Elastic and Self-Healing Copolymer Coatings with Antimicrobial Function.

The revolutionary self-healing function for long-term and safe service processes has inspired researchers to implement them in various fields, including in the application of antimicrobial protective coatings. Despite the great advances that have been made in the field of fabricating self-healing and antimicrobial polymers, their poor transparency and the trade-off between the mechanical and self-healing properties limit the utility of the materials as transparent antimicrobial protective coatings for wearable optical and display devices. Considering the compatibility in the blending process, our group proposed a self-healing, self-cross-linkable poly{(n-butyl acrylate)-co-[N-(hydroxymethyl)acrylamide]} copolymer (AP)-based protective coating combined with two types of commercial cationic antimicrobial agents (i.e., dimethyl octadecyl (3-trimethoxysilylpropyl) ammonium chloride (DTSACL) and chlorhexidine gluconate (CHG)), leading to the fabrication of a multifunctional modified compound film of (AP/b%CHG)-grafted-a%DTSACL. The first highlight of this research is that the reactivity of the hydroxyl group in the N-(hydroxymethyl)acrylamide of the copolymer side chains under thermal conditions facilitates the "grafting to" process with the trimethoxysilane groups of DTSACL to form AP-grafted-DTSACL, yielding favorable thermal stability, improvement in hydrophobicity, and enhancement of mechanical strength. Second, we highlight that the addition of CHG can generate covalent and noncovalent interactions in a complex manner between the two biguanide groups of CHG with the AP and DTSACL via a thermal-triggered cross-linking reaction. The noncovalent interactions synergistically serve as diverse dynamic hydrogen bonds, leading to complete healing upon scratches and even showing over 80% self-healing efficiency on full-cut, while covalent bonding can effectively improve elasticity and mechanical strength. The soft nature of CHG also takes part in improving the self-healing of the copolymer. Moreover, it was discovered that the addition of CHG can enhance antimicrobial effectiveness, as demonstrated by the long-term superior antibacterial activity (100%) against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria and the antifouling function on a glass substrate and/or a silica wafer coated by the modified polymer.

Multifunctional Hydrogel Dressing That Carries Three Antibiotics Simultaneously and Enables Real-Time Ultrasound Bacterial Colony Detection.

We have developed a multifunctional hydrogel that can carry three synergistic antibiotics commonly used in clinical practice. This hydrogel was discovered to have drug encapsulation efficiencies of 94% for neomycin, 97% for bacitracin, and 88% for polymyxin B. Drug release data indicated that the release profiles of these three antibiotics were different. A swelling test demonstrated that the hydrogel absorbed liquid after the release of its antibiotics until it became saturated, which occurred within 48 h. Moreover, this hydrogel exhibited excellent antibacterial effects against Escherichia coli and Pseudomonas aeruginosa and biocompatibility; it can thus protect a wound from microbial invasion. When the alginate hydrogel is used to cover a wound, the wound can be checked for colonization at any time using ultrasound imaging; this can thus enable the prevention of wound biofilm formation in the early stages of infection. We evaluated the hydrogel against commercially available wound dressings and discovered that these wound dressings did not have the aforementioned desirable features. In conclusion, our multifunctional hydrogel can carry three types of antibiotics simultaneously and is a suitable medium through which an ultrasound can be performed to detect the growth of colonies in wounds. The hydrogel is expected to make a valuable contribution to the prevention of wound infections in the future.

Co-exposure to toxic metals and phthalates in pregnant women and their children's mental health problems aged four years - Taiwan Maternal and Infant Cohort Study (TMICS).

BACKGROUND: Childhood and adolescent mental health problems may increase the global burden of disease. Neurotoxic metals are associated with inflammation and cytotoxicity in the brain. In addition, prenatal phthalate ester (PAE) exposure is associated with cognitive function deficits. However, the effect of co-exposure to toxic metals, PAEs, and their association with child behavior is less well studied. Hence, we aimed to investigate prenatal co-exposure to the metals and PAEs and the consequent behavioral outcomes in early childhood. METHODS: We followed pregnant women and their newborns from the Taiwan Maternal and Infant Cohort Study between 2015 and 2017, with a focus on women from the central, southern, and eastern areas of Taiwan. We quantified maternal urinary concentrations of metals and metabolites of PAEs as surrogates of prenatal exposure. We recorded the Child Behavior Checklist scores according to caregiver reports at 4 years of age, and identified Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)-oriented problems. RESULTS: Ultimately, 408 children were included in the statistical analysis. Maternal urinary copper levels were significantly associated with depressive problems (odds ratio [OR] = 2.13) in children. Maternal urinary concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) were also significantly associated with depressive symptoms (odds ratio [OR] = 1.51 and 1.53, respectively). Further analysis considering prenatal co-exposure to metals and PAEs showed that co-exposure to these materials was significantly associated with autism spectrum problems (OR = 3.11). CONCLUSIONS: We observed that prenatal single exposure or co-exposure to metals and PAEs may play a role in some DSM-5-oriented problems in children at 4 years of age. Reduction of exposure to toxic metals and PAEs in pregnancy is suggested to prevent increased mental health problems in children.

Protocol for standardized intrathymic injection in mice.

Currently available intrathymic injection techniques cause postoperative complications or difficulties in equipment acquisition. Here, we describe a standardized intrathymic injection protocol that requires only basic equipment with a minimally invasive procedure. We detail steps to identify injection sites for intrathymic delivery. We then describe how to visualize a successful intrathymic injection by including Indian ink in the injected solution. For complete details on the use and execution of this protocol, please refer to Tsai et al. (2022).1.

IFN-stimulated metabolite transporter ENT3 facilitates viral genome release.

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.

Nipple-areolar complex (NAC) or skin flap ischemia necrosis post nipple-sparing mastectomy (NSM)-analysis of clinicopathologic factors and breast magnetic resonance imaging (MRI) features.

BACKGROUND: The purpose of this study is to identify clinicopathologic factors and/or preoperative MRI vascular patterns in the prediction of ischemia necrosis of the nipple-areola complex (NAC) or skin flap post nipple-sparing mastectomy (NSM). METHODS: We performed a retrospective analysis of 441 NSM procedures from January 2011 to September 2021 from the breast cancer database at our institution. The ischemia necrosis of NAC or skin flap was evaluated in correlation with clinicopathologic factors and types of skin incision. Patients who received NSM with preoperative MRI evaluation were further evaluated for the relationship between vascular pattern and the impact on ischemia necrosis of NAC or skin flap. RESULTS: A total of 441 cases with NSM were enrolled in the current study, and the mean age of the cases was 49.1 ± 9.8 years old. A total of 41 (9.3%) NSM procedures were found to have NAC ischemia/necrosis. Risk factors were evaluated of which old age, large mastectomy specimen weight (> 450 g), and peri-areola incision were identified as predictors of NAC necrosis. Two-hundred seventy NSM procedures also received preoperative MRI, and the blood supply pattern was 18% single-vessel type and 82% double-vessel pattern. There were no correlations between MRI blood supply patterns or types of skin flap incisions with ischemia necrosis of NAC. There were also no correlations between blood loss and the pattern or size of the blood vessel. CONCLUSION: Factors such as the type of skin incision, age, and size of mastectomy weight played an important role in determining ischemia necrosis of NAC; however, MRI vascular (single or dual vessel supply) pattern was not a significant predictive factor.

Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress.

Tissue-resident macrophages (TRMs) are heterogeneous cell populations found throughout the body. Depending on their location, they perform diverse functions maintaining tissue homeostasis and providing immune surveillance. To survive and function within, TRMs adapt metabolically to the distinct microenvironments. However, little is known about the metabolic signatures of TRMs. The thymus provides a nurturing milieu for developing thymocytes yet efficiently removes those that fail the selection, relying on the resident thymic macrophages (TMφs). This study harnesses multiomics analyses to characterize TMφs and unveils their metabolic features. We find that the pentose phosphate pathway (PPP) is preferentially activated in TMφs, responding to the reduction-oxidation demands associated with the efferocytosis of dying thymocytes. The blockade of PPP in Mφs leads to decreased efferocytosis, which can be rescued by reactive oxygen species (ROS) scavengers. Our study reveals the key role of the PPP in TMφs and underscores the importance of metabolic adaptation in supporting Mφ efferocytosis.

Association Between Prenatal Exposure to Metals and Atopic Dermatitis Among Children Aged 4 Years in Taiwan.

Importance: The prevalence of atopic dermatitis has substantially increased in recent decades, and atopic dermatitis could lead to allergic airway inflammation later in life. A previous study found that inorganic arsenic exposure was associated with allergic airway inflammation in children aged 8 to 14 years. However, the association between prenatal exposure to arsenic and other metals and the risk of atopic dermatitis among young children remains unknown. Objective: To assess the association between prenatal exposure to arsenic and other metals and the occurrence of atopic dermatitis in children at age 4 years. Design, Setting, and Participants: In total, 1152 pregnant women were enrolled in the original Taiwan Maternal and Infant Cohort Study (TMICS), a multicenter birth cohort study conducted at 9 hospitals in northern, central, southern, and eastern Taiwan from October 2012 to May 2015. Of those, 586 mothers and children aged 4 years participated in follow-up questionnaire interviews from August 2016 to January 2019. After excluding 216 participants with missing data, the final statistical analysis of follow-up data included 370 mother and child pairs from the central and eastern regions of Taiwan. Data were analyzed from February 2 to August 12, 2021. Exposures: Arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc during pregnancy. Main Outcomes and Measures: The outcome was parent-reported atopic dermatitis history among children aged 4 years. The presence of atopic dermatitis was defined as a positive response to the question, "Has your child ever had atopic dermatitis diagnosed by a physician?" During the initial TMICS study period, concentrations of arsenic, cadmium, lead, cobalt, copper, nickel, thallium, and zinc were measured in maternal urine during the third trimester of pregnancy using an inductively coupled plasma mass spectrometer. Estimated total inorganic arsenic exposure was calculated using a model that included data on both total arsenic and arsenic species (arsenite, arsenate, monomethylarsonate, and dimethylarsenate) obtained from a previous TMICS cohort. Results: Among 370 children included in the analysis, the mean (SD) age was 3.94 (0.59) years; 208 children (56.2%) were male, and 267 children (72.2%) were from the central region of Taiwan. A total of 110 children (29.7%) had atopic dermatitis at age 4 years. Maternal estimated total inorganic arsenic exposure during pregnancy was associated with increased odds of atopic dermatitis among children at age 4 years (odds ratio [OR], 2.42 [95% CI, 1.33-4.39] for every doubled increase of total inorganic arsenic) after adjusting for parental allergies, child's sex, geographic area, maternal educational level, and exposure to tobacco smoke. Every increased unit in the weighted quantile sum index of maternal metal exposure was significantly associated with atopic dermatitis (OR, 1.63; 95% CI, 1.28-2.07). Arsenic (40.1%) and cadmium (20.5%) accounted for most of the metal mixture index. Conclusions and Relevance: This cohort study found that prenatal exposure to inorganic arsenic and coexposure to inorganic arsenic and cadmium were associated with a higher risk of atopic dermatitis in young children. These findings suggest that prevention of exposure to inorganic arsenic and cadmium during pregnancy may be helpful for the control of atopic dermatitis and other potential allergies in children.

Prenatal heavy metal exposure, total immunoglobulin E, trajectory, and atopic diseases: A 15-year follow-up study of a Taiwanese birth cohort.

Prenatal exposure to heavy metals may cause atopic diseases. Little association between cord blood total immunoglobulin E (CB-tIgE) levels and the occurrence of atopic diseases has been found. This study investigated the atopic status and tIgE trajectory trend in a Taiwanese birth cohort over 15 years. We also assessed the effect of maternal heavy metal exposure on maternal serum cytokine and CB-tIgE levels. We recruited 430 pregnant women during their third trimester in 2000-2001. Maternal urinary heavy metal concentrations and serum cytokine levels were measured. The CB-tIgE and serum tIgE levels of the women's children when they were aged 5, 8, 11, and 14 years were measured. The upper quartile of the maternal urinary arsenic concentration was associated with an increased risk of a CB-tIgE level higher than 1 IU/mL (odds ratio, 1.845; 95% confidence interval, 1.003-3.395). Serum tIgE trajectory levels were the highest in children with asthma, followed by those with atopic dermatitis and allergic rhinitis at the age of 5-14 years. Serum tIgE levels tended to peak at the age of 11 years in the atopic children but were stable from the age of 8 years in the non-atopic children. We first demonstrated that serum tIgE levels reached a trajectory peak in the atopic children aged 11 years. Prenatal exposure to arsenic may increase the risk of elevated CB-tIgE levels. Further investigation is warranted to elucidate the mechanism through which maternal serum cytokines affect the occurrence of atopic diseases in children.

Evaluation of Mitochondria Content and Function in Live Cells by Multicolor Flow Cytometric Analysis.

To evaluate how a cell responds to the external stimuli, treatment, or alteration of the microenvironment, the quantity and quality of mitochondria are commonly used as readouts. However, it is challenging to apply mitochondrial analysis to the samples that are composed of mixed cell populations originating from tissues or when multiple cell populations are of interest, using methods such as Western blot, electron microscopy, or extracellular flux analysis.Flow cytometry is a technique allowing the detection of individual cell status and its identity simultaneously when used in combination with surface markers. Here we describe how to combine mitochondria-specific dyes or the dyes targeting the superoxide produced by mitochondria with surface marker staining to measure the mitochondrial content and activity in live cells by flow cytometry. This method can be applied to all types of cells in suspension and is particularly useful for analysis of samples composed of heterogeneous cell populations.

Overcoming Radiation Resistance by Iron-Platinum Metal Alloy Nanoparticles in Human Copper Transport 1-Overexpressing Cancer Cells via Mitochondrial Disturbance.

BACKGROUND: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells. MATERIALS AND METHODS: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer. RESULTS: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors. CONCLUSION: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.

Association between arsenic exposure, DNA damage, and urological cancers incidence: A long-term follow-up study of residents in an arseniasis endemic area of northeastern Taiwan.

Arsenic is a well-established human carcinogen and is considered a health risk worldwide, especially where groundwater is consumed as drinking water. In 2018, bladder and kidney cancers were the 14th and 17th leading causes of global cancer mortality, respectively. Our aim was to investigate the association between arsenic exposure, DNA damage, and the incidence of bladder and kidney cancers. A total of 788 participants aged ≥40 years were enrolled in a prospective cohort study in Taiwan between 1991 and 1994, with follow-up between 2011 and 2014. Well-water and first-morning spot urine samples were collected between 1991 and 1994 to estimate arsenic exposure, and the baseline urinary levels of 8-Oxo-2'-deoxyguanosine (8-OHdG) and N7-methylguanine (N7-MeG) were quantified to assess DNA lesions. The Cox proportional hazard model was used to estimate the effects of arsenic exposure and DNA adduct levels on the risk of bladder or kidney cancer. Urinary arsenic species were associated with significantly increased 8-OHdG and N7-MeG after adjusting for age, sex, and cigarette smoking. Only non-statistically significant mediation effects of 8-OHdG were observed. In a fully adjusted Cox model, participants with arsenic exposure and urinary 8-OHdG levels higher than the median had a higher risk of bladder cancer (HR = 4.60, confidence interval: 1.43-14.85). Overall, the combined effects of high cumulative arsenic exposure from artesian well-water and advanced DNA damage predicted the risk of bladder cancer.

Maternal and childhood exposure to inorganic arsenic and airway allergy - A 15-Year birth cohort follow-up study.

BACKGROUND: The prevalence of allergic diseases in children has increased globally. Early-life exposure to inorganic arsenic has been found to be associated with impaired immune function and decreased lung function in children; however, the results are inconsistent. We aimed to evaluate the effect of prenatal and childhood exposure to inorganic arsenic on allergic diseases in children, through a 15-year follow-up birth cohort study, conducted in central Taiwan. METHODS: Children born to women enrolled in the Taiwan Maternal and Infant Cohort Study (TMICS-pilot) from December 2000 to November 2001 were recruited and followed every 2-3 years until the age of 14 years. Urinary specimens were collected in the pregnant women during the 3rd trimester and the followed children. Diagnoses of allergic diseases were based on physician diagnoses using the International Study of Asthma and Allergies in Childhood questionnaire. Urinary arsenic speciation was performed using high-performance liquid chromatography and inductively coupled plasma dynamic reaction cell mass spectrophotometry. RESULTS: Of the 261 children from 358 mother-infant pairs for this study, those with asthma and allergic rhinitis reported a higher prevalence of maternal allergy (49.47%) than did non-allergic children (29.81%). In the fully adjusted model, levels of maternal urine (iAs + MMA + DMA) greater than the median were found to be significantly associated with an increased risk of asthma (OR = 4.28; 95% CI 1.32, 13.85). Levels of urinary (iAs + MMA + DMA) in children higher than the median were associated with an increased risk of allergic rhinitis (OR = 2.26; 95% CI 1.20, 4.26). CONCLUSION: Prenatal and childhood exposure to inorganic arsenic were found to be significantly associated with the occurrence of asthma and allergic rhinitis in children, respectively. Further large cohort follow-up studies are important to validate the association between inorganic arsenic exposure and allergic diseases in children.

Effects of Coronavirus Persistence on the Genome Structure and Subsequent Gene Expression, Pathogenicity and Adaptation Capability.

Coronaviruses are able to establish persistence. However, how coronaviruses react to persistence and whether the selected viruses have altered their characteristics remain unclear. In this study, we found that the persistent infection of bovine coronavirus (BCoV), which is in the same genus as SARS-COV-2, led to alterations of genome structure, attenuation of gene expression, and the synthesis of subgenomic mRNA (sgmRNA) with a previously unidentified pattern. Subsequent analyses revealed that the altered genome structures were associated with the attenuation of gene expression. In addition, the genome structure at the 5' terminus and the cellular environment during the persistence were responsible for the sgmRNA synthesis, solving the previously unanswered question regarding the selection of transcription regulatory sequence for synthesis of BCoV sgmRNA 12.7. Although the BCoV variants (BCoV-p95) selected under the persistence replicated efficiently in cells without persistent infection, its pathogenicity was still lower than that of wild-type (wt) BCoV. Furthermore, in comparison with wt BCoV, the variant BCoV-p95 was not able to efficiently adapt to the challenges of alternative environments, suggesting wt BCoV is genetically robust. We anticipate that the findings derived from this fundamental research can contribute to the disease control and treatments against coronavirus infection including SARS-CoV-2.

The Impacts of Antivirals on the Coronavirus Genome Structure and Subsequent Pathogenicity, Virus Fitness and Antiviral Design.

With the global threat of SARS-CoV-2, much effort has been focused on treatment and disease control. However, how coronaviruses react to the treatments and whether the surviving viruses have altered their characteristics are also unanswered questions with medical importance. To this end, bovine coronavirus (BCoV), which is in the same genus as SARS-CoV-2, was used as a test model and the findings were as follows. With the treatment of antiviral remdesivir, the selected BCoV variant with an altered genome structure developed resistance, but its pathogenicity was not increased in comparison to that of wild type (wt) BCoV. Under the selection pressure of innate immunity, the genome structure was also altered; however, neither resistance developed nor pathogenicity increased for the selected BCoV variant. Furthermore, both selected BCoV variants showed a better efficiency in adapting to alternative host cells than wt BCoV. In addition, the previously unidentified feature that the spike protein was a common target for mutations under different antiviral treatments might pose a problem for vaccine development because spike protein is a common target for antibody and vaccine designs. The findings derived from this fundamental research may contribute to the disease control and treatments against coronaviruses, including SARS-CoV-2.

Prenatal and childhood phthalate exposure and attention deficit hyperactivity disorder traits in child temperament: A 12-year follow-up birth cohort study.

Temperamental tendencies may form the basis of personality development, and specific personality constellations are associated with increased incidences of behavioural problems. Phthalic acid ester (PAE) has been associated with symptoms of attention deficit hyperactivity disorder (ADHD) in cross-sectional studies. We hypothesised that early-life exposure to PAE affects the temperaments of children, particularly ADHD traits. In this study, we analysed the temperament evaluations completed at least once by maternal-infant pairs (n = 208) when the child was aged 2, 5, and/or 11 years between 2000 and 2012. We measured seven PAE metabolites in the urine of the mothers during pregnancy and their children using liquid chromatography-electrospray ionisation-tandem mass spectrometry. These metabolites included mono-methyl phthalate, mono-ethyl phthalate, mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three metabolites of di (2-ethylhexyl) phthalate. The phthalate metabolite levels in pregnant women were significantly associated with a decreased threshold of responsiveness (coefficients from -0.21 to -0.46) and increased distractibility (coefficients from 0.23 to 0.46) in pre-school children. After adjustment for maternal exposure, the phthalate metabolite concentrations of the children exhibited significantly increased odds ratios (ORs) with respect to the ADHD symptom traits. Specifically, mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP), the sum of the DEHP metabolites, and MBzP yielded ORs and 95% confidence intervals of 2.98 (1.05-8.48), 3.28 (1.15-9.35), and 9.12 (1.07-78.06), respectively, for every log10 creatinine unit (g/g creatinine) increase. Thus, early-life phthalate exposure was found to be associated with the behavioural characteristics of children, particularly temperamental traits associated with ADHD.

The Association Between Usage of Colchicine and Pneumonia: A Nationwide, Population-Based Cohort Study.

Objectives: A previous study suggested that colchicine may cause leukopenia and increase the risk of infection, such as pneumonia. Thus, we investigated the potential relationship between colchicine use and risk of developing pneumonia. Methods: Data were collected from Taiwan's National Health Insurance Research Database (NHIRD), a nationwide, population-based database. A 13-year retrospective cohort study was conducted, and all investigated subjects were identified by International Classification of Disease, Ninth Revision, Clinical Modification, codes between 2000 and 2012. Propensity score matching was applied to adjust for potential confounding variables, and then Cox proportional hazard model was used to evaluate the hazard ratio (HR) of pneumonia in gout patients and its associations with colchicine use, colchicine dosage, and days of colchicine use. Results: A total of 24,410 gout patients were enrolled in this study, including 12,205 cases who were treated with colchicine (colchicine group) and 12,205 cases who did not receive colchicine (non-colchicine group). The overall incidence rates of pneumonia in the colchicine group and non-colchicine group were 18.6 and 12.6 per 1,000 person-years, respectively. The colchicine group had a higher risk of pneumonia as compared with the non-colchicine group [adjusted HR, 1.42; 95% confidence interval (CI), 1.32 to 1.53; P < 0.05]. High cumulative dose and days of colchicine use notably increased the risk of contracting pneumonia. Conclusion: This nationwide population-based cohort study reveals that gout patients taking colchicine are at increased risk of developing pneumonia compared with gout patients who do not use colchicine. Therefore, it is crucial that gout patients being treated with colchicine be given the minimally effective dosage for the shortest possible duration to minimize their risk of pneumonia.

Fine particulate matter is a potential determinant of Alzheimer's disease: A systemic review and meta-analysis.

Air pollution is a modifiable and preventable factor, and it is a possible risk factor for dementia. However, evidence from epidemiological studies is still limited. We conducted a systematic review and meta-analysis to summarize the epidemiological evidence for long-term effects of particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) on dementia/Alzheimer's disease (AD). Our inclusion criteria for eligible studies were: longitudinal cohort study design, no overlap in study population, age of study subject ≥50 years, detailed description of exposure assessment for PM2.5, outdoor assessment of exposure to PM2.5, usage of a clear definition of dementia/AD, and accessibility of sufficient information for meta-analysis. Six databases were searched for eligible studies. The random-effect model was used to synthesize the associations between PM2.5 and dementia. After exclusion of all irrelevant studies, we analyzed the results of four cohort studies conducted in Canada, Taiwan, the UK, and the US during 2015-2018 among more than 12 million elderly subjects aged ≥50 years (N = 12,119,853). Our meta-analysis reveals that exposure to a 10 µg/m3 increase in PM2.5 was significantly and positively associated with dementia (pooled HR = 3.26, 95% CI: 1.20, 5.31). In subgroup analyses, exposure to a 10 µg/m3 increase in PM2.5 was found to be positively associated with AD (pooled HR = 4.82, 95% CI: 2.28, 7.36). Analysis of current epidemiological research on PM2.5 and dementia confirmed that exposure to PM2.5 was positively associated with a higher risk for dementia. However, it is to be noted that the included studies mainly relied on claim-based diagnosis and showed large differences in methods of exposure assessment, hence further epidemiological studies with well validated outcomes and with standardized exposure assessment models are required to ascertain the relationship between PM2.5 and dementia/AD.

Interaction of coronavirus nucleocapsid protein with the 5'- and 3'-ends of the coronavirus genome is involved in genome circularization and negative-strand RNA synthesis.

Synthesis of the negative-strand ((-)-strand) counterpart is the first step of coronavirus (CoV) replication; however, the detailed mechanism of the early event and the factors involved remain to be determined. Here, using bovine coronavirus (BCoV)-defective interfering (DI) RNA, we showed that (a) a poly(A) tail with a length of 15 nucleotides (nt) was sufficient to initiate efficient (-)-strand RNA synthesis and (b) substitution of the poly(A) tail with poly(U), (C) or (G) only slightly decreased the efficiency of (-)-strand synthesis. The findings indicate that in addition to the poly(A) tail, other factors acting in trans may also participate in (-)-strand synthesis. The BCoV nucleocapsid (N) protein, an RNA-binding protein, was therefore tested as a candidate. Based on dissociation constant (Kd ) values, it was found that the binding affinity between N protein, but not poly(A)-binding protein, and the 3'-terminal 55 nt plus a poly(A), poly(U), poly(C) or poly(G) tail correlates with the efficiency of (-)-strand synthesis. Such an association was also evidenced by the binding affinity between the N protein and 5'- and 3'-terminal cis-acting elements important for (-)-strand synthesis. Further analysis demonstrated that N protein can act as a bridge to facilitate interaction between the 5'- and 3'-ends of the CoV genome, leading to circularization of the genome. Together, the current study extends our understanding of the mechanism of CoV (-)-strand RNA synthesis through involvement of N protein and genome circularization and thus may explain why the addition of N protein in trans is required for efficient CoV replication.