Association of white matter hyperintensities with cognitive decline and neurodegeneration.

Background: The relationship between white matter hyperintensities (WMH) and the core features of Alzheimer's disease (AD) remains controversial. Further, due to the prevalence of co-pathologies, the precise role of WMH in cognition and neurodegeneration also remains uncertain. Methods: Herein, we analyzed 1803 participants with available WMH volume data, extracted from the ADNI database, including 756 cognitively normal controls, 783 patients with mild cognitive impairment (MCI), and 264 patients with dementia. Participants were grouped according to cerebrospinal fluid (CSF) pathology (A/T profile) severity. Linear regression analysis was applied to evaluate the factors associated with WMH volume. Modeled by linear mixed-effects, the increase rates (Δ) of the WMH volume, cognition, and typical neurodegenerative markers were assessed. The predictive effectiveness of WMH volume was subsequently tested using Cox regression analysis, and the relationship between WMH/ΔWMH and other indicators such as cognition was explored through linear regression analyses. Furthermore, we explored the interrelationship among amyloid-ß deposition, cognition, and WMH using mediation analysis. Results: Higher WMH volume was associated with older age, lower CSF amyloid-ß levels, hypertension, and smoking history (all p ≤ 0.001), as well as cognitive status (MCI, p < 0.001; dementia, p = 0.008), but not with CSF tau levels. These results were further verified in any clinical stage, except hypertension and smoking history in the dementia stage. Although WMH could not predict dementia conversion, its increased levels at baseline were associated with a worse cognitive performance and a more rapid memory decline. Longitudinal analyses showed that baseline dementia and positive amyloid-ß status were associated with a greater accrual of WMH volume, and a higher ΔWMH was also correlated with a faster cognitive decline. In contrast, except entorhinal cortex thickness, the WMH volume was not found to be associated with any other neurodegenerative markers. To a lesser extent, WMH mediates the relationship between amyloid-ß and cognition. Conclusion: WMH are non-specific lesions that are associated with amyloid-ß deposition, cognitive status, and a variety of vascular risk factors. Despite evidence indicating only a weak relationship with neurodegeneration, early intervention to reduce WMH lesions remains a high priority for preserving cognitive function in the elderly.

A prediction model of dementia conversion for mild cognitive impairment by combining plasma pTau181 and structural imaging features.

AIMS: The early stages of Alzheimer's disease (AD) are no longer insurmountable. Therefore, identifying at-risk individuals is of great importance for precise treatment. We developed a model to predict cognitive deterioration in patients with mild cognitive impairment (MCI). METHODS: Based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we constructed models in a derivation cohort of 761 participants with MCI (138 of whom developed dementia at the 36th month) and verified them in a validation cohort of 353 cognitively normal controls (54 developed MCI and 19 developed dementia at the 36th month). In addition, 1303 participants with available AD cerebrospinal fluid core biomarkers were selected to clarify the ability of the model to predict AD core features. We assessed 32 parameters as candidate predictors, including clinical information, blood biomarkers, and structural imaging features, and used multivariable logistic regression analysis to develop our prediction model. RESULTS: Six independent variables of MCI deterioration were identified: apolipoprotein E ε4 allele status, lower Mini-Mental State Examination scores, higher levels of plasma pTau181, smaller volumes of the left hippocampus and right amygdala, and a thinner right inferior temporal cortex. We established an easy-to-use risk heat map and risk score based on these risk factors. The area under the curve (AUC) for both internal and external validations was close to 0.850. Furthermore, the AUC was above 0.800 in identifying participants with high brain amyloid-ß loads. Calibration plots demonstrated good agreement between the predicted probability and actual observations in the internal and external validations. CONCLUSION: We developed and validated an accurate prediction model for dementia conversion in patients with MCI. Simultaneously, the model predicts AD-specific pathological changes. We hope that this model will contribute to more precise clinical treatment and better healthcare resource allocation.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

High power, broad tuning quantum cascade laser at λ ∼ 8.9 µm.

Many molecules have broad fingerprint absorption spectra in mid-wave infrared range which requires broadly tunable lasers to cover the interested spectrum in one scan. We report a strain-balanced, InAlAs/InGaAs/InP quantum cascade laser structure based on diagonal transition active region with high output power and and wide tuning range at λ ∼ 8.9 µm. The maximum pulsed optical power and the wall-plug efficiency at room temperature are 4 W and 11.7%, respectively. Maximum continuous wave double-facet power is 1.2 W at 25 °C for a 4 mm by 9 µm laser mounted epi-side down on a diamond/copper composite submount. The maximum pulsed and continuous wave external-cavity tuning range are from 7.71 µm to 9.15 µm and from 8 µm to 8.9 µm, respectively. The continuous wave power of the external cavity mode exceeds 200 mW across the entire spectrum.

ß2-adrenergic receptor agonist corrects immune thrombocytopenia by reestablishing the homeostasis of T cell differentiation.

BACKGROUND: The sympathetic nerve is known to regulate immune responses in autoimmunity. Aberrant T cell immunity plays a vital role in immune thrombocytopenia (ITP) pathogenesis. The spleen is the primary site of platelet destruction. However, little is known whether and how splenic sympathetic innervation and neuroimmune modulation contribute to ITP pathogenesis. OBJECTIVES: To determine the sympathetic distribution in the spleen of ITP mice and the association between splenic sympathetic nerves and T cell immunity in ITP development, and to evaluate the treatment potential of ß2-adrenergic receptor (ß2-AR) in ITP. METHODS: Chemical sympathectomy was performed in an ITP mouse model with 6-hydroxydopamine and treated with ß2-AR agonists to evaluate the effects of sympathetic denervation and activation. RESULTS: Decreased sympathetic innervation in the spleen of ITP mice was observed. Significantly increased percentages of Th1 and Tc1 cells and reduced percentages of regulatory T cells (Tregs) were also observed in ITP mice with chemical sympathectomy (ITP-syx mice) relative to mice without sympathectomy (controls). Expression of genes associated with Th1, including IFN-γ and IRF8, was significantly upregulated, whereas genes associated with Tregs, including Foxp3 and CTLA4, were significantly downregulated in ITP-syx mice compared with controls. Furthermore, ß2-AR restored the percentage of Tregs and increased platelet counts at days 7 and 14 in ITP mice. CONCLUSION: Our findings indicate that decreased sympathetic distribution contributes to ITP pathogenesis by disturbing the homeostasis of T cells and that ß2-AR agonists have potential as a novel treatment for ITP.

Cerebrospinal Fluid sTREM2 in Alzheimer's Disease Is Associated with Both Amyloid and Tau Pathologies but not with Cognitive Status.

BACKGROUND: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is considered a biomarker of microglial activation. The relationships between CSF sTREM2 levels and Alzheimer's disease (AD) CSF core biomarkers, cognitive status, and neurodegeneration remain unclear. OBJECTIVE: To assess the association between CSF sTREM2 levels and AD progression and other AD hallmarks. METHODS: Using the Alzheimer's Disease Neuroimaging Initiative database, we investigated 1,035 participants, including 310 cognitively normal controls, 527 patients with mild cognitive impairment, and 198 patients with dementia. They were grouped according to CSF pathology (A/T profile) severity. CSF sTREM2 levels were compared between the groups, and linear regression analysis was performed to evaluate the factors affecting sTREM2 levels. The predictive effectiveness of sTREM2 levels was tested, and the correlation with other indicators was explored. The increase rate was assessed using linear mixed-effects models. RESULTS: Higher CSF sTREM2 levels were associated with older age as well as higher CSF p-tau or t-tau and amyloid-ß levels (all p < 0.001), but not with cognitive status. sTREM2 levels were not correlated with the baseline or longitudinal scale and neuroimaging result changes, and could not predict clinical conversion, but were correlated with multiple non-amyloid-ß and non-tau CSF cytokines related to inflammation and neurodegeneration (p < 0.0001). The increased sTREM2 expression rate did not change among groups. CONCLUSION: CSF sTREM2 levels were jointly determined by age, amyloid-ß, and tau pathologies, leading to complex AD cognitive continuum changes. Although sTREM2 levels could not predict cognitive deterioration and neurodegeneration, they could reflect the microglial state as a non-specific biomarker.

Broad tuning range, high power quantum cascade laser at λ ∼ 7.4 µm.

In this article, we report a high power quantum cascade laser (QCL) at λ∼7.4 µm with a broad tuning range. By carefully designing and optimizing the active region and waveguide structure, a continuous-wave (CW) output power up to 1.36 W and 0.5 W is achieved at 293 K and 373 K which shows the excellent temperature stability. A high wall-plug efficiency (WPE) of 8% and 13.6% in CW and pulsed mode at 293 K are demonstrated. The laser shows a characteristic temperature T0 of 224 K and T1 of 381 K over a temperature range from 283 K to 373 K. In addition, a far field of pure zero order transverse mode and a fairly wide external cavity (EC) tuning range (280 cm-1) from 6.54 µm to 8 µm are achieved in pulsed operation. In addition, an EC single mode output power of 226 mW is obtained under CW operation at 293K.

GaSb surface grating distributed feedback interband cascade laser emitting at 3.25 µm.

A second-order distributed feedback interband cascade laser emitting at 3.25 µm was designed, grown, and fabricated. By coherent epitaxy of a GaSb cap layer instead of the conventional thin InAs cap on top of the laser structure, a high-quality surface grating was made of GaSb and gold. Enough coupling strength and a significant inter-modal loss difference were predicted according to the simulation within the framework of couple-wave theory. Lasers having 2-mm-long cavities and 4.5-µm-wide ridges with high-/anti-reflection coatings were fabricated. The continuous-wave threshold current and maximum single-mode output power were 60 mA and 24 mW at 20°C, respectively. The output power of 5 mW was still kept at 55°C. Continuous tuning free from mode hopping and high single-mode suppression ratios (>20 dB) were realized at all injection currents and heat-sink temperatures, covering a spectral range of over 20 cm-1.

ß-Amyloid promotes platelet activation and activated platelets act as bridge between risk factors and Alzheimer's disease.

Alzheimer's disease (AD) is an evolving challenge that places an enormous burden on families and society. The presence of obvious brain ß-amyloid (Aß) deposition is a premise to diagnose AD, which induces the subsequent tau hyperphosphorylation and neurodegeneration. Platelets are the primary source of circulating amyloid precursor protein (APP). Upon activation, they can secrete significant amounts of Aß into the blood, which can be actively transported to the brain across the blood-brain barrier and promote amyloid deposition. In this review, we summarized the changes in the platelet APP metabolic pathway in patients with AD and further comprehensively explored the targets and downstream events of Aß-activated platelets. In addition, we attempted to clarify whether patients with AD are in a state of general platelet activation, with inconsistent results. Considering the increasingly evident bidirectional relationship between AD and vascular events, we speculate that the AD pathology alone seems to be insufficient to induce the general activation of platelets; however, the intervention of third-party factors, such as atherosclerosis, exposes the extracellular matrix and leads to platelet activation, further promoting AD progression. Therefore, we proposed a framework in which the relationship between platelets and AD is indirect and mediated by vascular factors. Therapies targeting platelets and interventions for vascular risk factors are likely to contribute to the prevention and treatment of AD.

HCMV modulates c-Mpl/IEX-1 pathway-mediated megakaryo/thrombopoiesis via PDGFRα and αvß3 receptors after allo-HSCT.

Thrombocytopenia is a common complication of human cytomegalovirus (HCMV) infection in immunocompromised hosts, which contributes to poor prognosis even in patients receiving antiviral treatment. Here, we investigated the megakaryo/thrombopoiesis process, including the involvement of the c-Mpl/IEX-1 pathway, after HCMV infection, identified receptors mediating the interaction between megakaryocytes (MKs) and HCMV, and explored novel therapeutic targets. Our data shows that HCMV directly infects megakaryocytes in patients with HCMV DNAemia and influences megakaryopoiesis via the c-Mpl/IEX-1 pathway throughout megakaryocyte maturation, apoptosis, and platelet generation in vivo and in vitro. After treatment with inhibitors of PDGFRα and αvß3, the HCMV infection rate in MKs was significantly reduced, suggesting that IMC-3G3 and anti-αvß3 are potential therapeutic alternatives for viral infection. In summary, our study proposes a possible mechanism and potential treatments for thrombocytopenia caused by HCMV infection and other viral diseases associated with abnormal hemostasis.

Prediction of postpartum hemorrhage in pregnant women with immune thrombocytopenia: Development and validation of the MONITOR model in a nationwide multicenter study.

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal death. Women with immune thrombocytopenia (ITP) are at increased risk of developing PPH. Early identification of PPH helps to prevent adverse outcomes, but is underused because clinicians do not have a tool to predict PPH for women with ITP. We therefore conducted a nationwide multicenter retrospective study to develop and validate a prediction model of PPH in patients with ITP. We included 432 pregnant women (677 pregnancies) with primary ITP from 18 academic tertiary centers in China from January 2008 to August 2018. A total of 157 (23.2%) pregnancies experienced PPH. The derivation cohort included 450 pregnancies. For the validation cohort, we included 117 pregnancies in the temporal validation cohort and 110 pregnancies in the geographical validation cohort. We assessed 25 clinical parameters as candidate predictors and used multivariable logistic regression to develop our prediction model. The final model included seven variables and was named MONITOR (maternal complication, WHO bleeding score, antepartum platelet transfusion, placental abnormalities, platelet count, previous uterine surgery, and primiparity). We established an easy-to-use risk heatmap and risk score of PPH based on the seven risk factors. We externally validated this model using both a temporal validation cohort and a geographical validation cohort. The MONITOR model had an AUC of 0.868 (95% CI 0.828-0.909) in internal validation, 0.869 (95% CI 0.802-0.937) in the temporal validation, and 0.811 (95% CI 0.713-0.908) in the geographical validation. Calibration plots demonstrated good agreement between MONITOR-predicted probability and actual observation in both internal validation and external validation. Therefore, we developed and validated a very accurate prediction model for PPH. We hope that the model will contribute to more precise clinical care, decreased adverse outcomes, and better health care resource allocation.

Anomalous Mode Transitions in High Power Distributed Bragg Reflector Quantum Cascade Lasers.

In this paper, an anomalous spectral data of distributed Bragg reflector (DBR) quantum cascade lasers (QCLs) emitting around 7.6 µm is presented. The two-section DBR lasers, consisting of a gain section and an unpumped Bragg reflector, display an output power above 0.6 W in continuous wave (CW) mode at room temperature. The anomalous spectral data is defined as a longitudinal mode which moves toward shorter wavelengths with increasing temperature or injection current, which is unexpected. Although the longer wavelength modes are expected to start lasing when raising device temperature or injection current, occasional mode hops to a shorter wavelength are seen. These anomalous mode transitions are explained by means of modal analysis. The thermal-induced change of the refractive index implied by an increase in the temperature or injection current yields nearly periodic transitions between cavity modes.

Demonstration of High-Power and Stable Single-Mode in a Quantum Cascade Laser Using Buried Sampled Grating.

High-power, low-threshold stable single-mode operation buried distributed feedback quantum cascade laser by incorporating sampled grating emitting at λ ~ 4.87 µm is demonstrated. The high continuous wave (CW) output power of 948 mW and 649 mW for a 6-mm and 4-mm cavity length is obtained at 20 °C, respectively, which benefits from the optimized optical field distribution of sampled grating. The single-mode yields of the devices are obviously enhanced by controlling cleaved positions of the two end facets precisely. As a result, stable single-mode emission and mode tuning linearly without any mode hopping of devices are obtained under the different heat sink temperatures or high injection currents.

Analysis of differentially expressed genes in rheumatoid arthritis and osteoarthritis by integrated microarray analysis.

BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) were two major types of joint diseases. This study aimed to explore the mechanism underlying OA and RA and analyze their difference by integrated analysis of multiple gene expression data sets. METHODS: Gene expression data sets of RA and OA were downloaded from The Gene Expression Omnibus. Shared and specific differentially expressed genes (DEGs) in RA and OA were identified by integrated analysis of multiple gene expression data sets. Functional annotation and protein-protein interaction (PPI) network construction of OA- and RA-specific DEGs were performed to further explore the molecular mechanisms underlying RA and OA and analyze the mechanism differences between them. RESULTS: Compared with normal controls, 3757 and 2598 DEGs were identified in RA and OA, respectively. Among them, 2176 DEGs were RA-specific DEGs and 1017 DEGs were OA-specific DEGs. Moreover, the expression of 17 DEGs played opposite pattern in RA and OA compared with normal controls. Chemokine signaling pathway and oxidative phosphorylation were significantly enriched pathways for RA- and OA-specific DEGs, respectively. BIRC2 and CSNK1E were respective hub genes of RA- and OA-specific PPI network. CONCLUSION: Our findings provided clues for the specific mechanism and developing specific biomarkers for RA and OA.

Surgical therapy vs conservative therapy for patients with acute injury of lateral ankle ligament: A meta-analysis and systematic review.

The goal of this meta-analysis was to explore the overall safety and efficacy of surgical therapy vs conservative therapy for acute injury of the lateral ankle ligament based on eligible studies. Eligible studies were identified by searching PubMed, Cochrane, and Embase databases using appropriate updated index words to January 2018. We also searched relevant publication sources. Eligible studies included randomised controlled trials and comparative studies. Mean difference or relative risk (RR), along with 95% confidence interval (CI), was used to analyse the main outcomes. A total of 13 studies were eligible for this meta-analysis, with 834 patients in the surgical therapy group and 930 patients in the conservative therapy group. Compared with patients receiving conservative treatment, patients undergoing surgical treatment had a significant higher American Orthopedic Foot And Ankle Society (AOFAS) score (weighted mean difference(WMD): 10.33, 95% CI: 6.83-13.83) and an effective rate (RR: 1.15, 95% CI: 1.04-1.28). No significant differences were observed in the incidence of recurrent ankle injury (RR: 1.01, 95% CI: 0.62-1.65), limited range of motion (RR: 1.44, 95% CI: 0.83-2.50), deep vein thrombosis (RR: 1.33, 95% CI: 0.73-2.41), and wound infection or necrosis (RR: 3.99, 95% CI: 0.45-35.34). However, compared with patients receiving conservative treatment, patients undergoing surgical therapy had significantly increased rates of complications (RR: 3.31, 95% CI: 2.55-4.28), ankylosis (RR: 3.63, 95% CI: 2.16-6.08), scare tenderness (RR: 10.16, 95% CI: 3.89-26.52) and sensory loss (RR: 5.66, 95% CI: 2.76-11.59). The results demonstrated that surgical treatment increased the AOFAS score and effective rate compared with conservative treatment. Besides, surgical treatment increased the rate of complications. Nevertheless, more high-quality randomised controlled trials with a larger sample size conducted at multiple centres with a long-term follow up are needed to confirm our conclusions.

Low voltage-defect quantum cascade lasers based on excited-states injection at λ ∼ 8.5 µm.

A quantum cascade laser emitting at λ∼8.5 µm based on the excited-state injection is presented. The operating voltage is reduced for a low-voltage defect in the excited-state design, compared with the conventional ground-state injection design. The threshold voltage and voltage defect are as low as 6.3 V and 54 mV for a 30-stage active region, respectively. Devices were fabricated through standard buried-heterostructure processing to decrease the heat accumulation. A continuous-wave optical power of 340 mW is obtained at 283 K with a threshold current density of 2.7 kA/cm2. Such a design has the potential to further improve the wall plug efficiency for increased voltage efficiency.

Tapered Quantum Cascade Laser Arrays Integrated with Talbot Cavities.

Power scaling in broad area quantum cascade laser (QCL) usually leads to the deterioration of the beam quality with an emission of multiple lobes far-field pattern. In this letter, we demonstrate a tapered QCL array integrated with Talbot cavity at one side of the array. Fundamental supermode operation is achieved in the arrays with taper straight-end connected to the Talbot cavity. Lateral far-field of the fundamental supermode shows a near diffraction limited beam divergence of 2.7°. The output power of a five-element array is about three times as high as a single-ridge laser with an emission wavelength of around 4.8 µm. However, arrays with the taper-end connected to the Talbot cavity always show a high-order supermode operation whatever Talbot cavity length is.

Stable Single-Mode Operation of Distributed Feedback Quantum Cascade Laser by Optimized Reflectivity Facet Coatings.

In this work, quantum cascade lasers (QCLs) based on strain compensation combined with two-phonon resonance design are presented. Distributed feedback (DFB) laser emitting at ~ 4.76 µm was fabricated through a standard buried first-order grating and buried heterostructure (BH) processing. Stable single-mode emission is achieved under all injection currents and temperature conditions without any mode hop by the optimized antireflection (AR) coating on the front facet. The AR coating consists of a double layer dielectric of Al2O3 and Ge. For a 2-mm laser cavity, the maximum output power of the AR-coated DFB-QCL was more than 170 mW at 20 °C with a high wall-plug efficiency (WPE) of 4.7% in a continuous-wave (CW) mode.

Near-infrared and mid-infrared semiconductor broadband light emitters.

Semiconductor broadband light emitters have emerged as ideal and vital light sources for a range of biomedical sensing/imaging applications, especially for optical coherence tomography systems. Although near-infrared broadband light emitters have found increasingly wide utilization in these imaging applications, the requirement to simultaneously achieve both a high spectral bandwidth and output power is still challenging for such devices. Owing to the relatively weak amplified spontaneous emission, as a consequence of the very short non-radiative carrier lifetime of the inter-subband transitions in quantum cascade structures, it is even more challenging to obtain desirable mid-infrared broadband light emitters. There have been great efforts in the past 20 years to pursue high-efficiency broadband optical gain and very low reflectivity in waveguide structures, which are two key factors determining the performance of broadband light emitters. Here we describe the realization of a high continuous wave light power of >20 mW and broadband width of >130 nm with near-infrared broadband light emitters and the first mid-infrared broadband light emitters operating under continuous wave mode at room temperature by employing a modulation p-doped InGaAs/GaAs quantum dot active region with a 'J'-shape ridge waveguide structure and a quantum cascade active region with a dual-end analogous monolithic integrated tapered waveguide structure, respectively. This work is of great importance to improve the performance of existing near-infrared optical coherence tomography systems and describes a major advance toward reliable and cost-effective mid-infrared imaging and sensing systems, which do not presently exist due to the lack of appropriate low-coherence mid-infrared semiconductor broadband light sources.

Low Power Consumption Substrate-Emitting DFB Quantum Cascade Lasers.

In the present work, an ultra-low power consumption substrate-emitting distributed feedback (DFB) quantum cascade laser (QCL) was developed. The continuous-wave (CW) threshold power dissipation is reduced to 0.43 W at 25 °C by shortening the cavity length to 0.5 mm and depositing high-reflectivity (HR) coating on both facets. As far as we know, this is the recorded threshold power dissipation of QCLs in the same conditions. Single-mode emission was achieved by employing a buried second-order grating. Mode-hop free emission can be observed within a wide temperature range from 15 to 105 °C in CW mode. The divergence angles are 22.5o and 1.94o in the ridge-width direction and cavity-length direction, respectively. The maximum optical power in CW operation was 2.4 mW at 25 °C, which is sufficient to spectroscopy applications.