Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is ...characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy.
Cellular lipidome is highly regulated through lipogenesis, rendering diverse double-bond positional isomers (CC isomer) of a given unsaturated lipid species. In recent years, there are increasing ...reports indicating the physiological roles of CC isomer compositions associated with diseases, while the biochemistry has not been broadly investigated due to the challenge in characterizing lipid isomers inherent to conventional mass spectrometry-based lipidomics. To address this challenge, we reported a universal, user-friendly, derivatization-based strategy, MELDI (mCPBA Epoxidation for Lipid Double-bond Identification), which enables both large-scale identification and spatial mapping of biological CC isomers using commercial mass spectrometers without any instrument modification. With the developed liquid-chromatography mass spectrometry (LC-MS) lipidomics workflow, we elucidated more than 100 isomers among monounsaturated and polyunsaturated fatty acids and glycerophospholipids in human serum, where uncommon isomers of low abundance were quantified for the first time. The capability of MELDI-LC-MS in lipidome analysis was further demonstrated using the differentiated 3T3-L1 adipocytes, providing an insight into the cellular lipid reprogramming upon stearoyl-coenzyme A desaturase 1 (SCD1) inhibition. Finally, we highlighted the versatility of MELDI coupled with ambient mass spectrometry imaging to spatially resolve cancer-associated alteration of lipid isomers in a metastatic mouse tissue section. Our results suggested that MELDI will contribute to current lipidomics pipelines with a deeper level of structural information, allowing us to investigate the underlying lipid biochemistry.
Exposure to general anesthesia has been reported to induce neurotoxicity, impair learning, memory, attention, motor functions, as well as affect behavior in adult rodents and nonhuman primates. ...Though many have speculated similar effects in humans, previous literature has shown conflicting findings. To investigate the differences in risk of developmental delay among young children exposed to general anesthesia compared to matched unexposed individuals, a population-based cohort study was conducted with a longitudinal dataset spanning 2000 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD). Procedure codes were used to identify children who received anesthesia. For each exposed child, two unexposed children matched by gender and age were enrolled into the comparison cohort. Neurocognitive outcome was measured by the presence of ICD-9-CM codes related to developmental delay (DD). Cox regression models were used to obtain hazard ratios of developing DD after varying levels of anesthesia exposure. After excluding 4,802 individuals who met the exclusion criteria, a total of 11,457 children who received general anesthesia before two years of age was compared to 22,914 children (matched by gender and age) unexposed to anesthesia. Increased risk of DD was observed in the exposure group with a hazard ratio (HR) of 1.320 (95% CI 1.143-1.522, P 0.001). Subgroup analysis demonstrated further elevated risks of DD with multiple anesthesia exposures (1 anesthesia event: HR 1.145, 95% CI 1.010-1.246, P = 0.04; 2 anesthesia events: HR 1.476, 95% CI 1.155-1.887, P = 0.005; greater than or equal to3 anesthesia events: HR 2.222, 95% CI 1.810-2.621, P 0.001) and longer total anesthesia durations (Total anesthesia 4 hours: HR 1.598, 95% CI 1.343-1.982, P 0.001) compared with children unexposed to anesthesia. These results suggest that children exposed to general anesthesia before two years of age have an increased risk of DD. This risk is further elevated with increased frequency of anesthesia, and longer total anesthesia duration. The findings of this study should prompt clinical practitioners to proceed with caution when assessing young patients and planning managements involving procedures requiring general anesthesia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tuberculosis (TB) presents a global threat in the world and the lung is the frequent site of metastatic focus. A previous study demonstrated that TB might increase primary lung cancer risk by ...two-fold for more than 20 years after the TB diagnosis. However, no large-scale study has evaluated the risk of TB and secondary lung cancer. Thus, we evaluated the risk of secondary lung cancer in patients with or without tuberculosis (TB) using a nationwide population-based dataset.
In a cohort study of 1,936,512 individuals, we selected 6934 patients among patients with primary cancer and TB infection, based on the International Classification of Disease (ICD-p-CM) codes 010-011 from 2000 to 2015. The control cohort comprised 13,868 randomly selected, propensity-matched patients (by age, gender, and index date) without TB exposure. Using this adjusted date, a possible association between TB and the risk of developing secondary lung cancer was estimated using a Cox proportional hazards regression model.
During the follow-up period, secondary lung cancer was diagnosed in 761 (10.97%) patients with TB and 1263 (9.11%) patients without TB. After adjusting for covariates, the risk of secondary lung cancer was 1.67 times greater among primary cancer in the cohort with TB than in the cohort without TB. Stratification revealed that every comorbidity (including diabetes, hypertension, cirrhosis, congestive heart failure, cardiovascular accident, chronic kidney disease, chronic obstructive pulmonary disease) significantly increased the risk of secondary lung cancer when comparing the TB cohort with the non-TB cohort. Moreover, the primary cancer types (including head and neck, colorectal cancer, soft tissue sarcoma, breast, kidney, and thyroid cancer) had a more significant risk of becoming secondary lung cancer.
A significant association exists between TB and the subsequent risk for metastasis among primary cancers and comorbidities. Therefore, TB patients should be evaluated for the subsequent risk of secondary lung cancer.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Carotid intima–media thickness (IMT), plaque, and stenosis are widely used as early surrogate markers of subclinical atherosclerosis and strong predictors of future deaths and cardiovascular events. ...Albuminuria is an indicator of generalized endothelial dysfunction that speeds up atherosclerosis. However, previous studies reporting these associations cannot rule out the confounding effect of albuminuria. We aimed to examine the independent and joint relationships between IMT markers and 10-year mortality in community-dwelling Taiwanese adults. This work was a community-based prospective cohort study consisting of 2956 adults aged at least 30 years recruited in 2007 and followed up through 2019. Cox proportional hazard regression models were used to examine associations of these subclinical atherosclerosis markers with mortality. During an average of 9.41 years of follow up, 242 deaths occurred. The mortality rate was 8.70 per 1000 person-years. Compared with those with carotid IMT less than 1.0 mm, persons with severely increased carotid IMT (≥2.0 mm) had an increased risk for death (hazard ratio (HR): 1.79; 95% confidence interval (CI): 1.07, 3.00). Compared with those without carotid plaque, persons with carotid plaque were more likely to have an increased risk for death (1.65; 1.21–2.32). Compared with those with carotid stenosis less than 25%, persons with carotid stenosis of 25–36% had a significant increased risk for death (1.57; 1.12–2.22). Considering these three IMT markers along with the traditional risk factors (c-statistic: 0.85) significantly increased their predictive ability of mortality compared with any individual variable’s predictive ability (all p-values < 0.001 for comparisons of c-statistic values). Carotid IMT measures, including IMT thickness, carotid plaque, and carotid stenosis were significant independent predictors of mortality. Our study supports evidence of blood pressure-related media thickening markers to assess future mortality risks in Chinese adults of general population.
Approximately 25-30% of individuals worldwide are infected with Toxoplasma gondii (T. gondii), which is difficult to detect in its latent state. We aimed to evaluate the association between ...toxoplasmosis, the risk of dementia, and the effects of antibiotics in Taiwan.
This nationwide, population-based, retrospective cohort study was conducted using the Longitudinal Health Insurance Database containing the records of 2 million individuals retrieved from Taiwan's National Health Insurance Research Database. Fine-Gray competing risk analysis was used to determine the risk for the development of dementia in the toxoplasmosis cohort relative to the non-toxoplasmosis cohort. A sensitivity analysis was also conducted. The effects of antibiotics (sulfadiazine or clindamycin) on the risk of dementia were also analyzed.
We enrolled a total of 800 subjects, and identified 200 patients with toxoplasmosis and 600 sex- and age-matched controls without toxoplasmosis infection in a ratio of 1:3, selected between 2000 and 2015. The crude hazard ratio (HR) of the risk of developing dementia was 2.570 95% confidence interval (CI) = 1.511-4.347, P < 0.001. After adjusting for sex, age, monthly insurance premiums, urbanization level, geographical region, and comorbidities, the adjusted HR was 2.878 (95% CI = 1.709-4.968, P < 0.001). Sensitivity analysis revealed that toxoplasmosis was associated with the risk of dementia even after excluding diagnosis in the first year and the first 5 years. The usage of sulfadiazine or clindamycin in the treatment of toxoplasmosis was associated with a decreased risk of dementia.
This finding supports the evidence that toxoplasmosis is associated with dementia and that antibiotic treatment against toxoplasmosis is associated with a reduced risk of dementia. Further studies are necessary to explore the underlying mechanisms of these associations.
The nucleotide‐binding and oligomerization domain, leucine‐rich repeats, and pyrin domain‐containing protein 3 (NLRP3) inflammasome plays a crucial role in innate immunity and is involved in the ...pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that the inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC‐0160 or pioglitazone, increased NLRP3 inflammasome activation and IL‐1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP‐associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sens MSDC‐itizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU‐induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3‐related autoinflammatory diseases.
Inactivation of mitochondrial pyruvate carrier (MPC) with genetic depletion or pharmacological inhibitors pioglitazone or MSDC‐0160 blocks mitochondrial pyruvate import, thus reducing oxidative phosphorylation (OXPHOS) in macrophages. To compensate for energy demand, an increase in lactic fermentation maintains glycolysis through the NAD+ cycle to make glycolytic ATP but is also accompanied by lactate production. When combined with insulin therapy, insulin enables cells to take up glucose to promote lactate fermentation, maximizing lactate production. Cellular lactate controlled by MPC contributes to upgrading NOD, LRR, and pyrin domain‐containing protein 3 (NLRP3) inflammasome hyperactivation and exacerbating gout development. Downregulation of lactate production by the lactate dehydrogenase (LDH) inhibitor GSK2837808A efficiently prevented NLRP3 inflammasome activation.
Objectives To investigate the effect of botulinum toxin A (BTA) on the development of hip dislocation and scoliosis, surgical rates for hip and spine, and mortality in cerebral palsy (CP). Study ...design A cohort study was conducted using CP data from a Taiwan National Insurance Health Research Database. Diagnoses were defined using the International Classification of Diseases codes, 9th revision. Adjusted hazard ratios for outcomes were calculated using Cox regression analysis and adjusted for the following variables: BTA injection, sex, age, severities of CP, comorbidities, location, urbanization level, and level of care. Results A total of 1,405 CP children (670 female vs. 735 male), 281 in the BTA group and 1,124 in the controls, were followed-up for a mean of 5 years 4 months. There were no significant differences in the outcomes in both groups, in the incidence rates of hip dislocation and scoliosis, nor in the surgical rates for hip and spine surgery. Mortality rate in the BTA group was 0.49 times lower than that in the controls (p = 0.001). Moderate to severe types of CP had higher incidence rates of hip dislocation, scoliosis, hip surgery, spine surgery, and mortality. Conclusion Moderate to severe types of CP had poorer outcomes in all aspects, including a higher risk of hip dislocation, scoliosis, surgical rate for hip and spine, and mortality. Although BTA injection in children with CP proved to not significantly reduce hip dislocation and scoliosis, it is considered safe as an anti-spasticity treatment and may be beneficial for survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The major challenge in COVID‐19 vaccine effectiveness is immune escape by SARS‐CoV‐2 variants. To overcome this, an Omicron‐specific messenger RNA (mRNA) vaccine was designed. The extracellular ...domain of the spike of the Omicron variant was fused with a modified GCN4 trimerization domain with low immunogenicity (TSomi). After immunization with TSomi mRNA in hamsters, animals were challenged with SARS‐CoV‐2 virus. The raised nonneutralizing antibodies or cytokine secretion responses can recognize both Wuhan S and Omicron S. However, the raised antibodies neutralized SARS‐CoV‐2 Omicron virus infection but failed to generate Wuhan virus neutralizing antibodies. Surprisingly, TSomi mRNA immunization protected animals from Wuhan virus challenge. These data indicated that non‐neutralizing antibodies or cellular immunity may play a more important role in vaccine‐induced protection than previously believed. Next‐generation COVID‐19 vaccines using the Omicron S antigen may provide sufficient protection against ancestral or current SARS‐CoV‐2 variants.
Abstract
Trichomonas vaginalis
infection is one of the most widespread sexually transmitted infections in the world. There are approximately 276 million cases worldwide. Most men remain undiagnosed ...and untreated because they are asymptomatic. The chronic inflammation induced by persistent infection may increase the risk of developing genitourinary cancers. In this study, we aimed to investigate the association between trichomoniasis and benign prostate hyperplasia (BPH), prostate cancer (PCa), and bladder cancer (BC) in Taiwan. We designed a case–control study by using the database of the National Health Insurance program in Taiwan. We used the International Classification of Diseases, 9th Revision classifications to classify all the medical conditions in the case and control groups. All odds ratios (ORs) and 95% confidence intervals (CIs) were analyzed using multivariable logistic regression to adjust for all comorbidities and variables. From 2000 to 2015, we enrolled a total of 62,544 individuals as the case group and 187,632 as the control group. Trichomoniasis exposure had a significant association with BPH and PCa (adjusted OR: BPH = 2.685, 95% CI = 1.233–4.286,
P
= 0.013; PCa = 5.801, 95% CI = 1.296–26.035,
P
= 0.016). The relative risk was much higher if patients had both trichomoniasis and depression (adjusted OR = 7.682, 95% CI = 5.730–9.451,
P
< 0.001). Men with trichomoniasis had a significantly higher risk of developing BPH and PCa than those without. Healthcare professionals should not only pay more attention to disease treatment, but also to public health education.
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