Prognostic significances of systemic inflammatory response markers in patients with synchronous esophageal and head and neck cancers.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) frequently develop synchronous esophageal cancer (ESCC), but there is a lack of clinical predictors. The neutrophil to lymphocyte (NLR), platelet to lymphocyte (PLR), and lymphocyte to monocyte ratios (LMRs), reflect the balance between pro-cancer inflammation and anti-cancer immune responses, but their role in HNSCC and synchronous cancer remain uncertain. METHOD: The study consecutively enrolled a total of 717 patients with newly diagnosed HNSCC who received pre-treatment esophageal endoscopic screening. The pretreatment NLR, LMR and PLRs were calculated and analyzed in comparison with the clinical factors. RESULTS: A total of 103 patients (14.4%) were found to have synchronous ESCCs, and were associated with a significantly lower absolute lymphocyte count (p < 0.001), higher NLRs (p = 0.044) and lower LMRs (p = 0.001), but not PLRs (p = 0.49). The ROC curve for the presence of synchronous ESCC verified the optimal cutoff value as 2.5 for NLRs and 4.0 for LMRs. Multivariable logistic regression revealed that a LMR <4 (OR 2.22; 95% CI 1.27-3.88, p = 0.005), alcohol consumption (OR 4.19; 95% CI 1.47-11.91, p = 0.007), tumor location over the pharynx (OR 1.68; 95% CI 1.07-2.64, p = 0.025), and low body mass index (OR 0.94; 95% CI 0.88-0.99, p = 0.039) were risk factors for developing synchronous ESCC. A low-LMR was significantly associated with decreases in overall survival (p < 0.0001), in both synchronous and non-synchronous groups. Multivariate analysis demonstrated that LMR <4 (HR 1.97; 95% CI 1.38-2.81, p < 0.001), a low-BMI (HR 0.96; 95% CI 0.93-0.99, p = 0.044) and presence of synchronous ESCC (HR 1.56; 95% CI 1.10-2.22, p = 0.013) were independent prognostic factors for HNSCC patients. CONCLUSION: Incorporation of LMR into other identified risk factors, such as alcohol consumption, tumor location over pharynx, and low-BMI, may establish a more efficient screening program for esophageal exploration in HNSCC patients. The significances of LMR also suggest that anti-cancer immunity may play a role in the filed cancerization to initiate multiple cancers, and the immunotherapy may have potentials for prevention or as an adjuvant treatment for synchronous SCC in the future.

Exploring the genetic correlation of cardiovascular diseases and mood disorders in the UK Biobank.

AIMS: Cardiovascular diseases (CVDs) are the leading cause of deaths globally. Mortality and incidence of CVDs are significantly higher in people with mood disorders. About 81.1% of CVD patients were reported with comorbidities in 2019, where the second most common comorbidity was due to major depressive disorder (MDD). This study, therefore, aimed to evaluate the genetic correlation between CVDs and mood disorders by using data from the UK Biobank towards understanding the influence of genetic factors on the comorbidity due to CVDs and mood disorders. METHODS: The UK Biobank database provides genetic and health information from half a million adults, aged 40-69 years, recruited between 2006 and 2010. A total of 117,925 participants and 6,128,294 variants were included for analysis after applying exclusion criteria and quality control steps. This study focused on two CVD phenotypes, two mood disorders and 12 cardiometabolic-related traits to conduct association studies. RESULTS: The results indicated a significant positive genetic correlation between CVDs and overall mood disorders and MDD specifically, showing substantial genetic overlap. Genetic correlation between CVDs and bipolar disorder was not significant. Furthermore, significant genetic correlation between mood disorders and cardiometabolic traits was also reported. CONCLUSIONS: The results of this study can be used to understand that CVDs and mood disorders share a great deal of genetic liability in individuals of European ancestry.

Prognostic significance of systemic inflammatory response markers in patients with superficial esophageal squamous cell carcinomas.

Endoscopic resection or esophagectomy has becoming the standard treatment for superficial esophageal squamous cell carcinomas (SESCC), but some patients may develop disease progression or second primary cancers after the therapies. Neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) reflect the balance between pro-cancer inflammatory and anti-cancer immune responses, however their roles in SESCC are still unknown. We consecutively enrolled patients with newly diagnosed SESCC (clinical stage Tis or T1N0M0) who were treated at our institute. Pre-treatment NLR, LMR and PLR were assessed and then correlated with clinical factors and long-term survival. A total of 156 patients were enrolled (152 males, 4 females; median age: 52.2 years), of whom 104 received endoscopic resection and 52 were treated with esophagectomy or chemoradiation.. During a mean follow-up period of 60.1 months, seventeen patients died of ESCCs, and 45 died of second primary cancers. The 5-year ESCC-specific survival and 5-year overall survival rate were 86% and 57%, respectively. LMR (P < 0.05) and NLR (P < 0.05), but not PLR were significantly correlated with overall survival. Receiver operating characteristic curve analysis showed optimal LMR and NLR cut-off values of 4 and 2.5, respectively, to predict a poor prognosis. Patients with a high NLR or low LMR tended to have longer tumor length, larger circumferential extension, and presence of second primary cancers. Multivariate Cox regression analysis showed that presence of second primary cancers (HR: 5.05, 95%CI: 2.75-9.28), low LMR (HR: 2.56, 95%CI: 1.09-6.03) were independent risk factors for poor survival. A low pre-treatment LMR may be a non-invasive pretreatment predictor of poor prognosis to guide the surveillance program, suggesting that anti-cancer immunity may play a role in the early events of esophageal squamous cancer.

Impact of induction chemotherapy with concurrent chemoradiotherapy on nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

Purpose: Induction chemotherapy followed by concurrent chemoradiotherapy (IC-CCRT) may be beneficial for nasopharyngeal carcinoma. However, the evidence on medium- and long-term effects of IC-CCRT is limited, and new randomized controlled trials (RCTs) have been published after 2018. Therefore, this systematic review and meta-analysis compared survival rates between patients with nasopharyngeal carcinoma receiving IC-CCRT or concurrent chemoradiotherapy (CCRT). Methods: Four databases were searched for RCTs on this topic. Two authors independently selected studies, assessed evidence, and extracted data on progression-free survival, overall survival, metastasis-free survival, and local recurrence-free survival. Available data were pooled in a random-effects model and mainly presented in hazard ratio (HR). Heterogeneity and small study effects were also evaluated. Results: Eleven RCTs (n = 3345) were deemed eligible. Pooled results revealed that patients receiving IC-CCRT had significantly improved progression-free survival (HR = 0.66, P < 0.05), overall survival (HR = 0.64, P < 0.05), metastasis-free survival (HR = 0.58, P < 0.05), and local recurrence-free survival (HR = 0.69, P < 0.05) at 3 years, but no significant difference in 5-year overall survival was noted between IC-CCRT and CCRT (HR = 0.84, P > 0.05). Most findings had low heterogeneity. Conclusion: IC-CCRT may benefit patients with nasopharyngeal carcinoma in the medium term, although no significant difference was observed in 5-year survival compared with CCRT. All outcomes had decreased survival rate from the 3-years to 5-year follow-up. Differences in patient ethnicities and regimens of IC-CCRT may be sources of heterogeneity.

Aristolochic acid and the risk of cancers in patients with type 2 diabetes: Nationwide population-based cohort study.

BACKGROUND: Both aristolochic acid (AA) exposure and diabetic can increase risk of certain cancers,whetherAAexposureincreases cancer risk in diabetic patientsisunknown. The purpose of this study was to investigate the association between the use of Chinese herbal products containing AA and the risk of cancer in diabetic patients. METHODS: A cohort study was conducted using the National Health Insurance Research Database in Taiwan. Patients older than 18 years who were diagnosed with diabetes between 1997 and 2010 were enrolled in our cohort. The use of Chinese herbal products containing AA was recorded from the beginning of 1997 until the ban of herbs containing AA in November 2003. Patients were individually tracked to identify cancer incidence between 1997 and 2013. Only patients who visited traditional Chinese medicine clinics between 1997 and 1 year before the end of follow-up were included in the cohort to ensure comparability. Cox proportional hazards regression was used to calculate the hazard ratio for the association between the use of Chinese herbal products containing AA and the occurrence of cancer. RESULTS: Among the 430 377 male and 431 956 female patients with diabetes enrolled in our cohort, 37 554 and 31 535 cancer diagnoses were recorded during the study period, respectively. The use of AA-containing herbal products was associated with a significantly higher risk of liver, colorectum, kidney, bladder, prostate, pelvis, and ureter cancer in a dose-dependent manner. An increased risk of extrahepatic bile duct cancer in women was also associated with AA exposure at doses of more than 500 mg. CONCLUSIONS: Association between AA exposure and the risk of some cancers were found in this study. AA exposure might increase risk of kidney,bladder,pelvis, ureter,liver,colorectum,andprostatecancer in all patientsandextrahepatic bile duct cancerin women.

Assessment of tumor extension to the ductal system of submucosal glands in patients with superficial esophageal squamous neoplasms: Implications for endoscopic resection.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become the standard treatment for superficial esophageal squamous cell neoplasia (SESCN); however, local recurrence still occurs occasionally even in patients who meet the current curative criteria. Esophageal ducts of the submucosal gland may serve as a pathway for the spread of SESCN to a deeper layer. However, the clinical impact of ductal involvement (DI) in patients undergoing ESD has yet to be investigated. METHODS: We consecutively enrolled patients with SESCN who were treated with ESD. The resected specimens were meticulously reviewed in multiple section slices for the presence and resected margins of DI, and their correlations with clinical factors were evaluated. RESULTS: A total of 210 lesions were analyzed, of which 78 (37.1%) presented with DI. The presence of submucosal invasion, lymphovascular invasion (LVI), and DI were indicators of worse prognosis (P < .05). Deep extended DIs were misdiagnosed as deep submucosal invasive cancer in 4 cases (2%). Of the 185 patients who met the criteria for curative ESD (ie, R0 resection and no deep submucosal invasion or LVI), 11 (5.9%) developed local recurrence/metastasis during a mean follow-up of 55.2 months (range, 6 to 140) months. Compared with patients with without DI, patients with DI had worse recurrence-free survival (P = .008, log-rank test) and a higher local risk of recurrence (12.7% vs 2.5%) after curative ESD (hazard ratio, 4.20; P = .038). CONCLUSIONS: A precise histological assessment of DI in SESCN is crucial after ESD, given that DI is common and associated with worse outcome. Whether total removal of esophageal glands/ducts can improve outcome requires future study.

Association between short-term exposure to air pollution and sudden infant death syndrome.

The association between air pollution and infant mortality has been inconsistently reported. A few studies have estimated short-term effects of air pollution on infants' health. This population-based case-control study aimed to examine the potential effects of air pollution on sudden infant death syndrome (SIDS) in the post-neonatal period in Taiwan during 1997-2002. Each case of infant death was matched with 20 randomly selected sex-matched controls who were born on the same day and were still alive. We obtained 24-h measurements of air pollutants and meteorological factors in each case and control with 1- to 14-day lags from 55 air-quality monitoring stations. After controlling for potential confounders, conditional logistic regression analysis was performed to estimate effects of air pollutants on SIDS (n = 398) and respiratory death (n = 121) among neonates. In single- and multi-pollutant models, we found that 100-ppb increment in carbon monoxide (Odds Ratio = 1.04-1.07) and 10-ppb increment in nitrogen dioxide (Odds Ratio = 1.20-1.35) with 1- to 14-day lags were associated with significant increase in SIDS, although a significant relationship between air pollution and respiratory death was not determined in 1- to 14-day lags. Short-term carbon monoxide and nitrogen dioxide exposure were associated with significant increase in SIDS in the post-neonatal period, with latency estimated within days before death.

Intrinsic brain activity of subcortical-cortical sensorimotor system and psychomotor alterations in schizophrenia and bipolar disorder: A preliminary study.

OBJECTIVE: Alterations in psychomotor dimension cut across different psychiatric disorders, such as schizophrenia (SCZ) and bipolar disorder (BD). This preliminary study aimed to investigate the organization of intrinsic brain activity in the subcortical-cortical sensorimotor system in SCZ (and BD) as characterized according to psychomotor dimension. METHOD: In this resting-state functional magnetic resonance imaging (fMRI) study, functional connectivity (FC) between thalamus and sensorimotor network (SMN), along with FC from substantia nigra (SN) and raphe nuclei (RN) to basal ganglia (BG) and thalamic regions, were investigated by using an a-priori-driven and dimensional approach. This was done in two datasets: SCZ patients showing inhibited psychomotricity (n = 18) vs. controls (n = 19); SCZ patients showing excited psychomotricity (n = 20) vs. controls (n = 108). Data from a third dataset of BD in inhibited depressive or manic phases (reflecting inhibited or excited psychomotricity) were used as control. RESULTS: SCZ patients suffering from psychomotor inhibition showed decreased thalamus-SMN FC toward around-zero values paralleled by a concomitant reduction of SN-BG/thalamus FC and RN-BG/thalamus FC (as BD patients in inhibited depression). By contrast, SCZ patients suffering from psychomotor excitation exhibited increased thalamus-SMN FC toward positive values paralleled by a concomitant reduction of RN-BG/thalamus FC (as BD patients in mania). CONCLUSIONS: These findings suggest that patients exhibiting low or high levels of psychomotor activity show distinct patterns of thalamus-SMN coupling, which could be traced to specific deficit in SN- or RN-related connectivity. Notably, this was independent from the diagnosis of SCZ or BD, supporting an RDoC-like dimensional approach to psychomotricity.

Brain computerized tomography reading in suspected acute ischemic stroke patients: what are essentials for medical students?

BACKGROUND: Few systematic methods prioritize the image education in medical students (MS). We hope to develop a checklist of brain computerized tomography (CT) reading in patients with suspected acute ischemic stroke (AIS) for MS and primary care (PC) physicians. METHODS: Our pilot group generated the items indicating specific structures or signs for the checklist of brain CT reading in suspected AIS patients for MS and PC physicians. These items were used in a modified web-based Delphi process using the online software "SurveyMonkey". In total 15 panelists including neurologists, neurosurgeons, neuroradiologists, and emergency department physicians participated in the modified Delphi process. Each panelist was encouraged to express feedback, agreement or disagreement on the inclusion of each item using a 9-point Likert scale. Items with median scores of 7-9 were included in our final checklist. RESULTS: Fifty-two items were initially provided for the first round of the Delphi process. Of these, 35 achieved general agreement of being an essential item for the MS and PC physicians. The other 17 of the 52 items in this round and another two added items suggested by the panelists were further rated in the next round. Finally, 38 items were included in the essential checklist items of brain CT reading in suspected AIS patients for MS and PC physicians. CONCLUSIONS: We established a reference regarding the essential items of brain CT reading in suspected AIS patients. We hope this helps to minimize malpractice and a delayed diagnosis, and to improve competency-based medical education for MS and PC physicians.

Medical knowledge infused convolutional neural networks for cohort selection in clinical trials.

OBJECTIVE: In this era of digitized health records, there has been a marked interest in using de-identified patient records for conducting various health related surveys. To assist in this research effort, we developed a novel clinical data representation model entitled medical knowledge-infused convolutional neural network (MKCNN), which is used for learning the clinical trial criteria eligibility status of patients to participate in cohort studies. MATERIALS AND METHODS: In this study, we propose a clinical text representation infused with medical knowledge (MK). First, we isolate the noise from the relevant data using a medically relevant description extractor; then we utilize log-likelihood ratio based weights from selected sentences to highlight "met" and "not-met" knowledge-infused representations in bichannel setting for each instance. The combined medical knowledge-infused representation (MK) from these modules helps identify significant clinical criteria semantics, which in turn renders effective learning when used with a convolutional neural network architecture. RESULTS: MKCNN outperforms other Medical Knowledge (MK) relevant learning architectures by approximately 3%; notably SVM and XGBoost implementations developed in this study. MKCNN scored 86.1% on F1metric, a gain of 6% above the average performance assessed from the submissions for n2c2 task. Although pattern/rule-based methods show a higher average performance for the n2c2 clinical data set, MKCNN significantly improves performance of machine learning implementations for clinical datasets. CONCLUSION: MKCNN scored 86.1% on the F1 score metric. In contrast to many of the rule-based systems introduced during the n2c2 challenge workshop, our system presents a model that heavily draws on machine-based learning. In addition, the MK representations add more value to clinical comprehension and interpretation of natural texts.

Herbal Medicine Containing Aristolochic Acid and the Risk of Primary Liver Cancer in Patients with Hepatitis C Virus Infection.

BACKGROUND: We investigated the association between taking herbal medicine (HM) containing aristolochic acid (AA) and the risk of primary liver cancer (PLC) among patients with hepatitis C virus (HCV) infection. METHODS: This is a prospective study for the long-term follow-up of a nationwide population-based cohort of patients ages 18 years or older diagnosed with HCV infection during 1997 to 2010. A total of 223,467 HCV-infected patients were identified using the National Health Insurance Research Database in Taiwan. The use of HM containing AA was evaluated among patients who had visited traditional Chinese medicine clinics beginning from 1997 to 1 year prior to the diagnosis of PLC or dates censored (2003). We tracked each individual patient from 1997 to 2013 to identify incident cases of PLC since 1999. RESULTS: During the follow-up period of 3,052,132 person-years, we identified 25,502 PLC cases; this corresponded to an overall incidence rate of 835.5 PLCs per 100,000 person-years. The adjusted HRs were 1.21 [95% confidence interval (CI), 1.18-1.24], 1.48 (95% CI, 1.37-1.59), 1.50 (95% CI, 1.34-1.68), and 1.88 (95% CI, 1.61-2.19) for estimated AA usage groups: 1 to 250, 251 to 500, 501 to 1,000, and more than 1,000 mg, respectively, relative to no AA exposure (reference group). CONCLUSIONS: The current findings suggest that among HCV-positive patients, increasing exposure to AA poses an increased risk of acquiring PLC. IMPACT: AA may increase the risk of PLC in HCV-positive populations.

Cerebral Small Vessel Disease Biomarkers Detection on MRI-Sensor-Based Image and Deep Learning.

Magnetic resonance imaging (MRI) offers the most detailed brain structure image available today; it can identify tiny lesions or cerebral cortical abnormalities. The primary purpose of the procedure is to confirm whether there is structural variation that causes epilepsy, such as hippocampal sclerotherapy, local cerebral cortical dysplasia, and cavernous hemangioma. Cerebrovascular disease, the second most common factor of death in the world, is also the fourth leading cause of death in Taiwan, with cerebrovascular disease having the highest rate of stroke. Among the most common are large vascular atherosclerotic lesions, small vascular lesions, and cardiac emboli. The purpose of this thesis is to establish a computer-aided diagnosis system based on small blood vessel lesions in MRI images, using the method of Convolutional Neural Network and deep learning to analyze brain vascular occlusion by analyzing brain MRI images. Blocks can help clinicians more quickly determine the probability and severity of stroke in patients. We analyzed MRI data from 50 patients, including 30 patients with stroke, 17 patients with occlusion but no stroke, and 3 patients with dementia. This system mainly helps doctors find out whether there are cerebral small vessel lesions in the brain MRI images, and to output the found results into labeled images. The marked contents include the position coordinates of the small blood vessel blockage, the block range, the area size, and if it may cause a stroke. Finally, all the MRI images of the patient are synthesized, showing a 3D display of the small blood vessels in the brain to assist the doctor in making a diagnosis or to provide accurate lesion location for the patient.

Cerebral Motor Functional Connectivity at the Acute Stage: An Outcome Predictor of Ischemic Stroke.

Sixty-seven patients with first acute ischemic stroke onset between 3 to 7 days and 25 age- and sex- matched controls were analyzed for the performance of a resting-state functional MRI to investigate whether the functional connectivity (FC) of the motor network in acute ischemic stroke is independently associated with functional outcomes. The FC of cortical motor network and default mode network was analyzed. The FC was compared between controls, patients with favorable outcomes (modified Rankin Scale, mRS ≤1), and patients with unfavorable outcomes (mRS ≥2) at 3 months. Of the 67 patients, 23 (34%) exhibited unfavorable outcomes. In multivariate analysis, the FC between ipsilesional primary motor cortex (M1) and contralesional dorsal premotor area (PMd) ≤0.63, were independently associated with unfavorable outcomes (odds ratio = 6.32, P = 0.032), whereas the FC of default mode network was not different between groups. The interhemispheric FC of the motor network is an independent predictor of functional outcomes in patients with acute ischemic stroke.

Herbal medicine containing aristolochic acid and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.

It was suspected that aristolochic acid-induced mutations may be associated with hepatitis B virus (HBV), playing an important role in liver carcinogenesis. The purpose of this study was to investigate the association between the use of Chinese herbs containing aristolochic acid and the risk of hepatocellular carcinoma (HCC) among HBV-infected patients. We conducted a retrospective, population-based, cohort study on patients older than 18 years who had a diagnosis of HBV infection between January 1, 1997 and December 31, 2010 and had visited traditional Chinese medicine clinics before one year before the diagnosis of HCC or the censor dates. A total of 802,642 HBV-infected patients were identified by using the National Health Insurance Research Database in Taiwan. The use of Chinese herbal products containing aristolochic acid was identified between 1997 and 2003. Each patient was individually tracked from 1997 to 2013 to identify incident cases of HCC since 1999. There were 33,982 HCCs during the follow-up period of 11,643,790 person-years and the overall incidence rate was 291.8 HCCs per 100,000 person-years. The adjusted hazard ratios (HRs) were 1.13 (95% confidence interval [CI], 1.11-1.16), 1.21 (95% CI, 1.13-1.29), 1.37 (95% CI, 1.24-1.50) and 1.61 (95% CI, 1.40-1.84) for estimated aristolochic acid of 1-250, 251-500, 501-1,000 and more than 1,000 mg, respectively, relative to no aristolochic acid exposure. Our study found a significant dose-response relationship between the consumption of aristolochic acid and HCC in patients with HBV infection, suggesting that aristolochic acid which may be associated with HBV plays an important role in the pathogenesis of HCC.

Vascular-metabolic and GABAergic Inhibitory Correlates of Neural Variability Modulation. A Combined fMRI and PET Study.

Neural activity varies continually from moment to moment. Such temporal variability (TV) has been highlighted as a functionally specific brain property playing a fundamental role in cognition. We sought to investigate the mechanisms involved in TV changes between two basic behavioral states, namely having the eyes open (EO) or eyes closed (EC) in vivo in humans. To these ends we acquired BOLD fMRI, ASL, and [18F]-fluoro-deoxyglucose PET in a group of healthy participants (n = 15), along with BOLD fMRI and [18F]-flumazenil PET in a separate group (n = 19). Focusing on an EO- vs EC-sensitive region in the occipital cortex (identified in an independent sample), we show that TV is constrained in the EO condition compared to EC. This reduction is correlated with an increase in energy consumption and with regional GABAA receptor density. This suggests that the modulation of TV by behavioral state involves an increase in overall neural activity that is related to an increased effect from GABAergic inhibition in addition to any excitatory changes. These findings contribute to our understanding of the mechanisms underlying activity variability in the human brain and its control.

Nationwide study on the risk of unprovoked venous thromboembolism in non-traumatic osteonecrosis of femoral head.

PURPOSE: Endothelial dysfunction is a risk factor for osteonecrosis of femoral head (ONFH) and venous thromboembolism (VTE) [defined as deep venous thrombosis (DVT) or pulmonary embolism (PE)]. However, the risk of unprovoked VTE in non-traumatic ONFH patients remains unclear. METHODS: We investigated the relationship between ONFH and VTE using Taiwan National Health Insurance Research Database (NHIRD). Between 1997 and 2010, a total of 1514 non-traumatic ONFH patients were identified from 1,000,000 general populations after excluding initially concomitant diagnoses of DVT and PE, and subjects undergoing lower limb surgery within one year since enrollment. The comparison group (n = 15,140) without ONFH was set up by matching study cohort with age, gender, income and urbanization in a 1:10 ratio. Subjects diagnosed with VTE within one year after surgery were also excluded. RESULTS: The patients with non-traumatic ONFH had significantly higher frequency of unprovoked VTE, including DVT, than general population (1.19 vs. 0.5%, p < 0.0007), whereas the frequency of PE was similar between these two groups (p = 0.4922). The cumulative incidence of VTE and DVT was also remarkably higher in the ONFH than non-ONFH group (all p < 0.001). After adjusting for age, gender, medications and comorbidities with multivariate analysis, the ONFH patients had a 2.3-fold increase in risk of DVT compared with non-ONFH counterparts (95% CI 1.28 to 4.13, p = 0.0053). Apart from ONFH, age > 65 years and hypertension were also identified as risk factors for DVT occurrence. CONCLUSIONS: The incidence and risk of unprovoked VTE were significantly increased in the non-traumatic ONFH population.

Cardiovascular and Cerebrovascular Events Are Associated With Nontraumatic Osteonecrosis of the Femoral Head.

BACKGROUND: Endothelial dysfunction has been identified as an etiologic factor for osteonecrosis of the femoral head (ONFH) and major adverse cardiovascular and cerebrovascular events (defined as major cardiovascular disease [CVD] and cerebrovascular accident [CVA]). However, the incidence of major adverse cardiovascular and cerebrovascular events in patients with nontraumatic ONFH and any association between the two diagnoses remain unclear. QUESTIONS/PURPOSES: We compared a large cohort of patients with nontraumatic ONFH and a matched control group without this diagnosis and (1) examined the frequency and hazard ratio (HR) of major adverse cardiovascular and cerebrovascular events in both groups adjusted for age, sex, socioeconomic status, and associated comorbidities (which we defined as the adjusted HR), (2) determined whether any association of ONFH and major adverse cardiovascular and cerebrovascular events was stable after adjusting for confounding variables, and (3) compared the occurrence of major adverse cardiovascular and cerebrovascular events with time in both groups. METHODS: A population-based cohort with a 14-year dataset period (1997-2010) from the Taiwan National Health Insurance Research Database was used for this retrospective study. The database includes a greater than 99.5% Asian population randomly selected from more than 23 million citizens and foreigners residing in Taiwan for longer than 6 months. A total of 1562 patients with nontraumatic ONFH were identified from a population of one million patients in the database after excluding initially concomitant diagnoses of major CVD and CVA. The comparison group (n = 15,620) without ONFH was analyzed in a one-to-10 ratio by matching the study cohort based on age, sex, income, and urbanization. RESULTS: The patients with ONFH had a higher frequency of major adverse cardiovascular and cerebrovascular events than their counterparts without ONFH (19% versus 14%; p < 0.001). The patients with ONFH had 1.34- and 1.27-fold adjusted HRs for occurrence of major CVD and CVA as compared with the normal population (95% CI, 1.11-1.61, p = 0.002, and 95% CI, 1.09-1.47, p = 0.002, respectively). Sensitivity analysis showed a consistent association between ONFH and major adverse cardiovascular and cerebrovascular events after controlling for potentially relevant confounding variables such as hypertension and diabetes. After adjusting for potential confounders including surgery and medications, ONFH remained independently associated with major CVD (adjusted HR, 1.51, 95% CI 1.09-2.03, p = 0.026) and CVA (adjusted HR, 2.44, 95% CI 1.69-3.51, p < 0.001), apart from age older than 65 years and traditional atherosclerotic risk factors. The cumulative incidence of major adverse cardiovascular and cerebrovascular events also was higher in the ONFH group than the non-ONFH group (30.3% vs 23.1% at the end of followup, p < 0.001). CONCLUSIONS: Patients with ONFH have a strong association with major adverse cardiovascular and cerebrovascular events as compared with the normal population, suggesting a potential common pathway involving endothelial dysfunction. In view of this association in the relatively young population with ONFH, it is important to closely monitor these patients, treat relevant comorbidities early, and investigate preventative measures for these major adverse events. LEVEL OF EVIDENCE: Level III, prognostic study.

Diabetes and risk of Kaposi's sarcoma: effects of high glucose on reactivation and infection of Kaposi's sarcoma-associated herpesvirus.

Patients with diabetes are generally prone to pathogen infection and tumor progression. Here, we investigated the potential association between diabetes and Kaposi's sarcoma (KS), a tumor linked to infection with Kaposi's sarcoma-associated herpesvirus (KSHV). By using Taiwan's National Health Insurance Research Database, we found that diabetes is statistically associated with increased risk of KS in a case-control study. Since a high level of blood sugar is the hallmark of diabetes, we determined whether high glucose promotes both KSHV reactivation and infection, which are crucial for KS pathogenesis. Our results showed that high glucose significantly increases lytic reactivation of KSHV but not Epstein-Barr virus, another related human oncogenic gammaherpesvirus, in latently infected cells. Activation of the transcription factor AP1 by high glucose is critically required for the onset of KSHV lytic reactivation. We also demonstrated that high glucose enhances susceptibility of various target cells to KSHV infection. Particularly, in endothelial and epithelial cells, levels of specific cellular receptors for KSHV entry, including integrin α3ß1 and xCT/CD98, are elevated under high glucose conditions, which correlate with the enhanced cell susceptibility to infection. Taken together, our studies implicate that the high-glucose microenvironment may be an important predisposing factor for KS development.

Risk of aortic aneurysm and dissection in patients with autosomal-dominant polycystic kidney disease: a nationwide population-based cohort study.

Although cardiovascular complications are the most common cause of death in patients with autosomal-dominant polycystic kidney disease (ADPKD), the incidence and risk of aortic aneurysm and dissection (AAD) in ADPKD remains unclear due to limited data and insufficient cases. We utilized the data from Taiwan National Health Insurance Research Database (NHIRD) to do a population-based cohort study (1997-2008). After excluding those patients with age <18 years old and initially concomitant diagnoses of end-stage renal disease and AAD, a total of 2076 ADPKD patients were selected from 1,000,000 of general population. Additionally, the non-ADPKD group was set up as comparison group in 1:10 ratio after matching with age, gender, income and urbanization (n=20760). The result showed that ADPKD group had higher frequency of comorbidities than non-ADPKD group. The frequency of AAD in ADPKD was significantly higher than in general population (0.92% v.s. 0.11%, p<0.0001). Of them, 58% of AAD were acute aortic dissection. In addition, Kaplan-Meier analysis demonstrated that cumulative incidence of AAD was remarkably higher in the ADPKD than non-ADPKD group (p<0.001). The mean time period from ADPKD diagnosis to AAD occurrence was 4.02±3.16 years. After adjusting for age, gender and comorbidities, the ADPKD patients had up to 5.49-fold greater risk for AAD occurrence as compared to non-ADPKD counterparts (95% CI 2.86-10.52, p<0.0001). Particularly, those patients with co-existing ADPKD and hypertension had very high risk for future development of AAD. In conclusion, the risk of AAD significantly increases in patients with ADPKD as compared with those of general population.