Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

Association between Combustible Cigarettes and Noncombustible Nicotine or Tobacco Products and Generalized Anxiety Disorder Based on Data from the 8th Korea National Health and Nutrition Examination Survey 2021.

Background: Despite the increasing prevalence of anxiety disorders in Korea, there have been no nationwide studies on the association between tobacco status and generalized anxiety disorder (GAD). Furthermore, despite the increasing number of people using noncombustible nicotine or tobacco products (NNTPs), the association between NNTP use and GAD remains unclear. Therefore, this study investigated the association between tobacco use and GAD. Methods: This nationwide study used data from the 8th Korea National Health and Nutrition Examination Survey (2021) and included 5,454 adults aged ≥19 years who self-reported on the tobacco use and mental health sections. Multivariable logistic regression analysis was performed to investigate the odds ratios (ORs) of GAD (Generalized Anxiety Disorder-7 score ≥10) according to tobacco status among Korean adults. The severity of anxiety was assessed using the Generalized Anxiety Disorder-7 scale. Results: Compared to never tobacco users, the ORs of GAD for combustible cigarette smokers and NNTP users were 2.74 (95% confidence interval [CI], 1.66-4.50) and 2.11 (95% CI, 1.16-3.83), respectively. The OR of GAD for former tobacco users was 1.63 (95% CI, 0.98-2.72). Conclusion: Tobacco use (combustible cigarettes and NNTP) was positively associated with GAD. However, in former tobacco users, there was no significant association with GAD when compared with never tobacco users. Given the OR of GAD among tobacco users, it is crucial to pay attention to screening for GAD and implement appropriate early interventions.

Smoking Cessation and Pancreatic Cancer Risk in Individuals With Prediabetes and Diabetes: A Nationwide Cohort Study.

BACKGROUND: Individuals with diabetes and prediabetes are at increased risk of pancreatic cancer. However, little is known about the effects of smoking or smoking cessation on pancreatic cancer risk in individuals with diabetes and prediabetes. We investigated the association between smoking status (particularly smoking cessation) and pancreatic cancer risk according to glycemic status. PATIENTS AND METHODS: This nationwide cohort study included 9,520,629 adults without cancer who underwent the Korean National Health Screening in 2009 and were followed until 2018. Hazard ratios and 95% confidence intervals for pancreatic cancer were estimated after adjusting for potential confounders. RESULTS: During the 78.4 million person-years of follow-up, 15,245 patients were newly diagnosed with pancreatic cancer. Among individuals with diabetes and prediabetes, current smoking synergistically increased pancreatic cancer risk (all P<.01). However, quitters with diabetes and prediabetes had a pancreatic cancer risk comparable to that of never-smokers (all P>.05). For pancreatic cancer in current smokers, quitters, and never-smokers, respectively, the hazard ratios were 1.48 (95% CI, 1.40-1.58), 1.11 (95% CI, 1.03-1.19), and 1.00 (reference) among individuals with normoglycemia; 1.83 (95% CI, 1.70-1.97), 1.28 (95% CI, 1.18-1.39), and 1.20 (95% CI, 1.14-1.26) among individuals with prediabetes; and 2.72 (95% CI, 2.52-2.94), 1.78 (95% CI, 1.63-1.95), and 1.63 (95% CI, 1.54-1.72) among individuals with diabetes. There were no differences in risk between quitters with a <20 pack-year smoking history and never-smokers in all glycemic status groups. CONCLUSIONS: Pancreatic cancer risk synergistically increased in current smokers with diabetes and prediabetes. However, smoking cessation reduced the synergistically increased risk of pancreatic cancer to the level of never-smokers, especially when smoking history was <20 pack-years. More individualized and intensive cancer prevention education should be underscored for individuals at an increased risk of pancreatic cancer beyond the one-size-fits-all approach.

Association between Smoking Cessation and the Risk of Cholangiocarcinoma and Ampulla of Vater Cancer: A Nationwide Cohort Study.

Introduction: The association between smoking cessation and intrahepatic and extrahepatic cholangiocarcinoma (iCCA and eCCA) risk is unclear. Furthermore, the association in individuals with preexisting risk factors is unknown. We aimed to investigate the association between smoking status (especially smoking cessation) and CCA risk according to individuals' glycemic status. Methods: In this nationwide cohort study, 9,520,629 adults without cancer who underwent national health screening by the Korean National Health Insurance Service in 2009 were followed up through 2018. The hazard ratios (HRs) and 95% confidence intervals (CIs) for CCA were estimated after adjusting for potential confounders. Results: During the 78.3 person-years of follow-up, 16,236 individuals were newly diagnosed with CCA. Quitters had a significantly lower risk of iCCA and eCCA compared to current smokers in all glycemic status groups (all p < 0.01). The HRs (95% CIs) for iCCA in current smokers and quitters were 1.33 (1.24-1.43) versus 0.98 (0.90-1.06) in individuals with normoglycemia, 1.49 (1.37-1.63) versus 1.17 (1.06-1.28) in individuals with prediabetes, and 2.15 (1.96-2.37) versus 1.58 (1.42-1.75) in individuals with diabetes, compared to never-smokers with normoglycemia. Current smokers with diabetes or prediabetes had a synergistically increased risk of iCCA (all p < 0.01). However, quitters with diabetes and prediabetes had an iCCA risk comparable to that of never-smokers. Analysis of eCCA yielded similar results. Smoking was not independently associated with the risk of the ampulla of Vater cancer. However, smoking combined with diabetes or prediabetes was associated with an increased risk of the ampulla of Vater cancer (all p < 0.05). Conclusion: Smoking cessation was associated with a reduced risk of CCA, despite the synergistically increased risk in current smokers with diabetes and prediabetes. Our findings suggest a crucial opportunity to reduce the risk of CCA. More individualized and intensive cancer prevention education is needed against CCA.

Increased Risk of Young-Onset Digestive Tract Cancers Among Young Adults Age 20-39 Years With Nonalcoholic Fatty Liver Disease: A Nationwide Cohort Study.

PURPOSE: Although the incidence of young-onset digestive tract cancers is increasing worldwide, their risk factors remain largely unknown. We investigated the association between nonalcoholic fatty liver disease (NAFLD) and young-onset digestive tract cancers. PATIENTS AND METHODS: This nationwide cohort study included 5,265,590 individuals age 20-39 years who underwent national health screening under the Korean National Health Insurance Service between 2009 and 2012. The fatty liver index was used as a diagnostic biomarker for NAFLD. The participants were followed up until December 2018 to determine the incidence of young-onset digestive tract cancers (ie, esophageal, stomach, colorectal, liver, pancreatic, biliary tract, and gallbladder). Multivariable Cox proportional hazards models were conducted to estimate the risk after adjusting for potential confounders. RESULTS: During the 38.8 million person-years of follow-up, 14,565 patients were newly diagnosed with young-onset digestive tract cancers. The cumulative incidence probability of each cancer type was consistently higher in individuals with NAFLD than in those without NAFLD (all log-rank P < .05). NAFLD was associated with an increased risk of overall digestive tract (adjusted hazard ratio [aHR], 1.16; 95% CI, 1.10 to 1.22), stomach (aHR, 1.14; 95% CI, 1.06 to 1.24), colorectal (aHR, 1.14; 95% CI, 1.06 to 1.22), liver (aHR, 1.13; 95% CI, 1.12 to 1.52), pancreatic (aHR, 1.23; 95% CI, 1.09 to 1.40), biliary tract (aHR, 1.29; 95% CI, 1.00 to 1.66), and gallbladder (aHR, 1.53; 95% CI, 1.01 to 2.31) cancer. These associations remained significant regardless of age, sex, smoking status, alcohol consumption, and obesity status (all P < .05; P for interaction >.05). The aHR for esophageal cancer was 1.67 (95% CI, 0.92 to 3.03). CONCLUSION: NAFLD may be an independent, modifiable risk factor for young-onset digestive tract cancers. Our findings suggest a crucial opportunity to reduce premature morbidity and mortality associated with young-onset digestive tract cancers in the next generation.

Threshold dose-response association between smoking pack-years and the risk of gallbladder cancer: A nationwide cohort study.

BACKGROUND AND AIMS: The association between smoking and gallbladder cancer (GBC) risk is unclear. We investigated the association between smoking (including pack-years) and GBC risk. We also examined the combined effects of smoking and diabetes or prediabetes on GBC risk. METHODS: This Korean nationwide cohort study included 9,520,629 adults without cancer who underwent national health screening in 2009 and were followed-up until 2018. Multivariable Cox proportional hazards models were used to determine risk estimates after adjusting for potential confounders. RESULTS: During 78.4 million person-years (mean 8.2 ± 0.9 years) of follow-up, we identified 6066 patients with newly diagnosed GBC. Current and former smokers were associated with increased GBC risk (hazard ratio [HR], 95% confidence interval [CI]: 1.117, 1.029-1.212 and 1.105, 1.016-1.202, respectively). Smoking of 20 to <30 and ≥30 pack-years was independently associated with increased GBC risk compared with never smoking (HR, 95% CI; 1.241, 1.100-1.400 and 1.231, 1.107-1.370, respectively). However, smoking of <10 and 10 to <20 pack-years was not. This threshold dose-response association between smoking pack-years and GBC risk was observed regardless of the glycaemic status (all P < 0.01). Furthermore, smoking of ≥20 pack-years and hyperglycaemia had a synergistic effect on the GBC risk (all P < 0.01). Smokers with ≥20 pack-years with diabetes had the highest risk of GBC compared to never smokers with normoglycaemia (HR, 1.658; 95% CI, 1.437-1.914). CONCLUSIONS: Smoking was associated with increased GBC risk with a threshold dose-response effect for smoking pack-years. The risk of GBC increases synergistically when smoking and hyperglycaemia coexist. More individualised cancer prevention education is required to reduce GBC risk.

Association Between Glycemic Status and the Risk of Kidney Cancer in Men and Women: A Nationwide Cohort Study.

OBJECTIVE: Kidney cancer predominantly affects men, suggesting a biological protection against kidney cancer in women. We investigated the dose-response association between glycemic status and kidney cancer risk in men and women. RESEARCH DESIGN AND METHODS: In this nationwide cohort study, 9,492,331 adults without cancer who underwent national health screening in 2009 were followed up until 31 December 2018. We estimated kidney cancer risk using multivariable Cox proportional hazard regression models after adjusting for potential confounders. RESULTS: During the 78.1 million person-years of follow-up, incident kidney cancer occurred in 8,834 men and 3,547 women. The male-to-female ratio of the incidence rate was 2.1:1 in never-smokers with normoglycemia (17.8 vs. 8.5/100,000 person-years). Among never-smokers, men with diabetes, but not prediabetes, had an increased risk of kidney cancer (adjusted hazard ratio [aHR] 1.25 [95% CI 1.12-1.38] and 1.06 [0.97-1.15], respectively). Among never-smokers, women with both diabetes and prediabetes had an increased risk (aHR 1.34 [95% CI 1.21-1.49] and 1.19 [1.10-1.29], respectively) (Ptrend <0.01). Among smokers, men and women with diabetes had 49% and 85% increased kidney cancer risk (aHR 1.49 [95% CI 1.37-1.61] and 1.85 [1.26-2.73], respectively). CONCLUSIONS: Glycemic status and kidney cancer risk exhibited a dose-response association in women. Diabetes, but not prediabetes, was associated with an increased risk in men. Although women have a lower risk of kidney cancer than men, women with even prediabetes have an increased risk. These findings should not be overlooked when monitoring for kidney complications.

Association between History of Pregnancy and Liver Fibrosis Using Fibrosis-4 Index in Korean Postmenopausal Women: A Nationwide Population-Based Study.

BACKGROUND: The association between a history of pregnancy and liver fibrosis remains unclear. Herein, we investigated the association between reproductive factors, including a history of pregnancy and liver fibrosis, in postmenopausal Korean women. METHODS: This study used nationally representative, population-based data collected from the Korea National Health and Nutrition Examination Survey 2008-2017. Of 14,624 women with natural menopause, 11,085 with no previous history of any type of cancer, hepatitis, or chronic heavy alcohol consumption were enrolled. We investigated the reproductive factors, including a history of pregnancy, total reproductive years, age at menarche and menopause, and oral contraceptive use. Liver fibrosis was defined as a Fibrosis-4 index score ≥2.67 kg/m2. RESULTS: Of the study participants, 372 (3.3%) had advanced liver fibrosis. Multivariable logistic regression analysis showed that women with a history of more than one pregnancy were associated with a lower risk of liver fibrosis compared to women who had never been pregnant, after adjusting for potential confounders (adjusted odds ratio, 0.30; 95% confidence interval, 0.15-0.59). The risk of liver fibrosis did not increase significantly with an increasing number of pregnancies (P for trend=0.135). Other reproductive factors, including total reproductive years, age at menopause and menarche, and oral contraceptive use, were not significantly associated with liver fibrosis. CONCLUSION: Postmenopausal women who had experienced one or more pregnancies had a reduced risk of liver fibrosis. Our findings reveal a potential protective role of pregnancy against liver fibrosis.

Dietary Efficacy Evaluation by Applying a Prediction Model Using Clinical Fecal Microbiome Data of Colorectal Disease to a Controlled Animal Model from an Obesity Perspective.

Obesity associated with a Western diet such as a high-fat diet (HFD) is a known risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this study, we aimed to develop fecal microbiome data-based deep learning algorithms for the risk assessment of colorectal diseases. The effects of a HFD and a candidate food (Nypa fruticans, NF) on IBD and CRC risk reduction were also evaluated. Fecal microbiome data were obtained from 109 IBD patients, 111 CRC patients, and 395 healthy control (HC) subjects by 16S rDNA amplicon sequencing. IBD and CRC risk assessment prediction models were then constructed by deep learning algorithms. Dietary effects were evaluated based on fecal microbiome data from rats fed on a regular chow diet (RCD), HFD, and HFD plus ethanol extracts or water extracts of NF. There were significant differences in taxa when IBD and CRC were compared with HC. The diagnostic performance (area under curve, AUC) of the deep learning algorithm was 0.84 for IBD and 0.80 for CRC prediction. Based on the rat fecal microbiome data, IBD and CRC risks were increased in HFD-fed rats versus RCD-fed rats. Interestingly, in the HFD-induced obesity model, the IBD and CRC risk scores were significantly lowered by the administration of ethanol extracts of NF, but not by the administration of water extracts of NF. In conclusion, changes in the fecal microbiome of obesity by Western diet could be important risk factors for the development of IBD and CRC. The risk prediction model developed in this study could be used to evaluate dietary efficacy.

GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease - Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing.

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.

Light-to-Moderate Alcohol Consumption Increases the Risk of Biliary Tract Cancer in Prediabetes and Diabetes, but Not in Normoglycemic Status: A Nationwide Cohort Study.

PURPOSE: To determine whether the dose-response association between alcohol consumption and the risk of biliary tract cancer (BTC), including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), differs according to glycemic status. PATIENTS AND METHODS: This nationwide cohort study included 9,520,629 individuals age ≥ 20 years without a history of cancer who underwent national health screening under the Korean National Health Insurance Service in 2009. The participants were followed up until December 2018 for BTC development. Cox proportional hazard regression analysis was performed to estimate risk. RESULTS: During the 78.3 million person-years of follow-up, 21,079 patients were newly diagnosed with BTC. In individuals with prediabetes and diabetes, light-to-moderate alcohol consumption increased the risk of CCA (adjusted hazard ratio [aHR], 1.20; 95% CI, 1.13 to 1.28 and aHR, 1.58; 95% CI, 1.47 to 1.69) and GBC (aHR, 1.18; 95% CI, 1.07 to 1.31 and aHR, 1.45; 95% CI, 1.28 to 1.64). In normoglycemic individuals, light-to-moderate alcohol consumption was not associated with CCA or GBC risk. When heavy alcohol consumption was combined with diabetes, CCA and GBC risk increased synergistically (aHR, 2.04; 95% CI, 1.83 to 2.26; and aHR, 1.65; 95% CI, 1.33 to 2.04, respectively; all P < .001). Prediabetes and heavy alcohol consumption had a synergistic interactive effect on CCA and GBC risks (all P < .001). Comparable results were obtained for intrahepatic and extrahepatic CCA analyses. CONCLUSION: Even light-to-moderate alcohol consumption was associated with an increased risk of BTC in individuals with prediabetes and diabetes, but not in normoglycemic individuals. Complete avoidance of alcohol consumption may help reduce the risk of BTC in patients with prediabetes and diabetes, suggesting the need for individualized prevention strategies for BTC.

Obesity and abdominal obesity are risk factors for airway obstructive diseases in Korean women: nationwide population-based cohort study.

OBJECTIVE: Existing studies show that women are more susceptible to chronic obstructive pulmonary disease (COPD) and asthma, and that obesity affects the risk of these airway obstructive diseases. We aimed to determine the effect of body mass index (BMI) and waist circumference (WC) on COPD and asthma development in premenopausal and postmenopausal women. METHODS: This nationwide population-based cohort study included 1,644,635 women ages ≥30 years without diagnosis of COPD or asthma, who underwent national cancer screening in 2009. We classified them as premenopausal and postmenopausal women based on their menopause status at the time of cancer screening. Baseline BMI and WC were measured, and they were classified into five BMI groups (<18.5 kg/m2, 18.5-23 kg/m2, 23-25 kg/m2, 25-30 kg/m2, and ≥30 kg/m2) and WC groups (<60 cm, 65-75 cm, 75-85 cm, 85-95 cm, and ≥95 cm). The hazard ratios (HRs) for COPD and asthma were measured for each group. RESULTS: Regardless of the menopausal status, the high BMI and WC groups had a significantly higher COPD and asthma incidence than that of the normal group, and the HRs increased further with increases in BMI and WC. However, the HR in the underweight group was significantly higher among the postmenopausal women. The HR for asthma in the obese group was significantly higher for both premenopausal and postmenopausal women. The HR for COPD was significantly higher in the group with a WC of ≥95 cm for both premenopausal and postmenopausal women, respectively; the HR for asthma was also significantly higher in this group. CONCLUSIONS: Obesity and abdominal obesity are risk factors for COPD and asthma in premenopausal and postmenopausal Korean women. Controlling weight and maintaining a healthy body shape can help prevent COPD and asthma in women.

Increased risk of pancreatic cancer in individuals with non-alcoholic fatty liver disease.

The association between non-alcoholic fatty liver disease (NAFLD) and the risk of pancreatic cancer in the general population remains unclear. This nationwide cohort study included 8,120,674 adults who underwent a national health screening in 2009 from the Korean National Health Insurance Service database. Participants were followed-up until December 2017 for the development of pancreatic cancer. NAFLD was assessed using the fatty liver index: ≥ 60, NAFLD and < 30, no NAFLD. Multivariable Cox proportional hazards regression was performed. During the follow-up of 59.1 million person-years, 10,470 participants were newly diagnosed with pancreatic cancer. NAFLD was significantly associated with an increased risk of pancreatic cancer compared to no NAFLD (adjusted hazard ratio [aHR], 1.17; 95% CI 1.09-1.26). This association was significant in both the obese (aHR, 1.14; 95% CI 1.05-1.23) and non-obese groups (aHR, 1.14; 95% CI 1.003-1.29). Individuals with fatty liver index 30-59 also had an increased risk (aHR, 1.10; 95% CI 1.05-1.16). The risk of pancreatic cancer increased with increasing fatty liver index scores (P for trend < 0.001). This study demonstrated that NAFLD was independently associated with an increased risk of pancreatic cancer, regardless of obesity. Our finding suggests that NAFLD may be a modifiable risk factor for pancreatic cancer.

Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND ): Time to Move Beyond the Skin.

BACKGROUND: Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. OBJECTIVE: The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. METHODS: In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. RESULTS: We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. CONCLUSIONS: We introduce NERDND as adult-onset neurodegeneration (ND ) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Longitudinal Retrospective Observational Study on Obesity Indicators and the Risk of Impaired Fasting Glucose in Pre- and Postmenopausal Women.

The impact of obesity could differ according to menopausal status since women undergo significant physiologic and metabolic changes due to menopause. We investigated the association between various major obesity indicators and the risk of impaired fasting glucose (IFG) according to menopausal status using nationally representative data. A total of 571,286 premenopausal and 519,561 postmenopausal women who underwent both Korean National Health Insurance Service (NHIS) cancer screening in 2009 and health check-ups in 2017 were analyzed. Multivariate logistic regression analyses were used to assess the effect of independent variables of body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR) in 2009, on dependent variable IFG in 2017. After adjusting for potential confounders, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of developing IFG were analyzed. In the premenopausal group, the OR of obese BMI (≥25 kg/m2, <30 kg/m2) women was increased to 2.228 (95% CI: 2.139−2.321) compared to the normal BMI (≥18.5, <23 kg/m2) women as a reference. In the postmenopausal group, there was also a higher OR of 1.778 (95% CI: 1.715−1.843) in the obese BMI women compared to the normal group. A similar association of increasing ORs for IFG was shown in both groups when stratified by WC and WHtR. This nationwide study revealed that obesity and abdominal obesity, defined by various obesity indicators, consistently increased odds of acquiring IFG after 8 years in both pre- and postmenopausal groups, with the association being more robust in the premenopausal group. Our findings suggest that weight management and lifestyle modification may require more attention in premenopausal women.

Association between alcohol consumption and pancreatic cancer risk differs by glycaemic status: A nationwide cohort study.

BACKGROUND: The dose-response association between alcohol consumption and the subsequent pancreatic cancer risk by individuals' glycaemic status is unclear. RESEARCH DESIGN AND METHOD: This large-scale nationwide cohort study included 9,514,171 adults without cancer who underwent health examinations under the Korean National Health Insurance Service in 2009 and were followed-up until December 2017 for pancreatic cancer development. Multivariable Cox proportional hazards regression analysis was performed. RESULTS: During a median follow-up period of 7.3 years, 12,818 patients were newly-diagnosed with pancreatic cancer. Among individuals with normoglycemia, a J-shaped association was observed between the frequency of alcohol consumption (1-2 and ≥5 days/week: hazards ratio [HR]; 95% CI, 0.91; 0.85-0.97 and 1.13; 1.002-1.27, respectively) and pancreatic cancer risk, after adjusting for potential confounders. However, in patients with impaired fasting glucose (IFG), pancreatic cancer risk increased with increased frequency and average daily amount of alcohol consumption (all P for trend <0.01). IFG combined with heavy alcohol consumption (30 g/day) was associated with 38% increased pancreatic cancer risk (HR, 1.38; 95% CI, 1.23-1.54). Diabetes was associated with an increased pancreatic cancer risk regardless of alcohol consumption and 70% increased risk even in non-drinkers (HR, 1.70; 95% CI, 1.61-1.80). CONCLUSIONS: The J-shaped dose-response association between alcohol consumption and pancreatic cancer risk was observed only in individuals with normoglycemia, not in patients with IFG and diabetes. Complete alcohol abstinence may help reduce pancreatic cancer risk in patients with IFG and diabetes.

Changes in Metabolic Syndrome Status are Associated With Altered Risk of Pancreatic Cancer: A Nationwide Cohort Study.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is reversible; however, the effect of changes in MetS status on pancreatic cancer risk is unknown. We aimed to investigate the effects of changes and persistence in MetS status on pancreatic cancer risk. METHODS: This nationwide cohort study included 8,203,492 adults without cancer who underwent 2 consecutive biennial health screenings provided by the Korean National Health Insurance System between 2009 and 2012 and were followed up until 2017. MetS was defined as the presence of 3 of its 5 components, which were evaluated at 2 consecutive biennial health screenings. Participants were categorized into the MetS-free, MetS-recovered, MetS-developed, or MetS-persistent group. Multivariable Cox proportional hazards regression models were used. RESULTS: During the 40,464,586 person-years of follow-up (median, 5.1 years), 8010 individuals developed pancreatic cancer. Compared with the MetS-free group, the MetS-persistent group had the highest risk of pancreatic cancer (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.23-1.37), followed by the MetS-developed group (HR, 1.17; 95% CI, 1.09-1.25) and the MetS-recovered group (HR, 1.12; 95% CI, 1.04-1.21) after adjusting for potential confounders (P for trend <.001). The MetS-recovered group was associated with a lower risk of pancreatic cancer than that in the MetS-persistent group (P < .001). The association between changes in MetS status and pancreatic cancer risk did not differ according to sex or obesity (all P for interactions >.05). CONCLUSIONS: In this study, recovering from MetS was associated with a reduced risk of pancreatic cancer compared with persistent MetS, suggesting that pancreatic cancer risk can be altered by changes in MetS.

Detection of mobile elements insertions for routine clinical diagnostics in targeted sequencing data.

BACKGROUND: Targeted sequencing approaches such as gene panel or exome sequencing have become standard of care for the diagnosis of rare and common genetic disease. The detection and interpretation of point mutations, small insertions and deletions, and even exon-level copy number variants are well established in clinical genetic testing. Other types of genetic variation such as mobile elements insertions (MEIs) are technically difficult to detect. In addition, their downstream clinical interpretation is more complex compared to point mutations due to a larger genomic footprint that can not only predict a clear loss of protein function but might disturb gene regulation and splicing even when located within the non-coding regions. As a consequence, the contribution of MEIs to disease and tumor development remains largely unexplored in routine diagnostics. METHODS: In this study, we investigated the occurrence of MEIs in 7,693 exome datasets from individuals with rare diseases and healthy relatives as well as 788 cancer patients analyzed by panel sequencing. RESULTS: We present several exemplary cases highlighting the diagnostic value of MEIs and propose a strategy for the detection, prioritization, and clinical interpretation of MEIs in routine clinical diagnostics. CONCLUSION: In this paper, we state that detection and interpretation of MEIs in clinical practice in targeted NGS data can be performed relatively easy despite the fact that MEIs very rarely occur in coding parts of the human genome. Large scale reanalysis of MEIs in existing cohorts may solve otherwise unsolvable cases.