Deciphering head and neck cancer microenvironment: Single-cell and spatial transcriptomics reveals human papillomavirus-associated differences.

Human papillomavirus (HPV) is a major causative factor of head and neck squamous cell carcinoma (HNSCC), and the incidence of HPV- associated HNSCC is increasing. The role of tumor microenvironment in viral infection and metastasis needs to be explored further. We studied the molecular characteristics of primary tumors (PTs) and lymph node metastatic tumors (LNMTs) by stratifying them based on their HPV status. Eight samples for single-cell RNA profiling and six samples for spatial transcriptomics (ST), composed of matched primary tumors (PT) and lymph node metastases (LNMT), were collected from both HPV- negative (HPV- ) and HPV-positive (HPV+ ) patients. Using the 10x Genomics Visium platform, integrative analyses with single-cell RNA sequencing were performed. Intracellular and intercellular alterations were analyzed, and the findings were confirmed using experimental validation and publicly available data set. The HPV+ tissues were composed of a substantial amount of lymphoid cells regardless of the presence or absence of metastasis, whereas the HPV- tissue exhibited remarkable changes in the number of macrophages and plasma cells, particularly in the LNMT. From both single-cell RNA and ST data set, we discovered a central gene, pyruvate kinase muscle isoform 1/2 (PKM2), which is closely associated with the stemness of cancer stem cell-like populations in LNMT of HPV- tissue. The consistent expression was observed in HPV- HNSCC cell line and the knockdown of PKM2 weakened spheroid formation ability. Furthermore, we found an ectopic lymphoid structure morphology and clinical effects of the structure in ST slide of the HPV+ patients and verified their presence in tumor tissue using immunohistochemistry. Finally, the ephrin-A (EPHA2) pathway was detected as important signals in angiogenesis for HPV- patients from single-cell RNA and ST profiles, and knockdown of EPHA2 declined the cell migration. Our study described the distinct cellular composition and molecular alterations in primary and metastatic sites in HNSCC patients based on their HPV status. These results provide insights into HNSCC biology in the context of HPV infection and its potential clinical implications.

Surgical Outcomes in Non-Small Cell Lung Cancer with Distant Metastasis: The Prognostic Significance of Delayed Metastasis Diagnosis.

BACKGROUND: The diagnosis of distant metastasis on preoperative examinations for non-small cell lung cancer (NSCLC) can be challenging, leading to surgery for some patients with uncertain metastasis. This study evaluated the prognostic impact of delayed diagnosis of metastasis on patients who underwent upfront surgery. METHODS: The study enrolled patients who underwent lobectomy or pneumonectomy for NSCLC between June 2010 and December 2017 and evaluated the presence of distant metastasis before surgery. Overall survival (OS) for patients with stage IV cancer was compared with that for patients without metastasis, and the prognostic factors were analyzed. RESULTS: Of 3046 patients (mean age, 63 years; 1770 men), 100 (3.3 %) had distant metastasis, diagnosed preoperatively in 1.4 % (42/3046) and postoperatively in 1.9 % (58/3046) of the patients. The two most common metastasis sites diagnosed after surgery were contralateral lung (22/58, 37.9 %) and ipsilateral pleura (16/58, 27.6 %). The OS (median, 42.7 months) for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer (P = 0.865), whereas the OS (median OS, 91.7 months) for the patients with stage IV cancer diagnosed preoperatively was better than for the patients with stage IIIB cancer (P = 0.001). Among the patients with distant metastasis, squamous cell type (hazard ratio [HR], 3.15; P = 0.002) and systemic treatment for metastasis (HR, 2.42; P = 0.002) were independent predictors of worse OS. CONCLUSIONS: Among NSCLC patients undergoing upfront surgery, the OS for the patients with stage IV cancer diagnosed postoperatively was comparable with that for the patients with stage IIIB cancer. For patients with stage IV disease, squamous cell type and systemic treatment for metastasis were prognostic factors for poorer OS.

Effects of disability-related limitations in daily living on unmet needs: a longitudinal-study1.

BACKGROUND: Unmet health needs are particularly important to people with disabilities; however, these unmet needs owing to limitations in daily life have been under-researched thus far. This study examined the effects of disability-related limitations in daily life on unmet needs. METHODS: This study included 5,074 adults with disabilities from the 2018-2020 Korea Disability and Life Dynamics Panel. We analyzed the effects of disability-related limitations in daily life on unmet needs using logistic regression with a generalized estimating equation model. RESULTS: Overall, 4.8% men and 4.6% women with disabilities had unmet needs. For men, unmet needs were 1.46 times (95% confidence interval [CI] 1.09-1.96) higher for those with moderate limitations in daily life. For women, unmet needs were 1.79 times (95% CI 1.22-2.39) higher when there were moderate limitations in daily life. The prominent factors causing this effect were physical or brain lesion disability for men and internal or facial disability and burden of medical expenses for women. CONCLUSIONS: Limitations in daily life due to disability increase the risk of having unmet needs, an effect that is significantly more pronounced in men. These unmet needs differ depending on an individual's sex, disability type, limited body parts, and other specific causes. Efforts are required to reduce the unmet needs of people with disabilities by considering the type of disability, impaired body parts, and causes of unmet needs in daily life.

Cardiovascular disease risk and associated physical activity factors in gastrointestinal cancer survivors.

INTRODUCTION: Although the risk of CVD is increased in cancer survivors, few studies have investigated the CVD risk in survivors of gastrointestinal (GI) cancer. Therefore, we evaluated the CVD risk using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score for GI cancer survivors and associated physical activity factors. METHODS: Using the 2014-2019 Korean National Health and Nutrition Examination Surveys, data were collected for 262 GI cancer survivors and 1,310 cancer-free controls matched at a 1:5 ratio based on age and sex. The International Physical Activity Questionnaire Short-Form was used to assess physical activity, and the Euro QoL Questionnaire 5-Dimensional Classification (EQ-5D) was used to assess the health-related quality of life. RESULTS: A multiple logistic regression analysis demonstrated a lower risk of ASCVD in GI cancer survivors than in controls (adjusted odds ratio [aOR] = 0.73, 95% confidence interval [CI] = 0.55-0.97). Moreover, the risk of having a high ASCVD score was significantly lower in individuals who performed sufficient aerobic physical activity (aOR = 0.59, 95% CI = 0.47-0.75) and those with an EQ-5D score 1 or 2 (aOR = 0.36, 95% CI = 0.20-0.65 and aOR = 0.31, 95% CI = 0.16-0.58, respectively). CONCLUSIONS: This population-based study demonstrated that engaging in sufficient physical activity can reduce the ASCVD risk among GI cancer survivors.

A Causality Assessment Framework for COVID-19 Vaccines and Adverse Events at the COVID-19 Vaccine Safety Research Center.

During the coronavirus disease 2019 (COVID-19) pandemic, conclusively evaluating possible associations between COVID-19 vaccines and potential adverse events was of critical importance. The National Academy of Medicine of Korea established the COVID-19 Vaccine Safety Research Center (CoVaSC) with support from the Korea Disease Control and Prevention Agency to investigate the scientific relationship between COVID-19 vaccines and suspected adverse events. Although determining whether the COVID-19 vaccine was responsible for any suspected adverse event necessitated a systematic approach, traditional causal inference theories, such as Hill's criteria, encountered certain limitations and criticisms. To facilitate a systematic and evidence-based evaluation, the United States Institute of Medicine, at the request of the Centers for Disease Control and Prevention, offered a detailed causality assessment framework in 2012, which was updated in the recent report by the National Academies of Sciences, Engineering, and Medicine (NASEM) in 2024. This framework, based on a weight-of-evidence approach, allows the independent evaluation of both epidemiological and mechanistic evidence, culminating in a comprehensive conclusion about causality. Epidemiological evidence derived from population studies is categorized into four levels-high, moderate, limited, or insufficient-while mechanistic evidence, primarily from biological and clinical studies in animals and individuals, is classified as strong, intermediate, weak, or lacking. The committee then synthesizes these two types of evidence to draw a conclusion about the causal relationship, which can be described as "convincingly supports" ("evidence established" in the 2024 NASEM report), "favors acceptance," "favors rejection," or "inadequate to accept or reject." The CoVaSC has established an independent committee to conduct causality assessments using the weight-of-evidence framework, specifically for evaluating the causality of adverse events associated with COVID-19 vaccines. The aim of this study is to provide an overview of the weight-of-evidence framework and to detail the considerations involved in its practical application in the CoVaSC.

Bodily experiences of trauma and psychosis risk.

Bodily self-disturbances including anomalous embodiment of emotions are observed in psychosis-spectrum conditions. Psychosis is also associated with trauma exposure but the relationship between altered bodily experiences and trauma has not been extensively investigated in individuals at risk for psychosis (HR). We implemented a mapping task to localize felt sensations associated with trauma. Results show that trauma experiences were always localized in the body. HR reported increased rates of traumatic experiences than low-risk group (LR). HR reported sensations associated with trauma across widespread body areas. Further research is needed to elucidate how trauma might lead to psychotic-like experiences via bodily self-disturbances.

Concomitant Use of Sodium-Glucose Cotransporter 2 Inhibitors and Overactive Bladder Drugs and the Risk of Urinary Tract Infection.

Concomitant use of sodium glucose cotransporter-2 inhibitors (SGLT-2i) and overactive bladder (OAB) drugs potentially poses a risk of urinary tract infections (UTIs) due to the urinary retention of highly concentrated glucose in the urine. Thus, this study aimed to investigate the risk of UTIs among patients who initiated SGLT-2i treatment while taking OAB drugs. This population-based cohort study included new-users of SGLT-2i or comparator antidiabetics (dipeptidyl peptidase-4 inhibitor (DPP-4i); glucagon-like peptide-1 receptor agonist (GLP-1RA)) with OAB drugs between 2014 and 2020 using claim data from Korea. Primary outcome was a composite UTI event composite end point comprising pyelonephritis, cystitis, and urethritis, using both inpatient and outpatient diagnoses. Propensity score fine stratification was used to adjust for potential confounding factors. Weighted hazard ratios (HR) were calculated using the Cox proportional hazards model. In the first cohort, 796 and 9,181 new-users of SGLT-2i and DPP-4i with OAB drugs were identified, respectively. This study found a similar risk of UTIs in concomitant users of SGLT-2i and DPP-4i (weighted HR 1.08, 95% confidence interval: 0.88-1.32) with OAB drugs. In the second cohort, 2,387 and 280 new-users of SGLT-2i and GLP-1RA with OAB drugs were identified, respectively. Initiation of SGLT-2i while on OAB treatment was not associated with increased risk of UTI (0.89, 0.50-1.60), compared with initiation of GLP-1RA. These results show that the concomitant use of SGLT-2i with OAB drugs was not associated with an increased risk of UTI compared with the concomitant use of DPP-4i or GLP-1RA with OAB drugs.

Depressive symptoms of people living in areas with high exposure to environmental noise: a multilevel analysis.

Exposure and damage caused by noise have been reported in many countries around the world. However, few nationwide studies explored the association of residential environmental noise with depressive symptoms, this study aims to examine this association. The Korean Community Health Survey at the individual-level and the Korean Environmental Noise Measurement Database at the regional-level were used. A total of 30,630 individuals were eligible for the analysis. Multilevel model framework was applied to account for the clustered structure of the regional-level data in which individual-level data containing demographic characteristics and health information were nested. As a result of the analysis, Individuals living in the highest environmental noise area had a 1.55 times higher likelihood of experiencing depressive symptoms than those living in the lowest environmental noise area (95% CI, 1.04-2.31). After stratified analysis according to depressive symptom severity, individuals residing in areas with the highest environmental noise exposure had significantly higher odds of mild (aOR, 1.46; 95% CI, 1.02-2.07) and moderate symptoms (aOR, 1.70; 95% CI, 1.00-2.91). In conclusion, the higher the residential environmental noise, the higher the possibility of mild-to-moderate depressive symptoms. Our findings suggest the need for continued attention to and management of noise pollution, which has the potential to adversely affect individual's mental health.

The Effect of Time Spent on Online Gaming on Problematic Game Use in Male: Moderating Effects of Loneliness, Living Alone, and Household Size.

OBJECTIVE: This study aimed to investigate the association between gaming time and problematic game use (PGU) within a large sample of Korean male gamers and to examine the potential moderating effects of loneliness, living alone, and household size. METHODS: This study employed data from 743 male gamers from the National Mental Health Survey 2021, a nationally representative survey of mental illness conducted in South Korea. Self-reported data on the average gaming time per day, severity of PGU, loneliness, living alone, and household size were used. RESULTS: Gaming time was positively associated with PGU and this relationship was significantly moderated by loneliness such that the positive effect of gaming time on PGU was greater when the levels of loneliness were high. The three-way interaction effect of gaming time, loneliness, and living alone was also significant, in that the moderating effect of loneliness on the relationship between gaming time and PGU was significant only in the living alone group. However, household size (i.e., number of housemates) did not moderate the interaction between gaming time and loneliness among gamers living with housemates. CONCLUSION: These results suggest the importance of considering loneliness and living arrangements of male gamers, in addition to gaming time, in identifying and intervening with individuals at heightened risk of PGU.

Cardiovascular safety of evogliptin dual and triple therapy in patients with type 2 diabetes: a nationwide cohort study.

OBJECTIVE: To investigate the risk of cardiovascular events associated with commonly used dual and triple therapies of evogliptin, a recently introduced dipeptidyl peptidase-4 inhibitor (DPP4i), for managing type 2 diabetes in routine clinical practice. DESIGN: A retrospective cohort study. SETTING: Korean Health Insurance Review and Assessment database. PARTICIPANTS: Patients who initiated metformin-based dual therapy and metformin+sulfonylurea-based triple therapy in South Korea from 2014 to 2018. INTERVENTIONS: Initiation of combination therapy with evogliptin. PRIMARY AND SECONDARY OUTCOME MEASURES: Hazards of cardiovascular events, a composite endpoint of myocardial infarction, heart failure and cerebrovascular events, and its individual components. Cox proportional hazards model with propensity score-based inverse probability of treatment weighting were used to estimate HRs and 95% CIs. RESULTS: From the dual and triple therapy cohorts, 5830 metformin+evogliptin users and 2198 metformin+sulfonylurea+evogliptin users were identified, respectively. Metformin+evogliptin users, as compared with metformin+non-DPP4i, had a 29% reduced risk of cardiovascular events (HR 0.71, 95% CI 0.62 to 0.82); HRs for individual outcomes were cerebrovascular events (0.71, 95% CI 0.53 to 0.95), heart failure (0.70, 95% CI 0.59 to 0.82), myocardial infarction (0.89, 95% CI 0.60 to 1.31). Metformin+sulfonylurea+evogliptin users, compared with metformin+sulfonylurea+non-DPP4i, had a 24% reduced risk of cardiovascular events (0.76, 95% CI 0.59 to 0.97); HRs for individual outcomes were myocardial infarction (0.57, 95% CI 0.27 to 1.19), heart failure (0.74, 95% CI 0.55 to 1.01), cerebrovascular events (0.96, 95% CI 0.61 to 1.51). CONCLUSIONS: These findings suggest that dual or triple therapies of evogliptin for the management of type 2 diabetes in routine clinical practice present no cardiovascular harms, but could alternatively offer cardiovascular benefits in this patient population.

Gastric and colorectal cancer incidence attributable to dietary factors in Korea.

Background: Dietary factors play a role in the etiology of gastrointestinal cancer. We aimed to estimate the burden of gastric and colorectal cancer that can be attributable to dietary factors in adults aged 20 years and older in Korea in 2018. Methods: Dietary intakes in 2000 were estimated using data from the 2001, 2005, and 2007-2018 Korea National Health and Nutrition Examination Survey (KNHANES). For counterfactual scenarios, the optimal level of intake suggested by the Global Burden of Disease (GBD) study was used if it was available. Otherwise, the average intake values of reference groups among published studies globally were used. Relative risks (RRs) were pooled through dose-response meta-analyses of Korean studies. Results: In Korea in 2018, an estimated 18.6% of gastric cancer cases and 34.9% of colorectal cancer cases were attributed to the combined effect of evaluated dietary factors. High intake of salted vegetables accounted for 16.0% of gastric cancer cases, followed by salted fish at 2.4%. Low intakes of whole grains (16.6%) and milk (13.7%) were leading contributors to colorectal cancer cases, followed by high intakes of processed meat (3.1%) and red meat (5.9%), and a low intake of dietary fiber (0.5%). Conclusions: These results suggest that a considerable proportion of gastric and colorectal cancer incidence might be preventable by healthy dietary habits in Korea. However, further research is needed to confirm the associations between dietary factors and gastric and colorectal cancers in Korea and to formulate and apply effective cancer prevention strategies to Koreans.

Long-Term Use of Oral Corticosteroids and Safety Outcomes for Patients With Atopic Dermatitis.

Importance: The use of oral corticosteroids for prolonged periods may be associated with adverse events (AEs). Nevertheless, the risk of AEs with oral corticosteroids, especially among patients with atopic dermatitis (AD), has not been comprehensively investigated and lacks evidence on duration of treatment. Objective: To assess the association between long-term exposure to oral corticosteroids and AEs among adult patients with AD. Design, Setting, and Participants: This nested case-control study used data from the Health Insurance Review and Assessment Service database of South Korea between January 1, 2012, and October 31, 2021, which included 1 year prior to the cohort entry date of January 1, 2013, for assessing exclusion criteria and baseline characteristics, and 1 year after the study end date of October 31, 2020, to ensure a minimum duration for assessing exposure. Among the population of adults with AD, patients diagnosed with any of 11 AEs were matched with patients who had never received a diagnosis of any of the 11 AEs. Exposure: Long-term use of oral corticosteroids was defined as cumulative supply of more than 30 days or more than 90 days of oral corticosteroid prescription per year. Main Outcomes and Measures: We used multivariable conditional logistic regression analyses to measure the risk of 11 individual outcomes (osteoporosis, fracture, type 2 diabetes, hyperlipidemia, hypertension, myocardial infarction, stroke, heart failure, avascular necrosis, cataract, or glaucoma) as the composite outcome, controlling for potential confounders. We further classified the composite outcome to individual outcomes to evaluate the AE-specific risk. Results: Among 1 025 270 patients with AD between 2013 and 2020, 164 809 cases (mean [SD] age, 39.4 [14.8]; 56.9% women) were matched with 328 303 controls (mean [SD] age, 39.3 [14.7]; 56.9% women) for sex, age, cohort entry date, follow-up duration, and severity of AD, where the balance of most baseline characteristics was achieved. A total of 5533 cases (3.4%) and 10 561 controls (3.2%) were exposed to oral corticosteroids for more than 30 days, while 684 cases (0.4%) and 1153 controls (0.4%) were exposed to oral corticosteroids for more than 90 days. Overall, there was no increased risk of AEs with use of oral corticosteroids for more than 30 days (adjusted odds ratio [AOR], 1.00; 95% CI, 0.97-1.04), whereas the risk was slightly higher with use of oral corticosteroids for more than 90 days (AOR, 1.11; 95% CI, 1.01-1.23). The small elevation in experiencing an AE was observed with each cumulative or consecutive year of ever long-term use. Conclusions and Relevance: This case-control study found a slightly increased risk of AEs associated with use of oral corticosteroids for more than 90 days per year, which warrants future research to fully elucidate the observed findings.

Association between prenatal antipsychotic exposure and the risk of attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review and meta-analysis.

The paucity of evidence regarding the safety of gestational antipsychotic exposure has led to treatment discontinuation in pregnant women with severe mental health conditions. This systematic review and meta-analysis aimed to summarise the current evidence on the association between gestational antipsychotic exposure and attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children (Study protocol registered in PROSPERO:CRD42022311354). Five studies included in our meta-analysis with around 8.6 million pregnancy episodes in nine different countries/regions. Results from our meta-analysis indicate that the heightened risks of ASD and ADHD in children gestationally exposed to antipsychotics appear to be attributable to maternal characteristics, rather than having a causal relationship with the antipsychotic exposure during pregnancy. The results underscore the importance of meticulously monitoring the neurodevelopment of children born to mothers with mental illnesses, which can facilitate early interventions and provide requisite support.

Identification of acute myocardial infarction and stroke events using the National Health Insurance Service database in Korea.

OBJECTIVES: The escalating burden of cardiovascular disease (CVD) is a critical public health issue worldwide. CVD, especially acute myocardial infarction (AMI) and stroke, is the leading contributor to morbidity and mortality in Korea. We aimed to develop algorithms for identifying AMI and stroke events from the National Health Insurance Service (NHIS) database and validate these algorithms through medical record review. METHODS: We first established a concept and definition of "hospitalization episode," taking into account the unique features of health claims-based NHIS database. We then developed first and recurrent event identification algorithms, separately for AMI and stroke, to determine whether each hospitalization episode represents a true incident case of AMI or stroke. Finally, we assessed our algorithms' accuracy by calculating their positive predictive values (PPVs) based on medical records of algorithm- identified events. RESULTS: We developed identification algorithms for both AMI and stroke. To validate them, we conducted retrospective review of medical records for 3,140 algorithm-identified events (1,399 AMI and 1,741 stroke events) across 24 hospitals throughout Korea. The overall PPVs for the first and recurrent AMI events were around 92% and 78%, respectively, while those for the first and recurrent stroke events were around 88% and 81%, respectively. CONCLUSIONS: We successfully developed algorithms for identifying AMI and stroke events. The algorithms demonstrated high accuracy, with PPVs of approximately 90% for first events and 80% for recurrent events. These findings indicate that our algorithms hold promise as an instrumental tool for the consistent and reliable production of national CVD statistics in Korea.

The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.