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Background: Research investigating differences in the overall stroke risk between individuals with and without immune thrombocytopenia (ITP) is lacking. Methods: This real-world study used the National Health Insurance Research Database (NHIRD). Risk of stroke was compared between 13,085 individuals with ITP enrolled between 1 January 2000 and 31 December 2015 and a control cohort of 52,340 individuals without ITP (1:4 ratio propensity score–matched by age, sex, index year, relevant comorbidities, and medications). Sub-distribution hazards models were used to estimate adjusted sub-distribution hazard ratio (SHR) and 95% confidence intervals (CIs), with the non-ITP group as the control group. Results: Of the 65,425 participants, 13,085 had ITP, 63.3% were women, and the mean age was 52.59 years. The risk of both ischemic and hemorrhagic stroke was 1.14 times (adjusted SHR 1.14, 95% CI, 1.07–1.22) and 1.93 times (adjusted SHR 1.93, 95% CI, 1.70–2.20) higher in the ITP group than in controls. Patients with ITP in the 20- to 29-year subgroup had a higher risk of new-onset stroke (adjusted SHR, 4.06 (95% CI, 2.72–6.07), p value for interaction Conclusions: ITP is associated with increased risk of both ischemic and hemorrhagic stroke.

Objective: Obstructive sleep apnea (OSA), with daytime drowsiness, nocturnal hypoxia, could result in systemic inflammation and oxidative damage. We hypothesize that parental OSA, with chronic systemic inflammation and oxidative stress, might contribute to children’s neurodevelopmental disorders, such as ADHD. Method: By linking National Birth Registry with the National Health Insurance Research Database, Taiwan, we identified 2006–2015 birth cohort, which comprised 1,723,873 singleton live births, and conducted a nested case-control study. We included children with ADHD and compared them with non-ADHD controls matched with ADHD case on index date. Conditional logistic regression was utilized to calculate adjusted odds ratio (aOR) when investigating the association between parental diseases with risk of ADHD in their offspring. Results: The aOR (95% CI) of offspring’s ADHD was 1.758 (1.458–2.119) with paternal OSA and 2.159 (1.442–3.233) with maternal OSA. The subgroup analysis revealed different effects of parental diseases among children’s gender. Conclusion: Our study demonstrates an association in parental OSA and offspring ADHD, which could inspire further research to clarify the mechanisms.

Background ALKBH1 is an important enzyme involved in various cellular processes that regulates RNA demethylation in humans. While its contribution to tumor progression is known, its role in gastric cancer remains unclear. Further research is needed to explore the potential of ALKBH1 in clinicopathology, tumor immune microenvironment, and precision oncology for STAD. Methods This study used a multi-omics approach to identify ALKBH1 as an independent diagnostic biomarker for STAD with a correlation to advanced clinical status and poor overall survival rate. We analyzed publicly available datasets from GEO and TCGA, identifying differentially expressed genes in STAD and examined their relationship with immune gene expression, overall survival, tumor stage, gene mutation status, and infiltrating immune cells. We also explored ALKBH1 gene expression in different regions of the STAD using spatial transcriptomics. In addition, we utilized spatial transcriptomic and single-cell RNA-sequencing methods to investigate the correlation between PGAM1 and immune cells. We further confirmed our results by analyzing 60 STAD patient samples and examining the relationship between ALKBH1 expression, clinicopathological features, and prognosis using immunohistochemistry and bioinformatics. Results Our study revealed the expression of key gene regulators in gastric cancer that were associated with genetic variations, deletions, and the tumor microenvironment. Mutations in these regulators were positively linked to distinct immune cells in six immune datasets and played a vital role in immune cell infiltration in STAD. We found that high ALKBH1 expression was associated with macrophage infiltration in STAD. Moreover, pharmacogenomic analysis of renal cancer cell lines indicated that ALKBH1 inactivation was correlated with increased sensitivity to specific small-molecule drugs. Conclusion To sum up, the study indicates that alterations in ALKBH1 may play a role in STAD advancement and reveal new diagnostic and prognostic implications of ALKBH1 in STAD. It emphasizes the importance of ALKBH1 in the tumor immune microenvironment, implying its potential utility as a precision medicine tool and for drug screening in STAD.

Atopic dermatitis(AD) is a common inflammatory skin disorder induced by dysfunction of immune suppression, which resembles the mechanism of autoimmune diseases. To explore the association between autoimmune diseases and AD in their children, we linked the birth data from National Birth Registry with National Health Insurance Research Database. Demographic characteristics from 1174,941 parent-child linkages were obtained. There were 312,329 children diagnosed with AD before 5 years old, and they would be compared with the other 862,612 children without AD in the control group. Conditional logistic regression was utilized to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI). After adjusting infant’s characteristics, perinatal factors, and other parental diseases, the odds ratio of parental rheumatoid arthritis(RA) was 2.269 (95% CI 1.333–3.861) and parental psoriasis was1.610 (95% CI, 1.094–2.369). Parental allergic diseases such as AD (aOR 2.071, 95% CI 1.952–2.198) and asthma (aOR 1.494, 95% CI 1.400-1.594) were also significant predictors for childhood AD. The subgroup analysis showed significant difference between children’s sex. Parental RA (aOR 3.070, 95% CI, 1.532–6.154) was crucial for boys, while parental psoriasis (aOR 1.945, 95% CI, 1.129–3.350)was a risk factor for girls. In conclusion, parental autoimmune diseases were found to be related to AD in their children before 5 years old. Additionally, there were different risk factors for AD between children’s sex.

Background Previous studies have shown systemic lupus erythematosus (SLE) patients had a significantly higher prevalence of thyroid diseases and hypothyroidism than matched controls, and some case reports showed SLE may occur after Hashimoto’s thyroiditis (HT). Objective This study aimed to investigate the subsequent risk of SLE in patients with HT. Methods In this retrospective cohort study done by the Taiwan National Health Insurance Research Database, the HT group (exposure group) and the non-HT group (comparator group) were propensity score matched at a ratio of 1:2 by demographic data, comorbidities, medications, and the index date. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Several sensitivity analyses were done for cross-validation of our findings. Results We identified 15,512 HT patients and matched 31,024 individuals. The incidence rate ratio of SLE was 3.58 (95% CI, 2.43–5.28; p < 0.01). Several sensitivity analyses show adjusted hazard ratio (aHR) (CIs) of 4.35 (3.28–5.76), 4.39 (3.31–5.82), 5.11 (3.75–6.98), and 4.70 (3.46–6.38), consistent with the results of the main model. Conclusion Our study showed an increased risk of SLE in the HT group after adjustment for baseline characteristics, comorbidities, and medical confounders compared with the reference group.

Background: Although hallux valgus is known to cause lower-back pain, the association between hallux valgus and spinal degenerative disease remains unclear. Methods: A retrospective cohort study was conducted between 1 January 2000 and 31 December 2015 using data from the Longitudinal Health Insurance Database in Taiwan. After propensity score matching for age, sex, and some potential comorbidities, 1000 individuals newly diagnosed with hallux valgus were enrolled in the study group, while 1000 individuals never diagnosed with hallux valgus served as the control group. Both groups were followed up until 2015 to evaluate the incidence of hallux valgus. Kaplan-Meier analysis was used to determine the cumulative incidence of hallux valgus, while the Cox proportional hazard model was adopted to estimate the hazard ratio (HR) and adjusted hazard ratio (aHR) with 95% confidence intervals (CIs). Results: The incidence densities of spinal degeneration in the hallux valgus and non-hallux valgus groups were 73.10 and 42.63 per 1000 person-years, respectively. An increased risk of spinal degenerative changes was associated with hallux valgus (adjusted HR = 1.75, 95% CI = 1.50–2.05). Age- and sex-stratified analyses showed a significantly higher risk of spinal degeneration in the hallux valgus group. Moreover, sub-outcome evaluations revealed significantly higher risks of spondylosis (aHR = 2.01, 95% CI = 1.55–2.61), intervertebral disorder (aHR = 2.27, 95% CI = 1.62–3.17), and spinal stenosis (aHR = 1.24, 95% CI = 1.47–1.76). There was also an increased risk of spinal degenerative change in those with hallux valgus without surgical intervention (aHR = 1.95, 95% CI = 1.66–2.99, p < 0.001). Conclusions: Hallux valgus was associated with increased risk of degenerative spinal changes and other spinal disorders.

ImportanceIt remains unknown whether Taiwanese veterans have a lower risk of subsequent cancer compared with non-veterans.ObjectiveTo examine whether veterans are associated with reduced cancer risk.MethodsFrom January 2004 to December 2017, this study included 957 veterans and 957 civilians who were propensity score (PS) matched by years of birth, sex, residence, index year, days in the hospital, frequency of outpatient visits, and relevant comorbidities at baseline. Multivariate Cox proportional hazards regression analysis was applied to compare the risks of cancer, overall and by subgroup, and mortality. All the participants were cancer free at the baseline.ExposuresVeterans retrieved from Taiwan National Health Insurance Research Database (NHIRD).Main outcomeCancer extracted from the Registry for Catastrophic Illness Patients Database (RCIPD).ResultsOverall, 1,914 participants were included, and 957 veterans with a mean (SD) age of 75.9 (6.79) years and 946 men (98.9%). The mean follow-up was about 10.5 (±4.51) years. Cancer was recorded in 6.68% (N = 64) and 12.12% (N = 116) of veterans and non-veterans, respectively. Veterans were associated with decreased risk [adjusted hazard ratio (aHR), 0.57; 95% CI: 0.41–0.78; P < 0.001] of cancer compared with civilians after controlling for age, sex, urbanization, hypertension, diabetes, hyperlipidemia, cardiovascular event, COPD, asthma, chronic liver disease, alcohol-related illness, and Parkinson’s disease. Cancer subgroup analyses verified this finding (HRs P < 0.05).ConclusionTaiwanese older veterans are associated with reduced overall cancer risk than individuals without veteran status.

Summary Background and purpose Stroke is a rare complication of snakebites, but may lead to serious sequelae. We aimed to explore the relationship between venomous snakebite and the risk for acute stroke, in a nationwide population-based cohort study. Methods This retrospective cohort study used claims data between 1 January 2000 and 31 December 2012, from the Taiwan National Health Insurance Research Database. The study included data of patients aged 18 years or older with venomous snakebite (n = 535), matched for propensity score with controls without venomous snakebite (n = 2140). The follow-up period was the duration from the initial diagnosis of venomous snakebite and administration of antivenom to the date of an acute stroke, or until 31 December 2013. The competing risk model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of stroke, ischemic stroke and hemorrhagic stroke, after adjusting for demographic and other possible stroke risk factors. Results The adjusted HR for the venomous snakebite group compared with the control group was 2.68 for hemorrhagic stroke (95% CI = 1.35-5.33). Stratified analysis showed that the older age group (>65 years old) had a higher risk of hemorrhagic stroke. A 2.72-fold significant increase in the risk for hemorrhagic stroke was observed following venomous snakebite with antivenom usage (95% CI = 1.41–5.26). Conclusion Venomous snakebite is associated with an increased risk of hemorrhagic stroke after the use of antivenom. Further study of the underlying mechanism is warranted.

Background/Purpose: Flat foot can alter the lower limb alignment and cause knee and back pain. To explore the association between flat foot and spinal degeneration. Methods: By using a claims dataset containing 1 million random samples, individuals with flat foot were identified between January 1, 2000, and December 31, 2013. The study assembled a flat foot group and a matched non–flat foot group. Definition of flat foot was according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The diagnosis date was defined as the index date for follow-up initiation. The follow-up period was defined as the duration from the index date (or nested index date for controls) to the occurrence of spinal degenerative joint disease (DJD), or December 31, 2013. The primary outcome was record of spinal DJD retrieved from the same database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with the control group as a reference. Results: We identified 13,965 patients (most aged 45 years with history of flat foot, the adjusted hazard ratios were 1.434, 3.065, 3.110, and 2.061 in association with spondylosis, intervertebral disc disorder, cervical stenosis, thoracic-lumbar-sacral stenosis, respectively. Conclusion: Flat foot was found to be an independent risk factor for subsequent spinal DJD.

Flat foot can alter the lower limb alignment and cause knee and back pain. To explore the association between flat foot and spinal degeneration.By using a claims dataset containing 1 million random samples, individuals with flat foot were identified between January 1, 2000, and December 31, 2013. The study assembled a flat foot group and a matched non-flat foot group. Definition of flat foot was according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The diagnosis date was defined as the index date for follow-up initiation. The follow-up period was defined as the duration from the index date (or nested index date for controls) to the occurrence of spinal degenerative joint disease (DJD), or December 31, 2013. The primary outcome was record of spinal DJD retrieved from the same database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with the control group as a reference.We identified 13,965 patients (most aged30 years, 88%); 2793 patients were assigned to the flat foot group and 11,172 individuals to the non-flat foot group matched by age, sex, and index year. The mean follow-up duration was approximately 74 months. In total, 329 (11.78%) patients in the study group and 931 (8.33%) patients in the comparison group developed spinal DJD. The adjusted HR (95% CI) of spinal DJD for study group was 1.423(1.250-1.619) compared with the control. Sensitivity analyses with propensity score match and different scenario about spinal DJD enrollment showed similar results. Subgroup analysis showed that in patients aged45 years with history of flat foot, the adjusted hazard ratios were 1.434, 3.065, 3.110, and 2.061 in association with spondylosis, intervertebral disc disorder, cervical stenosis, thoracic-lumbar-sacral stenosis, respectively.Flat foot was found to be an independent risk factor for subsequent spinal DJD.

This study aimed to investigate the relationship between nontyphoidal salmonellosis (NTS) and new-onset hematological malignancy. We conducted a 17-year nationwide, population-based, retrospective cohort study to examine the association between NTS and the risk of hematological malignancies by using the Longitudinal Health Insurance Database (LHID) of Taiwan. Participants were enrolled from 2000 to 2015 and were monitored until 2017. We traced the years 1998–2000 to ensure that the cases included were newly diagnosed with NTS. The NTS cohort included 13,790 patients with newly diagnosed NTS between 2000 and 2015. Each patient was propensity score matched at a 1:4 ratio with people without NTS. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, income, urbanization, and medical comorbidities. The adjusted hazard ratio (aHR) of hematological malignancies for NTS patients relative to those without NTS was 1.42 (95% CI 0.91–2.20). In the age subgroup analysis, NTS had a significantly greater risk of hematological malignancies for patients older than 60 (aHR 3.04, 95% CI 1.46–6.34), with an incidence rate of 11.7 per 10,000 person-years. In patients over 60 years of age, a prominent risk of hematological malignancies was observed at a follow-up of more than 3 years after the index date (aHR 3.93, 95% CI 1.60–9.65). A history of NTS is associated with the risk of subsequent hematological malignancies in Taiwanese subjects older than 60.

This study aimed to investigate the relationship between nontyphoidal salmonellosis (NTS) and new-onset hematological malignancy. We conducted a 17-year nationwide, population-based, retrospective cohort study to examine the association between NTS and the risk of hematological malignancies by using the Longitudinal Health Insurance Database (LHID) of Taiwan. Participants were enrolled from 2000 to 2015 and were monitored until 2017. We traced the years 1998-2000 to ensure that the cases included were newly diagnosed with NTS. The NTS cohort included 13,790 patients with newly diagnosed NTS between 2000 and 2015. Each patient was propensity score matched at a 1:4 ratio with people without NTS. Cumulative incidence, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated after adjusting for age, sex, income, urbanization, and medical comorbidities. The adjusted hazard ratio (aHR) of hematological malignancies for NTS patients relative to those without NTS was 1.42 (95% CI 0.91-2.20). In the age subgroup analysis, NTS had a significantly greater risk of hematological malignancies for patients older than 60 (aHR 3.04, 95% CI 1.46-6.34), with an incidence rate of 11.7 per 10,000 person-years. In patients over 60 years of age, a prominent risk of hematological malignancies was observed at a follow-up of more than 3 years after the index date (aHR 3.93, 95% CI 1.60-9.65). A history of NTS is associated with the risk of subsequent hematological malignancies in Taiwanese subjects older than 60.

Influenza infection could trigger acute myocardial infarction. Obstructive sleep apnea (OSA) increases risk for myocardial infarction. Evidence evaluating the risk of influenza in patients with OSA is limited. We aimed to investigate the association between OSA and influenza using a nationwide population-based data set.A total of 5483 individuals with OSA were enrolled from January, 2000, to December, 2012, and compared with a control group of 21,932 individuals who had never been diagnosed with OSA (at a 1:4 ratio propensity score matched by age, sex, index years, and comorbidities) in the context of subsequent influenza infection. Cox proportional hazard regression analysis was conducted to analyze the association between OSA and influenza incidence. We conducted sensitivity analyses to examine our finding.During the 1.81 (±2.12) years of the follow-up period, the incidence rate of influenza infection was higher in the OSA group compared with the non-OSA group (36.40 and 30.09 per 100 person-years). After adjusting for age, sex, comorbidities, outpatients visits, the risk of influenza infection among patients with OSA was significantly higher (hazard ratio = 1.18; 95% confidence interval = 1.14-1.23; P 0.001). Sensitivity analyses showed consistent positive association. Males with OSA had increased risk of influenza infection compared with males without OSA (adjusted HR, 1.21; 95% CI, 1.16-1.27; P value for interaction = 0.03).This study found a significantly higher risk of influenza infection in patients with OSA, and sex acted as an effect modifier between OSA and risk of influenza infection.

Background This study investigated the correlation between a history of human papillomavirus (HPV) infection and skin cancer risk. Materials and Methods The study cohort comprised 26,919 patients with newly diagnosed HPV infection between 2000 and 2012; with the use of computer-generated numbers, patients without previous HPV infection were randomly selected as the comparison cohort. The patients in the HPV infection cohort were matched to comparison individuals at a 1:4 ratio by demographic characteristics and comorbidities. All study individuals were followed up until they developed skin cancer, withdrew from the National Health Insurance program, were lost to follow-up, or until the end of 2013. The primary outcome was subsequent skin cancer development. Cox proportional hazards regression analysis was used to analyze the risk of skin cancer with hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. Results The adjusted HR of skin cancer for patients with HPV relative to controls was 2.45 after adjusting sex, age and comorbidities. (95% CI, 1.44–4.18, p < .01). The subgroup analysis indicated that a patient with HPV infection had a significantly greater risk of skin cancer if they were aged >40 years. Notably, a risk of skin cancer was found in the group diagnosed with HPV within the first 5 years after the index date (adjusted HR, 3.12; with 95% CI, 1.58–5.54). Sensitivity analysis by propensity score, matching with balanced sex, age, and comorbidities, showed consistent results. Conclusion A history of HPV infection is associated with the development of subsequent skin cancer in Taiwanese subjects, and the risk wanes 5 years later. Implications for Practice In this Taiwan nationwide cohort study, there was a 2.45-fold increased risk of developing new-onset skin cancers for patients with incident human papillomavirus (HPV) infection, compared with the matched controls. Furthermore, the risk was noticeably significant among patients aged >40 years. A prominent risk of skin cancers was found in the group diagnosed with HPV within the first 5 years after the index date in this study. The results of this analysis may raise consensus on the effect of HPV infection on the risk of skin cancers. Clinicians are encouraged to implement prudently on the differential diagnosis of skin cancers and HPV prevention and treatment, especially in older patients.

To explore whether newly diagnosed Candida infection increases the risk of developing ankylosing spondylitis (AS). We investigated 61,550 patients with newly diagnosed Candida infection between 199...

The research is to explore the association between nontyphoidal salmonellosis (NTS) and subsequent gastric cancer. We conducted a retrospective study by analyzing hospitalization dataset from the National Health Insurance Research Database in Taiwan. Patients aged 20 years and older with NTS (n = 9 097) admitted between January 1, 2000, and December 31, 2012, were enrolled and followed up until December 31, 2013. The primary outcome was the incidence of gastric cancer. Cox proportional hazards regression was used to estimate the risk of malignancy, accounting for the competing risk of death. In addition, we conducted a sensitivity analysis by propensity score matching and exclusion of malignancy within 1 year observation to minimize measurable confounding and protopathic bias. Negative controls were applied to examine the presence of possible unmeasured confounders in the study. The study included 18 194 patients (9097 in each NTS and non-NTS group). The median follow-up time was 7 years. The incidence density rate of gastric cancer was 0.72 per 1000 person-years for the NTS group and 0.40 per 1000 person-years for the non-NTS group. The NTS group had a modestly higher risk of gastric cancer (aHR, 2.02; 95% CI 1.18–3.45) than the non-NTS group. The sensitivity analyses revealed consistent results. Patients with NTS are associated with increased risk of subsequent gastric cancer compared with non-NTS patients. Future research is needed to examine whether NTS is parallel, reactive or causative to gastric cancer.

Summary Objectives: To explore the association between nontyphoidal salmonellosis (NTS) and the risk of acute ischemic stroke (IS) by using a nationwide, population-based study. Methods A retrospective cohort study using claim data from Taiwan's National Health Insurance Research Database (NHIRD), patients aged 18 years and older with histories of NTS (N = 1618) were included from January 1, 2000-December 31, 2012, and the non-NTS group (N = 6472) without NTS were matched by propensity score. The follow-up period was defined as the time from the initial diagnosis of NTS to the date of development of IS, death or 31 December, 2013. Patients previously diagnosed with stroke were excluded. The Cox proportional hazard model with robust sandwich estimator was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of IS after adjusting for demographic and clinical covariates. Results: The adjusted hazard ratio (aHR) for the NTS group compared with the non-NTS group was 1.34 (95% confidence interval [CI], 1.10–1.65) for overall stroke. Furthermore, the NTS cohort had an increased risk of IS compared to the non-NTS groups (aHR, 1.42; 95% CI, 1.14–1.78). Stratified analysis showed that compared with propensity score matched non-NTS group, subjects aged ≥65 years, female, those with hypertension, hyperlipidemia, COPD, cancer and heart failure had higher risk of developing stroke. A 1.93-fold significant increase risk for stroke was observed during the first 3–12 months of follow-up (95% CI, 1.07–3.48). Conclusions: Patients with NTS is associated with increased risk of developing ischemic stroke compared with non-NTS patients. Timely and mindful treatment plan about NTS may be a milestone to stroke prevention especially in some subpopulation.

Objective: To explore whether newly diagnosed iron deficiency anemia (IDA) is associated with subsequent systemic autoimmune disease onset.Methods: The study identified 22,440 patients who received...

Background: Gastric cancer (GC) is one of the leading malignant diseases worldwide, especially in Asia. CAST is a potential oncogene in GC carcinogenesis. The character of macrophage infiltration in the GC microenvironment also remains unaddressed. Methods: We first applied machine searching to evaluate gene candidates for GC. CAST expression and pan-cancer surveyance were analyzed using the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. The protein–protein interaction (PPI) network was downloaded from STRING. We investigated the impact of CAST on clinical prognosis using a Kaplan–Meier plotter. The correlations between CAST and Lgr5 and macrophage infiltration in GC were determined using TIMER 2.0. Finally, GeneMANIA was also used to evaluate the possible functional linkages between genes. Results: After the machine-assisted search, CAST expression was found to significantly influence the overall survival of GC patients. STRING revealed CAST-related proteomic and transcriptomic associations, mainly concerning the CAPN family. Moreover, CAST significantly impacts the prognosis of GC based on the validation of other datasets. Notably, high CAST expression was correlated with worse overall survival in GC patients (hazard ratio = 1.59; log-rank P = 9.4 × 10−8). CAST and Lgr5 expression were both positively correlated with WNT 2 and WNT 2B. Among the GC patients in several datasets, CAST and macrophage infiltration, evaluated together, showed no obvious association with poor clinical overall survival. Conclusions: CAST plays an important role in the clinical prognosis of GC and is associated with WNT 2/WNT 2B/Lgr5. Our study demonstrates that CAST’s influence on overall survival in GC is regulated by macrophage infiltration.

Background and purpose: In the era of easily available antibiotic use, this study provides epidemiological evidence for a re-examination of the relationship between syphilis and ischemic stroke (IS). Methods: Patients aged 18 years and older with newly diagnosed syphilis were included (n = 1585) from 2000 to 2012, and participants without syphilis in the control group (n = 6340) were matched by propensity score (age, sex, index year, insured amount, urbanization, seasons, and comorbidities). The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of IS. Five different Cox regression models, sensitivity analyses, and negative control were conducted to test our findings. Results: In all, 1585 patients (1055 (66.56%) men; mean (SD) age, 49.59 (20.32) years) had syphilis, and 3.8% had new-onset IS. The syphilis group had a higher risk of IS than the controls (adjusted HR, 1.35; 95% CI, 1.01–1.80; p value Conclusion: Syphilis patients have higher risk of IS, and our data raise the question of implementation of prophylactic treatment for IS.

Background: Scabies is an infectious inflammatory skin disease. Cytokine-mediated inflammatory responses may be one of the pathological mechanisms underlying myocardial infarction. Objective: We explore the association between scabies and subsequent acute myocardial infarction (AMI) and all-cause mortality; Methods: We conducted a nationwide population-based study using data from the National Health Insurance Research Database (NHIRD) in Taiwan. Patients with scabies (n = 30,184) and 120,739 controls without scabies were included. The primary outcomes were incidental AMI and all-cause mortality. Using Cox proportional-hazards regression analysis, we estimated the risk of acute myocardial infarction for the study cohort; Results: The mean age of the study cohort was 51.81 ± 19.89 years. The adjusted sub-distribution hazard ratios (aSHRs) of AMI were 1.214 (95% CI, 1.068–1.381) after adjusting for demographic characteristics, income, OPD utility frequency, days in hospital, co-morbidities, and medication. The adjusted hazard ratio (aHR) of all-cause mortality after adjusting for age, gender, income, OPD utility frequency, days in hospital, co-morbidities, co-medication, and urbanization was 1.612 (95% CI, 1.557–1.669). Conclusions: Our study showed that patients with scabies infestations were at higher risk for subsequent AMI and all-cause mortality.

ObjectiveWe investigated the correlation between nontyphoidal Salmonella (NTS) infection and systemic lupus erythematosus (SLE) risk.MethodsThis case-control study comprised 6,517 patients with newly diagnosed SLE between 2006 and 2013. Patients without SLE were randomly selected as the control group and were matched at a case-control ratio of 1:20 by age, sex, and index year. All study individuals were traced from the index date back to their NTS exposure, other relevant covariates, or to the beginning of year 2000. Conditional logistic regression analysis was used to analyze the risk of SLE with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) between the NTS and control groups.ResultsThe mean age was 37.8 years in the case and control groups. Females accounted for 85.5%. The aOR of having NTS infection were significantly increased in SLE relative to controls (aOR, 9.20; 95% CI, 4.51-18.78) in 1:20 sex-age matching analysis and (aOR, 7.47; 95% CI=2.08-26.82) in propensity score matching analysis. Subgroup analysis indicated that the SLE risk was high among those who dwelled in rural areas; had rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome; and developed intensive and severe NTS infection during admission.ConclusionsExposure to NTS infection is associated with the development of subsequent SLE in Taiwanese individuals. Severe NTS infection and other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome also contributed to the risk of developing SLE.

Background: This is an investigation of the human papillomavirus (HPV) infection and its correlation with the risk of ectopic pregnancy (EP). Methods: The cohort study includes 11,239 patients with newly diagnosed HPV infections between 2000 and 2012, and by using computer-generated random numbers, patients who do not have HPV infections are selected randomly as the comparison cohort. The HPV infection cohort is matched to comparison individuals at a 1:10 ratio by age and index year. All individuals included in the study were followed up to the point they developed EP, pulled-out from the insurance program, lost to follow-up, or until the end of 2013. A Cox proportional-hazards regression analysis was used to analyze the risk of EP with the hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. Results: The adjusted hazard ratio (aHR) of EP for HPV patients relative to controls is 1.70 (95% CI = 1.04, 2.78), indicating a positive correlation between EP and HPV in the 13-year follow-up period, after adjusting for age and relevant comorbidities. The sensitivity analyses yield similar results. Conclusions: A history of HPV infection is a potential risk factor associated with the development of subsequent EP in Taiwanese individuals, especially those diagnosed with an HPV infection within 3 years.

IntroductionInfections play a role in autoimmune diseases (AD). Leptospirosis has been linked to the trigger of systemic lupus erythematosus.ObjectiveTo investigate subsequent risk of major AD in hospitalized Taiwanese for Leptospirosis.MethodsRetrospective observational cohort study was employed. The enrolled period was from 2000 to 2012. In the main model, we extracted 4026 inpatients with leptospirosis from the Taiwan National Health Insurance Research Database (NHIRD) and 16,104 participants without leptospirosis at a 1:4 ratio propensity-score matched (PSM) by age, gender, index year, and comorbidities. The follow-up period was defined as the time from the initial diagnosis of leptospirosis to major AD occurrence or 2013. This study was re-analyzed by frequency-matching as a sensitivity analysis for cross-validation. Univariable and multivariable Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsThe adjusted HR (95% CI) of major ADs for the leptospirosis group was 4.45 (3.25–6.79) (p < 0.001) compared to the controls after full adjustment. The risk of major ADs was 5.52-fold (95% CI, 3.82–7.99) higher in leptospirosis patients hospitalized for seven days and above than the controls, while 2.80-fold (95% CI, 1.68–5.61) in those hospitalized less than seven days. The sensitivity analysis yields consistent findings. Stratified analysis revealed that the association between leptospirosis and major ADs was generalized in both genders, and all age groups.ConclusionsSymptomatic leptospirosis is associated with increased rate of subsequent major ADs, and the risk seems to be higher in severe cases.

Metformin has been mentioned to be protective against inflammation, degeneration, and oxidative stress, conditions that are associated with rotator cuff disease. To access the association between metformin use and risk of rotator cuff disease in patients with type 2 diabetes mellitus (DM).This was a retrospective cohort study utilizing Taiwan National Health Insurance Research Database between January 1, 2000, and December 31, 2012 to retrieved participants. Metformin and propensity score matched never metformin users were determined at baseline (between the date of onset of DM and the index date), and followed to December 31, 2013. Propensity scores were adopted to address measurable confounders (including demographic variables, Diabetes Complications Severity Index, relevant comorbidities and co-medication). A multivariable Cox proportional hazards regression model was applied to estimate the adjusted hazard ratios (HRs) for the risk of the first diagnosis of rotator cuff disease on the full cohort and on the propensity score matched cohort.In the propensity score matched cohort, a total of 34,964 individuals (19,416 [55.5%] men), 17,482 individuals were taking metformin, 559 [3.2%] of whom developed rotator cuff disease. Incidence of rotator cuff disease was 4.51 per 10,000 person-months in the metformin users and 5.11 in the controls. Among metformin group, the aHR (95% CI) was 0.879 (0.784-0.984) after full adjustment. The potential beneficial effect on the risk of rotator cuff disease was consistently observed across all subgroups, including sex, age, concomitant other glucose lowering drugs, and level of Diabetes Complications Severity Index (all P for interaction0.050).Metformin use was associated with a lower risk of rotator cuff disease in patients with type 2 DM.

Linked Article: Paljarvi et al. Br J Dermatol 2022; 187:64–72.

Background: Gastric cancer (GC) is one of the leading malignancy diseases worldwide, especially in Asian. CAST is a potential oncogene in GC carcinogenesis process. The character of macrophage infiltration in GC microenvironment was also unaddressed. Methods: We first applied machine searching in gene candidate evaluation of GC. CAST expression was analyzed via the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. Protein-protein interaction (PPI) network was downloaded from STRING. We investigated the impact of CAST on clinical prognosis using Kaplan-Meier plotter. The correlations between CAST and Lgr5 and macrophage infiltration in GC was surveyed via TIMER 2.0. Finally, GeneMANIA was also used to evaluate the possible functional linkage between genes. Results: After machine-assisted searching, CAST expression was found signicant difference in the overall survival of GC patients. STRING revealed CAST related proteomics and transcriptomics associations, mainly about CAPN family. Moreover, CAST significantly impacts the prognosis of GC from other datasets validation. Notably, high CAST expression was correlated with worse overall survival in GC patients (hazard ratio = 1.59; logrank P = 9.4 x 10-8). CAST and Lgr5 expressions were both positively correlated with WNT 2 and WNT 2B. Among GC patients in several datasets, CAST and macrophage infiltration evaluated together showed no obvious trend toward poor clinical overall survival. Conclusion: CAST plays an important role in GC clinical prognosis and is associated with WNT 2/WNT 2B/Lgr5. Our study denmostrated that CAST in GC overall survival is regulated by macrophage infiltration.

Mycoplasma pneumoniae (M. pneumoniae) is not only one of the most common pathogenic bacteria for respiratory infection but also a trigger for many autoimmune diseases. Its infection process shared many similarities with the pathogenesis of myasthenia gravis (MG) at cellular and cytokine levels. Recent case reports demonstrated patients present with MG after M. pneumoniae infection. However, no epidemiological studies ever looked into the association between the two. Our study aimed to investigate the relationship between M. pneumoniae infection and subsequent development of MG. In this population-based retrospective cohort study, the risk of MG was analyzed in patients who were newly diagnosed with M. pneumoniae infection between 2000 and 2013. A total of 2428 M. pneumoniae patients were included and matched with the non-M. pneumoniae control cohort at a 1:4 ratio by age, sex, and index date. Cox proportional hazards regression analysis was applied to analyze the risk of MG development after adjusting for sex, age, and comorbidities, with hazard ratios and 95% confidence intervals. The incidence rates of MG in the non-M. pneumoniae and M. pneumoniae cohorts were 0.96 and 1.97 per 10,000 person-years, respectively. Another case–control study of patients with MG (n = 515) was conducted to analyze the impact of M. pneumoniae on MG occurrence as a sensitivity analysis. The analysis yielded consistent absence of a link between M. pneumoniae and MG. Although previous studies have reported that M. pneumoniae infection and MG may share associated immunologic pathways, we found no statistical significance between M. pneumoniae infection and subsequent development of MG in this study.

Objective We investigated the correlation between nontyphoidal Salmonella (NTS) infection and systemic lupus erythematosus (SLE) risk. Methods This case-control study comprised 6,517 patients with newly diagnosed SLE between 2006 and 2013. Patients without SLE were randomly selected as the control group and were matched at a case-control ratio of 1:20 by age, sex, and index year. All study individuals were traced from the index date back to their NTS exposure, other relevant covariates, or to the beginning of year 2000. Conditional logistic regression analysis was used to analyze the risk of SLE with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) between the NTS and control groups. Results The mean age was 37.8 years in the case and control groups. Females accounted for 85.5%. The aOR of having NTS infection were significantly increased in SLE relative to controls (aOR, 9.20; 95% CI, 4.51-18.78) in 1:20 sex-age matching analysis and (aOR, 7.47; 95% CI=2.08-26.82) in propensity score matching analysis. Subgroup analysis indicated that the SLE risk was high among those who dwelled in rural areas; had rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome; and developed intensive and severe NTS infection during admission. Conclusions Exposure to NTS infection is associated with the development of subsequent SLE in Taiwanese individuals. Severe NTS infection and other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or Sjogren’s syndrome also contributed to the risk of developing SLE.

ObjectiveThe aim of this study was to investigate the relationship between non-typhoidalSalmonella(NTS) infection and the risk of Kawasaki disease (KD) by using a nationwide population-based data set in Taiwan.MethodsIn this retrospective cohort study, we enrolled 69,116 patients under 18 years of age, with NTS from January 1st, 2000, to December 31st, 2013, using the population-based National Health Insurance Research Database of Taiwan. A comparison group without NTS was matched (at a 1:4 ratio) by propensity score. The two cohorts were followed from the initial diagnosis of NTS until the date of KD development or December 31st, 2013. Cox proportional hazard regression analysis was conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for covariates. Also, we conducted sensitivity analyses to examine our findings.ResultsAfter adjusting for covariates, the risk of KD for the children with NTS was significantly higher than that of the comparison group (hazard ratio = 1.31; 95% confidence interval = 1.03-1.66; p < 0.01). Stratified analysis showed that the associated risk of the investigated outcome was significant in children aged ≤2 years (aHR= 1.31, 95% C.I. 1.02-1.69), in female patients (aHR= 1.46, 95% C.I. 1.03-2.08), and in those without allergic diseases.ConclusionsNTS is associated with an increased risk of KD in Taiwanese children.