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Despite increasing evidence that social capital is positively associated with health, the pathways that link social capital to health are not definitive and invite further investigation. This paper uses household survey data from 22 villages in China in 2002 to test the relationship between social capital and the self-reported health status of the rural population. Focusing on the cognitive dimension of social capital, this paper complements current social capital research by introducing an overlooked distinction between trust and mistrust. Trust and mistrust are measured at the individual and aggregate levels, and the distinct ways in which they affect general and mental health are explored. We adopt an ordered logistic regression using survey procedures in SAS version 9.1 to account for the stratified and clustered data structure. The results suggest that: (1) individual-level trust and mistrust are both associated with self-reported health in rural China - trust is positively associated with both general health and mental health, while mistrust is more powerfully associated with worse mental health; and (2) the effects of individual-level trust and mistrust are dependent on village context - village-level trust substitutes for individual-level trust, while individual-level mistrust interacts positively with village-level mistrust to affect health. However, an unexpected protective health effect of mistrust is found in certain types of villages, and this unique result has yet to be examined. Overall, this study suggests the conceptual difference between trust and mistrust and the differential mechanisms by which trust and mistrust affect health in rural China. It also suggests that effective policies should aim at enhancing trust collectively or reducing mistrust at the personal level to improve health status in rural areas of China. [ABSTRACT FROM AUTHOR]

Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report GHN105 as an orally bioavailable covalent STING inhibitor. Late-stage diversification of the briarane-type diterpenoid excavatolide B allowed the installation of solubility-enhancing functional groups while enhancing its activity as a covalent STING inhibitor against multiple human STING variants, including the S154 variant responsible for a genetic autoimmune disease. Selectively engaging the membrane-proximal Cys91 residue of STING, GHN105 dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered GHN105 exhibited on-target engagement in vivo and markedly reversed key pathological features in a delayed treatment of the acute colitis mouse model. Our study provided proof of concept that the synthetic briarane analog GHN105 serves as a safe, site-selective, and orally active covalent STING inhibitor and devises a regimen that allows long-term systemic administration.

Background: Based on a longitudinal cohort design, the aim of this study was to investigate whether individual-based 18 F fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) regional signals can predict dementia conversion in patients with mild cognitive impairment (MCI)., Methods: We included 44 MCI converters (MCI-C), 38 non-converters (MCI-NC), 42 patients with Alzheimer's disease with dementia, and 40 cognitively normal controls. Data from annual cognitive measurements, 3D T1 magnetic resonance imaging (MRI) scans, and 18 F-FDG-PET scans were used for outcome analysis. An individual-based FDG-PET approach was applied using seven volumes of interest (VOIs), Z transformed using a normal FDG-PET template. Hypometabolism was defined as a Z score < -2 of regional standard uptake value ratio. For the longitudinal cognitive test scores, generalized estimating equations were used. A linear mixed-effects model was used to compare the temporal impact of cortical hypometabolism and cortical thickness degeneration., Results: The clinical follow-up period was 6.6 ± 3.8 years (range 3.1 to 16.0 years). The trend of cognitive decline could differentiate MCI-C from MCI-NC after 3 years of follow-up. In the baseline 18F-FDG-PET scan of the patients with MCI, medial temporal lobe (MTL; 94.7% sensitivity, 80.5% specificity) and posterior cingulate cortex (PCC; 89.5% sensitivity, 73.1% specificity) hypometabolism predicted conversion with high accuracy. 18 F-FDG-PET hypometabolism preceded dementia conversion at an interval of 3.70 ± 1.68 years and was earlier than volumetric changes, with the exception of the MTL., Conclusions: Our finding supports the use of individual-based 18 F-FDG-PET analysis to predict MCI conversion to dementia. Reduced FDG-PET metabolism in the MTL and PCC were strongly associated with future cognitive decline in the MCI-C group. Changes in 18 F-FDG-PET occurred 1 to 8 years prior to conversion to dementia. Progressive hypometabolism in the PCC, precuneus and lateral temporal lobe, but not MTL, preceded MRI findings at the MCI stage., (© 2024. The Author(s).)

The international consensus in support of universal health coverage (UHC), though commendable, thus far lacks a clear mechanism to finance and deliver accessible and effective basic healthcare to the two billion rural residents and informal workers of low- and lower-middle-income countries (LLMICs). Importantly, the two preferred financing modes for UHC, general tax revenue and social health insurance, are often infeasible for LLMICs. We identify from historical examples a community-based model that we argue shows promise as a solution to this problem. This model, which we call Cooperative Healthcare (CH), is characterized by community-based risk-pooling and governance and prioritizes primary care. CH leverages communities' existing social capital, such that even those for whom the private benefit of enrolling in a CH scheme is outweighed by the cost may choose to enroll (given sufficient social capital). For CH to be scalable, it needs to demonstrate that it can organize delivery of accessible and reasonable-quality primary healthcare that people value, with management accountable to the communities themselves through structures that people trust, combined with government legitimacy. Once LLMICs with CH programs have industrialized sufficiently to make universal social health insurance feasible, CH schemes can be rolled into such universal programs. We defend cooperative healthcare's suitability for this bridging role and urge LLMIC governments to launch experiments testing it out, with careful adaptation to local conditions., (Copyright © 2024. Published by Elsevier Ltd.)

We introduce a robust likelihood approach to inference for paired multiple binary endpoints data. One can easily implement the methodology without dealing with the model that incorporates a large number of joint probabilities of no direct relevance to the inference of interest. We present the robust score test statistic for testing the equality of two treatment effects to exemplify the utility and simplicity of the method. Our novel technique is applicable when patients have different numbers of endpoints and for unpaired endpoints. The extension of our robust approach to multiple endpoints data with more categories is straightforward. We use simulations and real data analysis to highlight the efficacy of our robust procedure., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 Informa UK Limited, trading as Taylor & Francis Group.)

The glymphatic system is a fluid-clearance pathway that clears cerebral waste products, and its dysfunction has been associated with protein aggregation diseases such as Alzheimer's disease. To understand how the glymphatic system changes with aging, we enrolled 433 cognitive unimpaired participants (236 women and 197 men, 13-88 years) and evaluated the glymphatic function by calculating diffusion tensor imaging analysis along the perivascular space (ALPS) index and explored how the ALPS index is associated with cortical atrophy and cognitive decline in older people. We found a significant inverse correlation between ALPS index and age (ρ = -0.45, p < 0.001), with a peak value in people in their thirties. A higher ALPS index indicated a better cortical reserve in regions coincided with the default mode network. Declines in mental manipulation and short-term memory performance in the older participants were associated with a lower ALPS index and cortical atrophy in the amygdala, anterior and posterior cingulate, thalamus and middle frontal regions. Our findings highlight that the ALPS index could be used to evaluate brain reserve and cognitive reserve in older people., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Natural products are important sources of therapeutic agents and useful drug discovery tools. The fused macrocycles and multiple stereocenters of briarane-type diterpenoids pose a major challenge to total synthesis and efforts to characterize their biological activities. Harnessing a scalable source of excavatolide B (excB) from cultured soft coral Briareum stechei, we generated analogs by late-stage diversification and performed structure-activity analysis, which was critical for the development of functional excB probes. We further used these probes in a chemoproteomic strategy to identify Stimulator of Interferon Genes (STING) as a direct target of excB in mammalian cells. We showed that the epoxylactone warhead of excB is required to covalently engage STING at its membrane-proximal Cys91, inhibiting STING palmitoylation and signaling. This study reveals a possible mechanism-of-action of excB, and expands the repertoire of covalent STING inhibitors., (© 2023. The Author(s).)

Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied in vitro and in vivo . We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent in vitro and in vivo . C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells., Competing Interests: None., (AJCR Copyright © 2023.)

Background: The diffusion tensor imaging analysis along the perivascular space (ALPS)-index can be used to model the glymphatic system in vivo., Aim: This study explores putative mechanisms between prediction of ALPS-index and cognitive outcomes in young-onset Alzheimer's disease (YOAD) and age-matched controls (CTLs) and analyzes whether the link was mediated by the integrity of ALPS-index-anchored cerebral gray matter (GM)., Methods: We enrolled 130 patients with YOAD and 137 CTLs. All participants underwent three-dimensional T 1 -weighted MRI, diffusion tensor imaging and cognitive tests. We constructed GM regions correlated with the ALPS-index in the YOAD and CTL groups. For the GM regions significantly correlated with the ALPS-index and cognitive measures, we extracted a 4-mm radius sphere. In the YOAD and CTL groups, we used mediator analysis to explore the ALPS-index as predictor, GM partitions as mediators, and significant cognitive test scores as outcomes., Results: Patient group had significantly lower ALPS-index. The ALPS-index was associated with GM volume in the cerebellar gray, dorsolateral prefrontal, thalamus, superior frontal, amygdala and hippocampus, and these coherent regions coincided with those showing GM atrophy in the YOAD group. Mediation analysis of the YOAD group suggested that the relationships between the ALPS-index and cognitive performance were fully mediated by the integrity of ALPS-index coherent GM areas., Discussion: Reserved GM mediates the link between the glymphatic system and cognition. Our findings suggest that GM integrity rather than the glymphatic system could serve as a direct cognitive test scores predictor in patients with YOAD., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Magnetotactic bacteria (MTB) are receiving attention for heavy metal biotreatment due to their potential for biosorption with heavy metals and the capability of the magnetic recovery. In this study, we investigated the characteristics of Cr(VI) bioreduction and biosorption by an MTB isolate, Magnetospirillum gryphiswaldense MSR-1, which has a higher growth rate and wider reflexivity in culture conditions. Our results demonstrated that the MSR-1 strain could remove Cr(VI) up to the concentration of 40 mg L -1 and with an optimal activity at neutral pH conditions. The magnetosome synthesis existed regulatory mechanisms between Cr(VI) reduction and cell division. The addition of 10 mg L -1 Cr(VI) significantly inhibited cell growth, but the magnetosome-deficient strain, B17316, showed an average specific growth rate of 0.062 h -1  at the same dosage. Cr(VI) reduction examined by the heat-inactivated and resting cells demonstrated that the main mechanism for MSR-1 strain to reduce Cr(VI) was chromate reductase and adsorption, and magnetosome synthesis would enhance the chromate reductase activity. Finally, our results elucidated that the chromate reductase distributes diversely in multiple subcellular components of the MSR-1 cells, including extracellular, membrane-associated, and intracellular cytoplasmic activity; and expression of the membrane-associated chromate reductase was increased after the cells were pre-exposed by Cr(VI)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Siang Chen Wu reports financial support was provided by National Science and Technology Council, Taiwan., (Copyright © 2023. Published by Elsevier Ltd.)

Carbon monoxide poisoning (COP) can lead to various cerebral white matter (WM) lesions across different disease phases and clinical manifestations, and fractional anisotropy (FA) of diffusion tensor imaging has been widely applied to investigate WM injury in these patients. Here we conducted a systematic review and meta-analysis to investigate the utility of FA in evaluating the regional vulnerability of WM injury caused by COP and explore differences between different disease phases and patient subtypes. We systematically searched PubMed, Medline, Scopus and reference lists of appropriate publications to identify relevant studies. Eight studies with 217 patients with COP and 207 healthy controls (HCs) were included. Eight regions of interest were available to investigate regional vulnerability. The results showed the most significant decrease in FA in orbitofrontal subcortical regions. Comparisons of different disease phases revealed lower FA in the centrum semiovale and corpus callosum in the acute phase, while in the chronic phase, only FA in the centrum semiovale remained significantly decreased. Analysis of different patient subtypes showed that the FA values in the splenium of the corpus callosum were significantly decreased in the patients with delayed neurologic sequelae (DNS) but not in the mixed population (with and without DNS). In conclusion, this meta-analysis highlights the frontal-subcortical regional vulnerability in COP. FA changes in the corpus callosum across different disease phases reflect alterations in underlying microstructures. Extended corpus callosum injury involving the splenium could be an imaging biomarker of the occurrence of DNS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Versican is a chondroitin sulfate proteoglycan (CSPG), which deposits in perineurium as a physical barrier and prevents the growth of axons out of the fascial boundary. Several studies have indicated that the chondroitin sulfate (CS) chains on versican have several possible functions beyond the physical barrier, including the ability to stabilize versican core protein in the extracellular matrix. As chondroitin sulfate synthase 1 (Chsy1) is a crucial enzyme for CS elongation, we hypothesized that in vivo knockdown of Chsy1 at peripheral nerve lesion site may decrease CS and versican accumulation, and result in accelerating neurite regeneration. In the present study, end-to-side neurorrhaphy (ESN) in Wistar rats was used as an in vivo model of peripheral nerve injury to evaluate nerve regeneration after surgical intervention. The distribution and expression of versican and Chsy1 in regenerating axons after ESN was studied using confocal microscopy and western blotting. Chsy1 was silenced at the nerve lesion (surgical) site using in vivo siRNA transfection. The results indicated that Chsy1 was successfully silenced in nerve tissue, and its downregulation was associated with functional recovery of compound muscle action potential. Silencing of Chsy1 also decreased the accumulation of versican core protein, suggesting that transient treating of Chsy1-siRNA may be an alternative and an effective strategy to promote injured peripheral nerve regeneration.

Since the outbreak of COVID-19, as of January 2023, there have been over 670 million cases and more than 6.8 million deaths worldwide. Infections can cause inflammation in the lungs and decrease blood oxygen levels, which can lead to breathing difficulties and endanger life. As the situation continues to escalate, non-contact machines are used to assist patients at home to monitor their blood oxygen levels without encountering others. This paper uses a general network camera to capture the forehead area of a person's face, using the RPPG (remote photoplethysmography) principle. Then, image signal processing of red and blue light waves is carried out. By utilizing the principle of light reflection, the standard deviation and mean are calculated, and the blood oxygen saturation is computed. Finally, the effect of illuminance on the experimental values is discussed. The experimental results of this paper were compared with a blood oxygen meter certified by the Ministry of Health and Welfare in Taiwan, and the experimental results had only a maximum error of 2%, which is better than the 3% to 5% error rates in other studies The measurement time was only 30 s, which is better than the one minute reported using similar equipment in other studies. Therefore, this paper not only saves equipment expenses but also provides convenience and safety for those who need to monitor their blood oxygen levels at home. Future applications can combine the SpO2 detection software with camera-equipped devices such as smartphones and laptops. The public can detect SpO2 on their own mobile devices, providing a convenient and effective tool for personal health management.

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or β-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Kidney allograft torsion is a rare complication of kidney transplant that can lead to allograft loss from prolonged ischemia if not quickly corrected with detorsion and nephropexy. We report a case of late intraperitoneal renal allograft torsion in a pediatric transplant recipient., Case Report: The patient is a 7-year-old male with a history of end-stage renal disease secondary to renal dysplasia in the setting of bilateral high-grade vesicoureteral reflux. He underwent bilateral native nephrectomies for recurrent pyelonephritis and right ureteral kink with urinary tract obstruction. Torsion occurred 3 years after transplant in the setting of one day of emesis, loose stool, severe abdominal pain, and decreased urine output. Diagnosis of transplant torsion was suspected on non-contrast CT scan done after transplant Doppler ultrasound showed no flow to the allograft. The CT scan showed that the kidney had been medialized and renal hilum was flipped from the expected orientation. The patient required a transplant nephrectomy., Conclusions: Renal transplant torsion is a rare event but should be suspected in any renal transplant recipient with acute onset of abdominal pain, acute kidney injury, and decreased urine output, regardless of length of time from transplantation. Patients suspected to have renal torsion should be evaluated emergently with a transplant ultrasound Doppler., (© 2021 Wiley Periodicals LLC.)

In the current investigation, a native crude fucoidan (Ex) was extracted from Sargassum crispifolium , pretreated by single-screw extrusion, and two degraded fucoidans, i.e., ExAh (degradation of Ex by ascorbic acid) and ExHp (degradation of Ex by hydrogen peroxide), were obtained. The extrusion pretreatment increased the extraction yield of fucoidan by approximately 1.73-fold as compared to the non-extruded sample. Among Ex, ExAh, and ExHp, their molecular weight and chemical compositions varied, but the structural features were similar. ExHp possessed the greatest antioxidant activities among the extracted fucoidans. According to the outcome, ExAh exhibited the maximum immune promoting effects via enhanced NO, TNF-α, IL-1β, IL-6, and IL-10 secretion. Thus, both ExHp and ExAh may potentially be used as an effective antioxidant and as immunostimulant agents, which could be of great value in the development of food and nutraceutical products.

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Part of this work was financially supported by RDD Lab, Inc. The authors declare the following competing financial interest(s): Chia-Hwa Chang is a current employee in RDD Lab, Inc. Jin-Chen Yu is a current employee in Bio-Thera Solutions Ltd., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Streptomyces are an important source and reservoir of natural products with diverse applications in medicine, agriculture, and food. Engineered Streptomyces strains have also proven to be functional chassis for the discovery and production of bioactive compounds and enzymes. However, genetic engineering of Streptomyces is often laborious and time-consuming. Here we describe protocols for CRISPR/Cas-mediated genome editing of Streptomyces. Starting from the design and assembly of all-in-one CRISPR/Cas constructs for efficient double-strand break-mediated genome editing, we also present protocols for intergeneric conjugation, CRISPR/Cas plasmid curing, and validation of edited strains., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To examine the clinical characteristics and therapeutic outcome of Escherichia (E.) coli adult bacterial meningitis (ABM)., Methods: The demographic data, clinical and laboratory features and therapeutic outcome of 25 E. coli ABM patients were examined retrospectively. The clinical features of the reported E. coli ABM cases were also included for analysis., Results: The 25 E. coli ABM patients included 12 women and 13 men, aged 33-78 years (mean= 59.9). Of these 25 patients, 13 had a postneurosurgical state as the underlying condition. As to the underlying medical conditions, diabetes mellitus was the most common, found in 9 of the 25 cases. Of the clinical manifestation, severe neurologic manifestations including altered consciousness (19), hydrocephalus (10), seizure (7) acute/subacute cerebral infarct (5), brain abscess (2), subdural empyema (1) and spinal abscess (1) were found, and the other clinical features included fever (21), septic shock (8), bacteremia (6) and hyponatremia (3). With treatment, the mortality rate was more than 44.0% and the presence of septic shock was a significant prognostic factor. With literature review, 29 community-acquired and 12 postneurosurgical E. coli ABM cases were enrolled, and severe neurologic manifestation and high mortality rate were also found., Conclusions: This preliminary overview of E. coli ABM revealed the underlying conditions, severe neurologic manifestation and high mortality rate. Further large-scale, prospective study is needed for a better delineation of this specific infectious syndrome of adult E. coli meningitis.

Nitro-fatty acids are a class of endogenous electrophilic lipid mediators with anti-inflammatory and cytoprotective effects in a wide range of inflammatory and fibrotic disease models. While these beneficial biological effects of nitro-fatty acids are mainly attributed to their ability to form covalent adducts with proteins, only a small number of proteins are known to be nitro-alkylated and the scope of protein nitro-alkylation remains undetermined. Here we describe the synthesis and application of a clickable nitro-fatty acid probe for the detection and first global identification of mammalian proteins that are susceptible to nitro-alkylation. 184 high confidence nitro-alkylated proteins were identified in THP1 macrophages, majority of which are novel targets of nitro-fatty acids, including extended synaptotagmin 2 (ESYT2), signal transducer and activator of transcription 3 (STAT3), toll-like receptor 2 (TLR2), retinoid X receptor alpha (RXRα) and glucocorticoid receptor (NR3C1). In particular, we showed that 9-nitro-oleate covalently modified and inhibited dexamethasone binding to NR3C1. Bioinformatic analyses revealed that nitro-alkylated proteins are highly enriched in endoplasmic reticulum and transmembrane proteins, and are overrepresented in lipid metabolism and transport pathways. This study significantly expands the scope of protein substrates targeted by nitro-fatty acids in living cells and provides a useful resource towards understanding the pleiotropic biological roles of nitro-fatty acids as signaling molecules or as multi-target therapeutic agents., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The distortion-product otoacoustic emission (DPOAE) is a backward propagating wave generated inside the cochlea during the wave amplification process. The DPOAE signal can be detected rapidly under relatively noisy conditions. In recent years, the earphone industry demonstrated interest in adopting DPOAE as an add-on feature to make their product "intelligent" of inner-ear status. However, a technical challenge remains to be tackled-the loudspeaker in an earphone generates its own cubic distortion at the same frequency as DPOAE. Unfortunately, the intensity of loudspeaker distortion is typically comparable to that of the DPOAE, if not higher. In this research, we propose two strategies, namely compensation and cancellation , to enable DPOAE measurement with a single loudspeaker. The compensation strategy exploits the part of the growth function of the loudspeaker distortion which is almost linear, and thus suppresses the distortion it generates while retaining a larger portion of DPOAE in the residual signal. The cancellation strategy utilizes a one-dimensional Volterra filter to remove the cubic distortion from the loudspeaker. Testing on normal-hearing ears shows that the compensation strategy improved the DPOAE-to-interference ratio by approximately 7 dB, resulting in a cross-correlation of 0.62 between the residual DPOAE level and the true DPOAE level. Meanwhile, the cancellation strategy directly recovered both the magnitude and the phase of DPOAE, reducing the magnitude estimation error from 15.5 dB to 3.9 dB in the mean-square sense. These pilot results suggest that the cancellation strategy may be suitable for further testing with more subjects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hsiao, Chen and Liu.)

Recently Perera et al. introduced two new binocular accuracy measures to evaluate diagnostic tests for paired organs. They adopted the Gaussian copula model to account for correlation between fellow eyes. As the measures are functions of several joint probabilities and due to the nature of the joint models, variations of the estimates for the two new measures were assessed via bootstrapping. We provide a different approach to inference about the two interesting and innovative measures. In our opinion, when patients are independent, the binomial models suffice for inference about the parameters of interest. Inference becomes simple and straightforward. We perform numerical studies and analyse the data set as of Perera et al. for illustration. Also, we investigate thru simulations the issue of robustness of the Gaussian copula and the binomial models under model misspecification.

An increasing interest in initiating and expanding social health insurance through labor taxes in low- and low-middle-income countries goes against available empirical evidence. This article builds on existing recommendations by leading health financing experts and summarizes recent research that makes the case against labor-tax financing of health care in low- and low-middle-income countries. We found very little evidence to justify the pursuit of labor-tax financing for health care in these countries and persistent evidence that such policies could lead to increased inequality and fragmentation of the health system. We recommend that countries considering such policies heed the evidence on labor-tax financing and seek alternative approaches to health financing: primarily using general taxes or, depending on the context, general taxes combined with adequately regulated insurance premiums.

Competing Interests: Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

The United Nations has incorporated the noble goal of Universal Health Coverage (UHC) in its 2030 Agenda for Sustainable Development. Most nations have already embraced UHC as their goal. However, an intense policy debate has risen about which health system structure can best achieve UHC. Is a single-payer system more efficient, equitable and effective than a multiple-payer system for middle income countries? We argue that empirical evidence and in-depth analysis of single-payer and multiple-payer systems should inform this debate. First, we need a clear definition of single- and multiple-payer health systems that enables us to compare their differences and clarify the issues to be debated. Second, at least four key issues confront any nation that wishes to achieve UHC: (1) how to design an affordable comprehensive health benefit package for UHC and to finance it (2) how the health expenditure inflation rate can be managed to sustain UHC (3) how modern information technology can be used to enhance efficiency and quality of healthcare and (4) how to assure an adequate supply of high-quality services will be distributed equitably throughout a nation. This paper offers a definition of single- and multiple-payer and compares them. We then use Taiwan's National Health Insurance system to address the four key issues, and illuminate how its policies and operations led to Taiwan's successful UHC., (Copyright © 2016. Published by Elsevier Ltd.)

Background: The elderly, and especially those with an immuno-compromised status, are vulnerable to infectious diseases. The purpose of this study was to examine the clinical characteristics and therapeutic outcomes of cryptococcal meningitis (CM) in elderly patients in Taiwan., Methods: Ninety-nine adult patients with CM were identified during a 15-year study period (2002-2016), of whom 38 elderly (≥ 65 years) patients (16 men and 22 women, median age 72.9 years; range 65-86 years) were included for analysis. The clinical characteristics and therapeutic outcomes of these patients were analyzed and compared to non-elderly adult patients (< 65 years) with CM., Results: Among the 38 patients, diabetes mellitus was the most common underlying condition (15), followed by adrenal insufficiency (7), malignancy (6), hematologic disorders (5), chronic obstructive pulmonary disease (5), autoimmune diseases (3), liver cirrhosis (3) and acquired immunodeficiency syndrome (1). Altered consciousness (29), fever (21) and headache (17) were the leading clinical manifestations. Positive cerebrospinal fluid and blood cultures for Cryptococcus (C.) neoformans were found in 26 and 9 patients, respectively. There were significant differences in gender, altered consciousness and recent cerebral infarction between the elderly and non-elderly groups. The elderly group had a high mortality rate (36.8%, 14/38), and the presence of cryptococcemia was the most significant prognostic factor., Conclusions: This study offers a preliminary view of the clinical characteristics of CM in the elderly. The results suggest that elderly patients (≥ 65 years) are more vulnerable to CM than adults aged < 65 years. Compared to the non-elderly group, the elderly group had female predominance, higher rates of altered consciousness and recent cerebral infarction as the clinical presentation. The presence of cryptococcemia was a significant prognostic factor in the elderly group. This study is limited by the small number of patients, and further large-scale studies are needed to better delineate this specific infectious syndrome.

Suicide gene therapy using the herpes simplex virus thymidine kinase (HSV-tk) gene, combined with the prodrug ganciclovir (GCV) medication, is a promising approach for the treatment of malignant tumors, including prostate cancer. The success of this therapeutic strategy requires tissue- or tumor-specific gene expression and efficient gene delivery. In this chapter, we describe the experimental protocols of key methodologies, including promoter construction, reporter assay, adenoviral vector construction and preparation, HSV-tk enzymatic assay and cytotoxicity assay to evaluate the specificity and efficacy of osteonectin promoter-mediated HSV-tk/GCV suicide gene therapy of prostate cancer.

Background/purpose: Cell behaviors in three-dimensional spheroids are known to be different from those in monolayer cultures; however, very few studies have compared the characteristics of cell spheroids formed through different biomaterial-induced processes. This study investigated the mechanism of melanocyte spheroid formation by using membranes composed of two hydrophilic polymer-based biomaterials, namely chitosan and polyvinyl alcohol (PVA). Our findings revealed that different spheroid-forming processes occurred on the two biomaterials., Methods: Human melanocytes were provided by the cell bank of the Department of Dermatology, National Taiwan University Hospital. The cell viability was determined through the MTT (3-(4,5-dimethylthiazol-2-yl)-diphenyl tetrazolium bromide; Sigma) colorimetric assay. The cell living rate was determined using the trypan blue exclusion test. The amount of fibronectin adsorbed was quantified through Western blot analysis. Statistical significance was calculated using one-way analysis of variance (ANOVA) followed by Duncan's test, and p values <0.05 or <0.01 was considered significant., Results: In the study, the melanocytes attached to, migrated on, and aggregated on the chitosan surface and then formed spheroids. By contrast, on the PVA surface, the melanocytes directly aggregated to form three-dimensional spheres in suspension. The proliferative ability and survival rate of the melanocytes were considerably higher on the chitosan membranes than on the PVA membranes., Conclusion: We concluded that only cell-cell interactions dominated in melanocytes seeded on the PVA membrane, whereas cell-cell and cell-substrate interactions occurred on the chitosan membranes and further enhanced cellular functions. The chitosan-induced spheroids could probably overcome the diffusion and assimilation of trophic factors., (Copyright © 2018. Published by Elsevier B.V.)

This study investigated the degradation of sulfonamide antibiotics (SAs) and microbial community changes in sludge-amended soil. In batch experiments, SA degradation was enhanced by addition of spent mushroom compost (SMC), SMC extract, and extract-containing microcapsule, with SMC showing higher SA degradation rate than the other additives in soil-sludge mixtures. In bioreactor experiments, the degradation of SAs in soil-sludge mixtures was in the order of sulfamethoxazole > sulfadimethoxine > sulfamethazine during four times of SA addition. SA removal was higher in soil-sludge mixtures than in soil alone. The bacterial composition differed in soil-sludge mixtures with and without SMC. In total, 44 differentially distributed bacterial genera were identified from different experimental settings and stages. Four bacterial genera, Acinetobacter, Alcaligenes, Brevundimonas, and Pseudomonas, were previously found involved in SA degradation, and 20 of the 44 bacterial genera were previously found in aromatic hydrocarbon degradation. Therefore, these bacteria have high potential to be SA degradation bacteria in this study.

In 2016, the Flagship Program for improving health systems performance and equity, a partnership for leadership development between the World Bank and the Harvard T.H. Chan School of Public Health and other institutions, celebrates 20 years of achievement. Set up at a time when development assistance for health was growing exponentially, the Flagship Program sought to bring systems thinking to efforts at health sector strengthening and reform. Capacity-building and knowledge transfer mechanisms are relatively easy to begin but hard to sustain, yet the Flagship Program has continued for two decades and remains highly demanded by national governments and development partners. In this article, we describe the process used and the principles employed to create the Flagship Program and highlight some lessons from its two decades of sustained success and effectiveness in leadership development for health systems improvement.

Sulfonamide antibiotics are widely used in human and veterinary medicine. This study assessed the degradation of three sulfonamides (100 mg kg(-1) each of sulfamethoxazole, sulfadimethoxine and sulfamethazine) and changes in the microbial communities of sewage sludge. Sulfamethoxazole degradation was enhanced by spent mushroom compost (SMC), SMC extract, and extract-containing microcapsules in the sludge. The degradation of sulfonamides in sludge and SMC mixtures occurred in the order of sulfamethoxazole > sulfadimethoxine > sulfamethazine. Bioreactor experiments revealed that the sulfonamides removal rates in sludge with SMC were greater than those in sludge alone. The sulfonamides removal rates were enhanced by the addition of SMC for six time additions. The sulfonamides concentrations were 200 and 500 mg kg(-1) for the first to third additions and the fourth to sixth additions, respectively. With the high correlations between TOC and the proportions of sulfonamides remaining in sludge, sulfonamides may be mineralized to a greater extent with SMC in sludge than in sludge alone. Four bacterial genera were identified from the different settings and stages of the bioreactor experiments. Acinetobacter and Pseudomonas were major bacterial communities that were responsible for sulfonamide degradation in sludge., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.

A structure-based virtual screening strategy, comprising homology modeling, ligand-support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.

In this case study, we present a safe and novel treatment for a patient with soft tissue hand disability caused by severe and chronic lupus and cutis laxa (CL). This patient was a woman in her 50s with a 20-year history of systemic lupus erythematous (SLE) and multiple sclerosis who developed hand disability because of the drastic loss of firmness in her soft tissue, extending from the dermis down to the ligaments. The likely cause was CL with SLE synovitis, exacerbated by corticosteroid tapering. Fractional photothermolysis (FP) LASER (Fraxel DUAL 1550/1927; Solta Medical) therapy profoundly alleviated her joint locking in addition to improving the firmness of the overlying skin to reverse her hand disability. This case illustrates a novel approach to CL hand treatment and the profound impact the treatment had on the patient's disabled hand. FP therapy is quick and safe, and its medical application to skin and joints should be further explored., (© 2015 Wiley Periodicals, Inc.)

Magnetofection has received increasing attention for its great potential on gene therapy. To promote its clinical therapeutic applications, development of safe and effective magnetic nanocarriers is in high demand. Herein, we present a redox-sensitive polymer/metal nanocomplex system (PSPIO) for efficient magnetofection and magnet resonance imaging (MRI) on cancer cells. PSPIO was prepared by modifying SPIO with redox-sensitive polyethylenimine (SSPEI) via a ligand exchange process. PSPIO could efficiently condense plasmid DNA (pDNA) into nanoparticles, which exhibited several favorable properties for gene delivery, including protection of nucleic acids from enzymatic degradation, stable colloids in serum, and redox-responsive pDNA release. As a potential MR imaging agent, PSPIO displayed good magnetization (28.3 emu/g) and dose-dependent T2-weighted imaging contrast (R2 = 291.1 s(-1) mM(-1)) in vitro. The use of redox-sensitive SSPEI polymer contributed to much lower cytotoxicity of PSPIO compared to nondegradable bPEI25k. In vitro transfection efficiency of PSPIO was significantly enhanced under an external magnetic field. In the presence of serum, PSPIO exhibited higher transgene expression than SSPEI or bPEI25k polymer on mouse glioma (ALTS1C1) or human prostate cancer (PC3) cell lines. Taken together, it is demonstrated that PSPIO possess great potential for cancer gene therapy and molecular imaging.

Aim: To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet-induced obese (DIO) mice., Methods: The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined., Results: Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R-mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake-independent mechanism, which contributes to weight loss. Genes involved in β-oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2-adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice., Conclusion: BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders., (© 2015 John Wiley & Sons Ltd.)

The design of high-affinity lectin ligands is critical for enhancing the inherently weak binding affinities of monomeric carbohydrates to their binding proteins. Glyco-gold nanoparticles (glyco-AuNPs) are promising multivalent glycan displays that can confer significantly improved functional affinity of glyco-AuNPs to proteins. Here, AuNPs are functionalized with several different carbohydrates to profile lectin affinities. We demonstrate that AuNPs functionalized with mixed thiolated ligands comprising glycan (70 mol %) and an amphiphilic linker (30 mol %) provide long-term stability in solutions containing high concentrations of salts and proteins, with no evidence of nonspecific protein adsorption. These highly stable glyco-AuNPs enable the detection of model plant lectins such as Concanavalin A, wheat germ agglutinin, and Ricinus communis Agglutinin 120, at subnanomolar and low picomolar levels through UV/Vis spectrophotometry and dynamic light scattering, respectively. Moreover, we develop in situ glyco-AuNPs-based agglutination on an oriented immobilized antibody microarray, which permits highly sensitive lectin sensing with the naked eye. In addition, this microarray is capable of detecting lectins presented individually, in other environmental settings, or in a mixture of samples. These results indicate that glyconanoparticles represent a versatile and highly sensitive method for detecting and probing the binding of glycan to proteins, with significant implications for the construction of a variety of platforms for the development of glyconanoparticle-based biosensors., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Abstract- In recent years, the World Health Organization's "Cube Diagram" has been widely used to illustrate the policy options in moving toward Universal Health Coverage. The Cube has become a globally recognized visual representation of health system reform choices, with its axes defined by: (1) the services covered by pooled funds, (2) the population covered, and (3) the proportion of costs covered. The Cube shows the difference between the current national coverage situation in a country and the policy goal of universal health coverage, identifying where major gaps exist. The essential feature of the Cube diagram is that it shows a country's coverage situation in terms of national averages. As a result, it does not present or call attention to significant disparities in coverage across population groups, which are characteristic of most low- and middle-income countries. This article recommends adding a new diagram that disaggregates the Cube. The new diagram, called the Step Pyramid, allows a policy maker to visualize specific choices in expanding the coverage status of different population groups. This new diagram can help policy makers focus explicitly on equity concerns as they set priorities in moving toward universal health coverage. The paper explains how to construct a Step Pyramid diagram, provides a hypothetical illustration, and then uses data from Mexico to create an example of a Step Pyramid diagram. The paper concludes with a discussion of the strengths, limits, and implications of both the Cube and the Step Pyramid.

Abstract -Since 1978 when China liberalized its economy and moved from a central planning to a socialistic market economy, its health care system has gone through two major cycles of reform-oscillating from relying on the market to fund and deliver health care, to one in which the government plays a central role in financing health care, prioritizes prevention and primary care, and redistributes resources to poorer and rural regions. Consequently, performance of the Chinese health system improved and China was finally able to extend a basic health safety net to more than 95% of its 1.3 billion people over the last decade. Then, in 2013, China launched its new cycle of reform, and vigorously pushed privatization and marketization as a core strategy to reform its public hospitals. What explains China's oscillating health policies and performances? This paper examines the thesis that ideologies of the government and the market are the main drivers for the reforms. The social value that undergirds the government actions, especially how much priority it gives to equity vis-à-vis economic growth has exerted a major influence on whether China chooses a pro-government or pro-market approach.

The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression.

The SAGA (Spt-Ada-Gcn5 acetyltransferase) coactivator complex contains distinct chromatin-modifying activities and is recruited by DNA-bound activators to regulate the expression of a subset of genes. Surprisingly, recent studies revealed little overlap between genome-wide SAGA-binding profiles and changes in gene expression upon depletion of subunits of the complex. As indicators of SAGA recruitment on chromatin, we monitored in yeast and human cells the genome-wide distribution of histone H3K9 acetylation and H2B ubiquitination, which are respectively deposited or removed by SAGA. Changes in these modifications after inactivation of the corresponding enzyme revealed that SAGA acetylates the promoters and deubiquitinates the transcribed region of all expressed genes. In agreement with this broad distribution, we show that SAGA plays a critical role for RNA polymerase II recruitment at all expressed genes. In addition, through quantification of newly synthesized RNA, we demonstrated that SAGA inactivation induced a strong decrease of mRNA synthesis at all tested genes. Analysis of the SAGA deubiquitination activity further revealed that SAGA acts on the whole transcribed genome in a very fast manner, indicating a highly dynamic association of the complex with chromatin. Thus, our study uncovers a new function for SAGA as a bone fide cofactor for all RNA polymerase II transcription., (© 2014 Bonnet et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: To estimate the clinical and economic trade-offs involved in using a molecular assay (92-gene assay, CancerTYPE ID) to aid in identifying the primary site of difficult-to-diagnose metastatic cancers and to explore whether the 92-gene assay can be used to standardize the diagnostic process and costs for clinicians, patients, and payers., Methods: Four decision-analytic models were developed to project the lifetime clinical and economic impact of incorporating the 92-gene assay compared with standard care alone. For each model, total and incremental costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and the proportion of patients treated correctly versus incorrectly were projected from the payer perspective. Model inputs were based on published literature, analyses of SEER (Surveillance Epidemiology and End RESULTS) data, publicly available data, and interviews with clinical experts., Results: In all four models, the 92-gene assay increased the proportion of patients treated correctly, decreased the proportion of patients treated with empiric therapy, and increased quality-adjusted survival. In the primary model, the ICER was $50,273/QALY; thus, the 92-gene assay is therefore cost effective when considering a societal willingness-to-pay threshold of $100,000/QALY. These findings were robust across sensitivity analyses., Conclusions: Use of the 92-gene assay for diagnosing metastatic tumors of uncertain origin is associated with reduced misdiagnoses, increased survival, and improved quality of life. Incorporating the assay into current practice is a cost-effective approach to standardizing diagnostic methods while improving patient care. Limitations of this analysis are the lack of data availability and resulting modeling simplifications, although sensitivity analyses showed these to not be key drivers of results.