We demonstrate that energetic femtosecond pulses tunable from 1.3 to 1.7 µm can be achieved using self-phase modulation enabled spectral broadening followed by spectral lobe filtering. Based on a ...home-built 5-W Er-fiber laser system operating at 31-MHz repetition rate, we obtain femtosecond pulses that can be continuously tuned from 1.3 to 1.7 µm with >4.5 nJ pulse energy. We further optimize the spectral broadening process using a fiber with larger mode area and scale up the pulse energy to >10 nJ; the resulting pulse duration is as short as ~50 fs. Such a widely tunable, energetic femtosecond source is well suited for driving a laser scanning microscope to perform deep tissue multiphoton microscopy.
We demonstrate an energy scalable approach to implement ultrafast fiber laser sources suitable for deep tissue multi-photon microscopy imaging. Enabled by fiber-optic nonlinearities (dominated by ...self-phase modulation), these unique ultrafast sources produce nearly transform-limited pulses of 50-90 fs in duration with the center wavelength tunable in the wavelength range of 1030-1215 nm. The resulting pulse energy can be scaled up to 20 nJ by optimizing fiber dispersion, shortening fiber length, and using large-mode-area fibers. We applied such an energetic source to a proof-of-principle study of ex vivo human skin based on harmonics (i.e., second-harmonic generation and third-harmonic generation) imaging. This new type of fiber-format energetic ultrafast source provides a robust solution for multiphoton microscopy applications.
Abstract
Introduction
Hypothyroidism is a rare and possible cause of hyponatremia. However, the clinical epidemiology and risk of mortality (ROM) when they coexist still remain elusive.
Objectives
We ...assessed the epidemiology and ROM among index patients with coexisting hypothyroidism and hyponatremia via a national population database.
Patients and methods
This retrospective cohort study utilized Taiwan’s National Health Insurance program database. Distributions of definite sociodemographic factors were analyzed. The annual incidence among the overall group and sex-subgroups was investigated. In addition, potential factors influencing the ROM were also evaluated.
Results
Of 4,549,226 patients from 1998 to 2015, a total of 3,140 index patients with concurrent hypothyroidism and hyponatremia were analyzed. The incidence rate increased tenfold from 1998 to 2015; average annual incidence rate was 174. Among the total participants, 57.1% were women; mean age was 72.6 ± 14.7 years and 88.8% were aged > 55 years. Although average length of stay (LOS) was 13.1 ± 15.4 days, the mortality group had significantly longer LOS than that in the survival group (12.9 days vs 22.2 days). Old age, catastrophic illness, cardiac dysrhythmia, and low hospital hierarchy were independent predictors of hospital mortality. The optimal LOS cutoff value for ROM prediction was 16 days. Index patients with LOS > 16 days increased ROM by 2.3-fold.
Conclusions
Coexistent hypothyroidism and hyponatremia is rare, although the incidence increased gradually. Factors influencing the ROM, such as old age, underlying catastrophic status, cardiac dysrhythmia, hospital hierarchy, and LOS should be considered in clinical care.
Studies have confirmed that osteoporosis has been considered as one of the complications of diabetes, and the health hazards to patients are more obvious. This study is mainly based on the Taiwan ...National Health Insurance Database (TNHID). Through the analysis of TNHID, it is shown that the combined treatment of traditional Chinese medicine (TCM) medicine in patients of diabetes with osteoporosis (T2DOP) with lower related risks.
According to the study design, 3131 patients selected from TNHID who received TCM treatment were matched by 1-fold propensity score according to gender, age, and inclusion date as the control group. Cox proportional hazards analyzes were performed to compare fracture surgery, hospitalization, and all-cause mortality during a mean follow-up from 2000 to 2015.
A total of 1055/1469/715 subjects (16.85%/23.46%/11.42%) had fracture surgery/inpatient/all-cause mortality of which 433/624/318 (13.83%/19.93%/10.16%) were in the TCM group) and 622/845/397 (19.87%/26.99%/12.68%) in the control group. Cox proportional hazards regression analysis showed that subjects in the TCM group had lower rates of fracture surgery, inpatient and all-cause mortality (adjusted HR = 0.467; 95% CI = 0.225-0.680, P<0.001; adjusted HR = 0.556; 95% CI = 0.330-0.751, P<0.001; adjusted HR = 0.704; 95% CI = 0.476-0.923, P = 0.012). Kaplan-Meier analysis showed that the cumulative risk of fracture surgery, inpatient and all-cause mortality was significantly different between the case and control groups (all log-rank p<0.001).
This study provides longitudinal evidence through a cohort study of the value of integrated TCM for T2DOP. More research is needed to fully understand the clinical significance of these results.
Carotid intima–media thickness (IMT), plaque, and stenosis are widely used as early surrogate markers of subclinical atherosclerosis and strong predictors of future deaths and cardiovascular events. ...Albuminuria is an indicator of generalized endothelial dysfunction that speeds up atherosclerosis. However, previous studies reporting these associations cannot rule out the confounding effect of albuminuria. We aimed to examine the independent and joint relationships between IMT markers and 10-year mortality in community-dwelling Taiwanese adults. This work was a community-based prospective cohort study consisting of 2956 adults aged at least 30 years recruited in 2007 and followed up through 2019. Cox proportional hazard regression models were used to examine associations of these subclinical atherosclerosis markers with mortality. During an average of 9.41 years of follow up, 242 deaths occurred. The mortality rate was 8.70 per 1000 person-years. Compared with those with carotid IMT less than 1.0 mm, persons with severely increased carotid IMT (≥2.0 mm) had an increased risk for death (hazard ratio (HR): 1.79; 95% confidence interval (CI): 1.07, 3.00). Compared with those without carotid plaque, persons with carotid plaque were more likely to have an increased risk for death (1.65; 1.21–2.32). Compared with those with carotid stenosis less than 25%, persons with carotid stenosis of 25–36% had a significant increased risk for death (1.57; 1.12–2.22). Considering these three IMT markers along with the traditional risk factors (c-statistic: 0.85) significantly increased their predictive ability of mortality compared with any individual variable’s predictive ability (all p-values < 0.001 for comparisons of c-statistic values). Carotid IMT measures, including IMT thickness, carotid plaque, and carotid stenosis were significant independent predictors of mortality. Our study supports evidence of blood pressure-related media thickening markers to assess future mortality risks in Chinese adults of general population.
Wavelength widely tunable femtosecond sources can be implemented by optically filtering the leftmost/rightmost spectral lobes of a broadened spectrum due to self-phase modulation (SPM) dominated ...fiber-optic nonlinearities. We numerically and experimentally investigate the feasibility of implementing such a tunable source inside optical fibers with negative group-velocity dispersion (GVD). We show that the spectral broadening prior to soliton fission is dominated by SPM and generates well-isolated spectral lobes; filtering the leftmost/rightmost spectral lobes results in energetic femtosecond pulses with the wavelength tuning range more than 400 nm. Employing an ultrafast Er-fiber laser and a dispersion-shifted fiber with negative GVD, we implement an energetic tunable source that produces ~100-fs pulses tunable between 1.3 µm and 1.7 µm with up to ~16-nJ pulse energy. Further energy scaling is achieved by increasing the input pulse energy to ~1-μJ and reducing the fiber length to 1.3 cm. The resulting source can produce >100-nJ femtosecond pulses at 1.3 µm and 1.7 µm with MW level peak power, representing an order of magnitude improvement of our previous results. Such a powerful source covers the 2nd and the 3rd biological transmission window and can facilitate multiphoton deep-tissue imaging.
The early detection of dementia depends on efficient methods for the assessment of cognitive capacity. Existing cognitive screening tools are ill-suited to the differentiation of cognitive status, ...particularly when dealing with early-stage impairment.
The study included 8,979 individuals (> 50 years) with unimpaired cognitive functions, mild cognitive impairment (MCI), or dementia. This study sought to determine optimal cutoffs values for the Cognitive Abilities Screening Instrument (CASI) aimed at differentiating between individuals with or without dementia as well as between individuals with or without mild cognitive impairment. Cox proportional hazards models were used to evaluate the value of CASI tasks in predicting conversion from MCI to all-cause dementia, dementia of Alzheimer's type (DAT), or to vascular dementia (VaD).
Our optimized cutoff scores achieved high accuracy in differentiating between individuals with or without dementia (AUC = 0.87-0.93) and moderate accuracy in differentiating between CU and MCI individuals (AUC = 0.67 - 0.74). Among individuals without cognitive impairment, scores that were at least 1.5 × the standard deviation below the mean scores on CASI memory tasks were predictive of conversion to dementia within roughly 2 years after the first assessment (all-cause dementia: hazard ratio HR = 2.81 - 3.53; DAT: 1.28 - 1.49; VaD: 1.58). Note that the cutoff scores derived in this study were lower than those reported in previous studies.
Our results in this study underline the importance of establishing optimal cutoff scores for individuals with specific demographic characteristics and establishing profiles by which to guide CASI analysis.
The major challenge in COVID‐19 vaccine effectiveness is immune escape by SARS‐CoV‐2 variants. To overcome this, an Omicron‐specific messenger RNA (mRNA) vaccine was designed. The extracellular ...domain of the spike of the Omicron variant was fused with a modified GCN4 trimerization domain with low immunogenicity (TSomi). After immunization with TSomi mRNA in hamsters, animals were challenged with SARS‐CoV‐2 virus. The raised nonneutralizing antibodies or cytokine secretion responses can recognize both Wuhan S and Omicron S. However, the raised antibodies neutralized SARS‐CoV‐2 Omicron virus infection but failed to generate Wuhan virus neutralizing antibodies. Surprisingly, TSomi mRNA immunization protected animals from Wuhan virus challenge. These data indicated that non‐neutralizing antibodies or cellular immunity may play a more important role in vaccine‐induced protection than previously believed. Next‐generation COVID‐19 vaccines using the Omicron S antigen may provide sufficient protection against ancestral or current SARS‐CoV‐2 variants.
Lipid-lowering drugs (LLDs) have protective effects against coronary artery disease (CAD) and cerebrovascular disease (CVD); however, a paradoxical association with cholesterol has been identified in ...several diseases, such as diabetes, dementia, and atrial fibrillation. We aimed to analyze the association between LLDs and cholesterol levels in older adults with type 2 diabetes mellitus (T2DM). This cross-sectional study enrolled consecutive patients aged ≥50 years from three centers in Taiwan. A multiple logistic regression model was used, and odds ratios (ORs) for different levels of total cholesterol (TC) or low-density-lipoprotein cholesterol (LDL-C) compared with the highest level were adjusted for age, triglyceride level, sex, comorbidities, and medications. Among the 3688 participants, 572 with and 676 without T2DM used LLDs. After adjusting for age and sex, the non-T2DM group demonstrated better medical conditions, cognition, and daily function than the T2DM group, regardless of LLD use. Compared to the highest TC level (≥240 mg/dL), ORs were significantly increased as TC levels decreased. A similar pattern of T2DM prevalence was observed in LDL-C levels. Older people with T2DM demonstrated low cognitive and daily functions. Significantly reduced TC and LDL levels were associated with a higher T2DM prevalence in older adults regardless of LLD use. T2DM was associated with impaired cognitive and daily functioning. A higher prevalence of T2DM in older people with low cholesterol levels raises doubt surrounding cognition and daily function being jeopardized when the "lower is better" strategy is applied for the secondary prevention of CAD or CVD.
Upon pathogen infection, the nervous system regulates innate immunity to confer coordinated protection to the host. However, the precise mechanisms of such regulation remain unclear. Previous studies ...have demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamine, functions in the sensory neurons designated "ASH" to suppress innate immune responses in
It is unknown what molecules act as OCTR-1 ligands in the neural immune regulatory circuit. Here we identify neurotransmitter octopamine (OA) as an endogenous ligand for OCTR-1 in immune regulation and show that the OA-producing RIC neurons function in the OCTR-1 neural circuit to suppress innate immunity. RIC neurons are deactivated in the presence of pathogens but transiently activated by nonpathogenic bacteria. Our data support a model whereby an octopaminergic immunoinhibitory pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to a myriad of human health concerns, our study could potentially benefit the development of more-effective treatments for innate immune disorders.
Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. Here we show the existence of an octopaminergic immunoinhibitory pathway in
Our study results indicate that this pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease, elucidating octopaminergic neural regulation of innate immunity could be helpful in the development of new treatments for innate immune diseases.
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