (85)Kr is of great interest as tracers for environmental samples such as air, groundwater and ice. Atom Trap Trace Analysis (ATTA) is an emerging method for the analysis of rare krypton isotopes at isotopic abundance levels as low as 10(-14) using krypton gas samples of a few micro-liters. Both the reliability and reproducibility of the method are examined in the present study by an inter-comparison among different instruments. The (85)Kr/Kr ratios of 12 samples, in the range of 10(-13) to 10(-10), are measured independently in three laboratories: a low-level counting laboratory in Bern, Switzerland, and two ATTA laboratories, one in Hefei, China, and another in Argonne, USA. The results are in agreement at the precision level of 5%.

The 4ν(CH) overtone of 12C2H2: sub-MHz precision spectrum reveals perturbations.

The third CH stretching vibration overtone (4ν(CH)) of the acetylene molecule has been a prototype for intra-molecular dynamics studies. Using a sensitive cavity ring-down spectrometer calibrated with precise atomic transitions, the absolute line frequencies of 50 lines of this band have been determined with sub-MHz accuracy, or relatively 2 × 10(-9). The accuracy is also confirmed by the combination differences between the transitions sharing the same upper level. The improved accuracy, two orders of magnitude better than previous studies, allows us to reveal finer ro-vibrational couplings. Fitting of the rotational energies indicates that the J-dependent interactions take place after J > 7. The precise line positions present useful confinements to the models of the intra-molecular interactions of the acetylene molecule.

Normalization of the single atom counting rate in an atom trap.

The single atom counting rate of a rare isotope and the loading rate of another stable isotope with an abundance over 10 orders of magnitude larger are measured in one atom trap. The linear correlation between the measured counting/loading rates is examined to determine the (84)Kr/(82)Kr and (85)Kr/(83)Kr ratios of a Kr gas sample. Experiments show that the relative uncertainty is reduced to 1.3% when the single atom counting rate of (85)Kr is normalized by the measured (83)Kr loading rate. The measurement of the normalized single atom counting rate can be used to determine extremely low (10(-16)-10(-11)) isotope abundance. This normalization method is robust and can also be applied in other atomic systems.

A comprehensive 4-year survey of adverse drug reactions using a network-based hospital system.

WHAT IS KNOWN AND OBJECTIVE: Spontaneous Adverse Drug Reaction Reporting Systems (ADRRS) provide early warnings or 'signals' for adverse drug reactions (ADRs). Our aim was to survey reports of ADRs made through our teaching-hospital-based pharmacovigilance system to identify the drugs most commonly associated with allergies and the types of immunological reactions reported. METHODS: Adverse drug reactions records were retrieved from our network-based electronic notification system. RESULTS AND DISCUSSION: Four hundred and seventy four reports of adverse drug effects were studied. 37.3% of the reactions were immune-mediated drug hypersensitivity reactions. True drug hypersensitivity reactions involving IgE-mediated drug allergies accounted for 15% of all reactions. Of the drug hypersensitivity reactions, more than half (67%) were morbilliform skin eruptions, whereas cases of urticaria accounted for 20%. Antibiotics (33% of cases) were the most commonly reported drug allergies, followed by non-steroidal anti-inflammatory drugs (13%) and anti-epileptic agents (10%). WHAT IS NEW AND CONCLUSIONS: A hospital-based ADR reporting system can generate useful data. In our study, antibiotics accounted for the majority of drug allergies, particularly anaphylactic reactions. More cases of drug allergies were owing to cephalosporin allergies than penicillins. Anti-epileptic agents caused most of the severe drug hypersensitivity syndromes.

Cavity ring-down spectroscopy of Doppler-broadened absorption line with sub-MHz absolute frequency accuracy.

A continuous-wave cavity ring-down spectrometer has been built for precise determination of absolute frequencies of Doppler-broadened absorption lines. Using a thermo-stabilized Fabry-Pérot interferometer and Rb frequency references at the 780 nm and 795 nm, 0.1 - 0.6 MHz absolute frequency accuracy has been achieved in the 775-800 nm region. A water absorption line at 12579 cm(-1) is studied to test the performance of the spectrometer. The line position at zero-pressure limit is determined with an uncertainty of 0.3 MHz (relative accuracy of 0.8 × 10(-9)).

Laser-locked, continuously tunable high resolution cavity ring-down spectrometer.

A continuous-wave cavity ring-down spectrometer with sub-MHz precision has been built using the sideband of a frequency stabilized laser as the tunable light source. The sideband is produced by passing the carrier laser beam through an electro-optic modulator (EOM) and then selected by a short etalon on resonance. The carrier laser frequency is locked to a longitude mode of a thermo-stabilized Fabry-Perot interferometer (FPI) with a long-term absolute frequency stability of 0.2 MHz (5 × 10(-10)). Broad and precise spectral scanning is accomplished, respectively, by selecting a different longitudinal mode of the FPI and by tuning the radio-frequency driving the EOM. The air broadened water absorption line at 12,321 cm(-1) was studied to test the performance of the spectrometer.

Application of cavity ring-down spectroscopy to the Boltzmann constant determination.

The Boltzmann constant can be optically determined by measuring the Doppler width of an absorption line of molecules at gas phase. We propose to apply a near infrared cavity ring-down (CRD) spectrometer for this purpose. The superior sensitivity of CRD spectroscopy and the good performance of the near-ir lasers can provide ppm (part-per-million) accuracy which will be competitive to present most accurate result obtained from the speed of sound in argon measurement. The possible influence to the uncertainty of the determined Doppler width from different causes are investigated, which includes the signal-to-noise level, laser frequency stability, detecting nonlinearity, and pressure broadening effect. The analysis shows that the CRD spectroscopy has some remarkable advantages over the direct absorption method proposed before. The design of the experimental setup is presented and the measurement of C2H2 line near 0.8 µm at room temperature has been carried out as a test of the instrument.

Toward an ideal animal model to trace donor cell fates after stem cell therapy: production of stably labeled multipotent mesenchymal stem cells from bone marrow of transgenic pigs harboring enhanced green fluorescence protein gene.

The discovery of postnatal mesenchymal stem cells (MSC) with their general multipotentiality has fueled much interest in the development of cell-based therapies. Proper identification of transplanted MSC is crucial for evaluating donor cell distribution, differentiation, and migration. Lack of an efficient marker of transplanted MSC has precluded our understanding of MSC-related regenerative studies, especially in large animal models such as pigs. In the present study, we produced transgenic pigs harboring an enhanced green fluorescent protein (EGFP) gene. The pigs provide a reliable and reproducible source for obtaining stable EGFP-labeled MSC, which is very useful for donor cell tracking after transplantation. The undifferentiated EGFP-tagged MSC expressed a greater quantity of EGFP while maintaining MSC multipotentiality. These cells exhibited homogeneous surface epitopes and possessed classic trilineage differentiation potential into osteogenic, adipogenic, and chondrogenic lineages, with robust EGFP expression maintained in all differentiated progeny. Injection of donor MSC can dramatically increase the thickness of infarcted myocardium and improve cardiac function in mice. Moreover, the MSC, with their strong EGFP expression, can be easily distinguished from the background autofluorescence in myocardial infarcts. We demonstrated an efficient, effective, and easy way to identify MSC after long-term culture and transplantation. With the transgenic model, we were able to obtain stem or progenitor cells in earlier passages compared with the transfection of traceable markers into established MSC. Because the integration site of the transgene was the same for all cells, we lessened the potential for positional effects and the heterogeneity of the stem cells. The EGFP-transgenic pigs may serve as useful biomedical and agricultural models of somatic stem cell biology.

Effects of the different frequencies of whole-body vibration during the recovery phase after exhaustive exercise.

AIM: This study was to investigate the effects of vibration exercise on the oxygen consumption (VO2) and heart rate variability (HRV) during the recovery phase after exhaustive exercise. METHODS: Twenty male college students volunteered as subjects to participate in the study. The subjects were randomly crossover assigned to perform three 10 min vibration exercises, namely non-vibration (CON, 0 Hz, 0 mm), low-frequency (LFT, 20 Hz, 0.4 mm) and high-frequency (HFT, 36 Hz, 0.4 mm) treatments immediately after an incremental exhaustive cycling exercise in separated days. The beat-to-beat HRV, blood lactate concentration and VO2 were measured during the 1-hour recovery phase. The time- and frequency-domain indices of HRV were analyzed to confirm the effects of vibration exercises on the cardiac autonomic modulation. RESULTS: There were no significant differences on the VO2, HRV and blood lactate concentrations at 30th minute (post-30 min) or 60th minute (post-60 min) during the recovery phase among the three treatments. There were also no significant differences on the excess post-exercise oxygen consumption (EPOC) during the recovery phase among the treatments. However, the VO2 at post-30 min in CON and LFT were significantly higher than the baseline values, whereas the VO2 in HFT returned to resting condition at the post-30 min. CONCLUSIONS: The results indicate that both low and high frequency vibration exercises could not improve the physiological recovery after exhaustive cycling exercise. However, the high frequency vibration exercise probably has a potential to facilitate the VO2 to return to the resting level during the recovery phase.