The role of mental illness and neurodevelopmental conditions in human papillomavirus vaccination uptake within the Swedish school-based vaccination programme: a population-based cohort study.

BACKGROUND: Despite documented mental illness-related disparities in cervical cancer screening and incidence, insufficient data exist on differences in cervical cancer prevention strategies, such as human papillomavirus (HPV) vaccination. We aimed to investigate the association of mental illness and neurodevelopmental conditions among girls and their parents with uptake of HPV vaccination in Sweden. METHODS: This population-based cohort study was based on the Swedish school-based HPV vaccination programme, which offers the first vaccine dose to girls aged 10-13 years, with a second dose offered within 12 months. We identified all girls born between Jan 1, 2002, and March 1, 2004, using the Swedish Total Population Register-ie, those eligible for two vaccine doses in the vaccination programme from its initiation in autumn 2012, to March, 2019. Nationwide Swedish register data (National Patient Register, Prescribed Drug Register, HPV Vaccination Register, National Vaccination Register, Total Population Register, Multi-Generation Register, Longitudinal Integrated Database for Health Insurance and Labour Market Studies, Education Register, National Cervical Screening Registry, and Cancer Register) were used to define individual and parental mental health conditions, including mental illness and neurodevelopmental conditions (defined by a clinical diagnosis and prescribed psychotropic medication use), HPV vaccine uptake (first and second dose), and sociodemographic and clinical characteristics. The two outcomes were uptake of the first HPV vaccine dose by the girl's 14th birthday and uptake of the second dose by the 15th birthday in relation to individual and parental mental health conditions, calculated using multivariable Poisson regression models. FINDINGS: 115 104 girls were included in the study population. 2211 girls (1·9%) had a specialist diagnosis of any mental health condition. Uptake of the first HPV vaccine dose was 80·7% (92 912 of 115 104) and was lower among girls with versus without any mental health condition (adjusted relative risk 0·89 [95% CI 0·87-0·91]). The diagnosis of autism (0·79 [0·75-0·85]) or intellectual disability (0·78 [0·73-0·83]) were most strongly associated with lower HPV vaccine uptake. Vaccine uptake was also lower among girls with versus those without prescribed use of psychotropic medication (0·93 [0·92-0·95]), with the strongest association observed for antipsychotics (0·68 [0·56-0·82]). Uptake of the second dose was 95·0% (88 308 of 92 912), with no strong associations between uptake and mental health conditions in girls or their parents. INTERPRETATION: Our findings suggest disparities in cervical cancer prevention among girls with mental health conditions, and call for further research to ensure equitable protection. FUNDING: Swedish Cancer Society.

Psychiatric morbidity across the life course and provoked vulvodynia: is it dependent upon the presence of non-stress-related immune dysfunction?

BACKGROUND: Vulvodynia impacts up to 8% of women by age 40, and these women may have a more compromised immune system than women with no vulvar pain history. AIM: Given that psychiatric morbidity is associated with vulvodynia and is known to activate immune inflammatory pathways in the brain and systemically, we sought to determine whether the association between psychiatric morbidity and vulvar pain was independent of or dependent upon the presence of immune-related conditions. METHODS: Women born in Sweden between 1973 and 1996 with localized provoked vulvodynia (N76.3) and/or vaginismus (N94.2 or F52.5) diagnosed between 2001 and 2018 were matched to two women from the same birth year with no vulvar pain. International Statistical Classification of Diseases and Related Health Problems (ICD-9 or -10 codes) were used to identify women with a history of depression, anxiety, attempted suicide, neurotic disorders, stress-related disorders, behavioral syndromes, personality disorders, psychotic disorders, or chemical dependencies, as well as a spectrum of immune-related conditions. The Swedish National Prescribed Drug Register was used to identify women with filled prescriptions of antidepressants or anxiolytics. OUTCOMES: Vulvodynia, vaginismus, or both were outcomes assessed in relation to psychiatric morbidity. RESULTS: Women with vulvodynia, vaginismus, or both, relative to those without vulvar pain, had adjusted odds ratios between 1.4 and 2.3, with CIs highly compatible with harmful effects. When we assessed women with and those without a lifetime history of immune-related conditions separately, we also observed elevated odds ratios in both groups for mood, anxiety, and neurotic and stress disorders. CLINICAL IMPLICATIONS: Documenting psychiatric impairment as a cause or consequence of vulvodynia is critical in clinical practice because psychiatric conditions may impact treatment efficacy. STRENGTHS AND LIMITATIONS: Strengths of this study include a data source that represents the entire population of women in Sweden that is known to be highly accurate because Sweden provides universal healthcare. Limitations include difficulty in making an accurate assessment of temporality between psychiatric morbidity and the first onset of vulvar pain. In addition, because Swedish registry data have limited information on lifestyle, behavioral, and anthropomorphic factors such as smoking, diet, physical activity, and obesity, these conditions could not be assessed as confounders of psychiatric morbidity and vulvar pain. CONCLUSIONS: Immune pathways by which women with psychiatric conditions increase their risk of vulvar pain could be independent from other immune pathways.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden.

BACKGROUND: Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. METHODS AND FINDINGS: Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. CONCLUSIONS: Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

The bidirectional association between premenstrual disorders and perinatal depression: A nationwide register-based study from Sweden.

BACKGROUND: Premenstrual disorders (PMDs) and perinatal depression (PND) share symptomology and the timing of symptoms of both conditions coincide with natural hormonal fluctuations, which may indicate a shared etiology. Yet, there is a notable absence of prospective data on the potential bidirectional association between these conditions, which is crucial for guiding clinical management. Using the Swedish nationwide registers with prospectively collected data, we aimed to investigate the bidirectional association between PMDs and PND. METHODS AND FINDINGS: With 1,803,309 singleton pregnancies of 1,041,419 women recorded in the Swedish Medical Birth Register during 2001 to 2018, we conducted a nested case-control study to examine the risk of PND following PMDs, which is equivalent to a cohort study, and transitioned that design into a matched cohort study with onward follow-up to simulate a prospective study design and examine the risk of PMDs after PND (within the same study population). Incident PND and PMDs were identified through clinical diagnoses or prescribed medications. We randomly selected 10 pregnant women without PND, individually matched to each PND case on maternal age and calendar year using incidence density sampling (N: 84,949: 849,482). We (1) calculated odds ratio (OR) and 95% confidence intervals (CIs) of PMDs using conditional logistic regression in the nested case-control study. Demographic factors (country of birth, educational level, region of residency, and cohabitation status) were adjusted for. We (2) calculated the hazard ratio (HR) and 95% CIs of PMDs subsequent to PND using stratified Cox regression in the matched cohort study. Smoking, BMI, parity, and history of psychiatric disorders were further controlled for, in addition to demographic factors. Pregnancies from full sisters of PND cases were identified for sibling comparison, which contrasts the risk within each set of full sisters discordant on PND. In the nested case-control study, we identified 2,488 PMDs (2.9%) before pregnancy among women with PND and 5,199 (0.6%) among controls. PMDs were associated with a higher risk of subsequent PND (OR 4.76, 95% CI [4.52,5.01]; p < 0.001). In the matched cohort with a mean follow-up of 7.40 years, we identified 4,227 newly diagnosed PMDs among women with PND (incidence rate (IR) 7.6/1,000 person-years) and 21,326 among controls (IR 3.8). Compared to their matched controls, women with PND were at higher risk of subsequent PMDs (HR 1.81, 95% CI [1.74,1.88]; p < 0.001). The bidirectional association was noted for both prenatal and postnatal depression and was stronger among women without history of psychiatric disorders (p for interaction < 0.001). Sibling comparison showed somewhat attenuated, yet statistically significant, bidirectional associations. The main limitation of this study was that our findings, based on clinical diagnoses recorded in registers, may not generalize well to women with mild PMDs or PND. CONCLUSIONS: In this study, we observed a bidirectional association between PMDs and PND. These findings suggest that a history of PMDs can inform PND susceptibility and vice versa and lend support to the shared etiology between both disorders.

A nomogram based on cuproptosis-related genes predicts 7-year relapse-free survival in patients with estrogen receptor-positive early breast cancer.

Introduction: Excess copper induces cell death by binding to lipoylated components of the tricarboxylic acid cycle. Although a few studies have examined the relationship between cuproptosis-related genes (CRGs) and breast cancer prognosis, reports on estrogen receptor-positive (ER+) breast cancer are lacking. Herein, we aimed to analyze the relationship between CRGs and outcomes in patients with ER+ early breast cancer (EBC). Methods: We conducted a case-control study among patients with ER+ EBC presenting poor and favorable invasive disease-free survival (iDFS) at West China Hospital. Logistic regression analysis was performed to establish the association between CRG expression and iDFS. A cohort study was performed using pooled data from three publicly available microarray datasets in the Gene Expression Omnibus database. Subsequently, we constructed a CRG score model and a nomogram to predict relapse-free survival (RFS). Finally, the prediction performance of the two models was verified using training and validation sets. Results: In this case-control study, high expression of LIAS, LIPT1, and ATP7B and low CDKN2A expression were associated with favorable iDFS. In the cohort study, high expression of FDX1, LIAS, LIPT1, DLD, PDHB, and ATP7B and low CDKN2A expression were associated with favorable RFS. Using LASSO-Cox analysis, a CRG score was developed using the seven identified CRGs. Patients in the low CRG score group had a reduced risk of relapse in both training and validation sets. The nomogram included the CRG score, lymph node status, and age. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram was significantly higher than the AUC of the CRG score at 7 years. Conclusions: The CRG score, combined with other clinical features, could afford a practical long-term outcome predictor in patients with ER+ EBC.

Exploring different research questions via complex multi-state models when using registry-based repeated prescriptions of antidepressants in women with breast cancer and a matched population comparison group.

BACKGROUND: Multi-state models are used to study several clinically meaningful research questions. Depending on the research question of interest and the information contained in the data, different multi-state structures and modelling choices can be applied. We aim to explore different research questions using a series of multi-state models of increasing complexity when studying repeated prescriptions data, while also evaluating different modelling choices. METHODS: We develop a series of research questions regarding the probability of being under antidepressant medication across time using multi-state models, among Swedish women diagnosed with breast cancer (n = 18,313) and an age-matched population comparison group of cancer-free women (n = 92,454) using a register-based database (Breast Cancer Data Base Sweden 2.0). Research questions were formulated ranging from simple to more composite ones. Depending on the research question, multi-state models were built with structures ranging from simpler ones, like single-event survival analysis and competing risks, up to complex bidirectional and recurrent multi-state structures that take into account the recurring start and stop of medication. We also investigate modelling choices, such as choosing a time-scale for the transition rates and borrowing information across transitions. RESULTS: Each structure has its own utility and answers a specific research question. However, the more complex structures (bidirectional, recurrent) enable accounting for the intermittent nature of prescribed medication data. These structures deliver estimates of the probability of being under medication and total time spent under medication over the follow-up period. Sensitivity analyses over different definitions of the medication cycle and different choices of timescale when modelling the transition intensity rates show that the estimates of total probabilities of being in a medication cycle over follow-up derived from the complex structures are quite stable. CONCLUSIONS: Each research question requires the definition of an appropriate multi-state structure, with more composite ones requiring such an increase in the complexity of the multi-state structure. When a research question is related with an outcome of interest that repeatedly changes over time, such as the medication status based on prescribed medication, the use of novel multi-state models of adequate complexity coupled with sensible modelling choices can successfully address composite, more realistic research questions.

The Association Between Immune-Related Conditions Across the Life-Course and Provoked Vulvodynia.

Vulvodynia, impacts up to 8% of women by age 40, and is hypothesized to manifest through an altered immune-inflammatory response. To test this hypothesis, we identified all women born in Sweden between 1973 and 1996 diagnosed with localized provoked vulvodynia (N76.3) and/or vaginismus (N94.2 or F52.5) between 2001 and 2018. We matched each case to two women from the same birth year with no vulvar pain ICD codes. As a proxy for immune dysfunction, we used Swedish Registry data to capture 1) immunodeficiencies, 2) single organ and multiorgan autoimmune conditions, 3) allergy and atopies, and 4) malignancies involving immune cells across the life course. Women with vulvodynia, vaginismus or both were more likely to experience immune deficiencies (OR 1.8, 95% CI, 1.2-2.8), single organ (OR 1.4, 95% CI, 1.2-1.6) and/or multi-organ (OR 1.6, 95% CI, 1.3-1.9) immune disorders, and allergy/atopy conditions (OR 1.7, 95% CI, 1.6-1.8) compared to controls. We observed greater risk with increasing numbers of unique immune related conditions (1 code: OR = 1.6, 95% CI, 1.5-1.7; 2 codes: OR = 2.4, 95% CI, 2.1-2.9; 3 or more codes: OR = 2.9, 1.6-5.4). These findings suggest that women with vulvodynia may have a more compromised immune system either at birth or at points across the life course than women with no vulvar pain history. PERSPECTIVE: Women with vulvodynia are substantially more likely to experience a spectrum of immune related conditions across the life course. These findings lend support to the hypothesis that chronic inflammation initiates the hyperinnervation that causes the debilitating pain in women with vulvodynia.

Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Breast Cancer: Evidence from a General Female Population and a Mammographic Screening Cohort in Sweden.

A link has been proposed between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of breast cancer. There is, however, insufficient data regarding the subtype and stage of breast cancer, and few studies have assessed the interaction between the use of NSAIDs and breast density or previous breast disorders. There is also a lack of data from population-based studies. We first conducted a nested case-control study within the general female population of Sweden, including 56,480 women with newly diagnosed breast cancer during 2006-2015 and five breast cancer-free women per case as controls, to assess the association of NSAID use with the risk of incident breast cancer, focusing on subtype and stage of breast cancer as well as the interaction between NSAID use and previous breast disorders. We then used the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma) cohort to assess the interaction between NSAID use and breast density in relation to the risk of breast cancer. Conditional logistic regression was used to estimate the hazard ratio (HR) and a 95% confidence interval (CI) was used for breast cancer in relation to the use of aspirin and non-aspirin NSAIDs. In the nested case-control study of the general population, exclusive use of aspirin was not associated with the risk of breast cancer, whereas exclusive use of non-aspirin NSAIDs was associated with a modestly higher risk of stage 0-2 breast cancer (HR: 1.05; 95% CI: 1.02-1.08) but a lower risk of stage 3-4 breast cancer (HR 0.80; 95% CI: 0.73-0.88). There was also a statistically significant interaction between the exclusive use of NSAIDs and previous breast disorders (p for interaction: <0.001). In the analysis of Karma participants, the exclusive use of non-aspirin NSAIDs was associated with a lower risk of breast cancer among women with a breast dense area of >40 cm2 (HR: 0.72; 95% CI: 0.59-0.89). However, the possibility of finding this by chance cannot be ruled out. Overall, we did not find strong evidence to support an association between the use of NSAIDs and the risk of breast cancer.

Breast cancer prevention by short-term inhibition of TGFß signaling.

Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFß signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFß in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.

Cardiovascular disease and risk of lung cancer incidence and mortality: A nationwide matched cohort study.

Purpose: Previous studies have suggested a link between cardiovascular disease (CVD) and the subsequent development of lung cancer. However, empirical evidence on the association of CVDs, particularly type-specific CVDs, with lung cancer incidence and survival remains limited. Methods: The cohort study included 306,285 patients with CVD and 1,222,140 individuals without CVD. We performed stratified Cox regression to estimate the hazard ratio (HR). Results: During up to 42 years of follow-up, 243 (0.08%) and 537 (0.04%) participants were diagnosed with lung cancer among CVD patients and matched individuals, respectively. Patients with CVD had a 67% increased risk of lung cancer (HR: 1.67, 95% confidence interval [CI]: 1.42-1.96). The increased risks were observed in patients with heart disease (1.93, 1.30-2.85), vascular disease (1.88, 1.35-2.61), and hypertensive disease (1.46, 1.15-1.85), respectively. Patients with CVD had a 95% increased risk of lung cancer mortality (1.95, 1.50-2.55), particularly vascular disease (3.24, 1.74-6.02) and heart disease (2.29, 1.23-4.26). Patients with CVD diagnosed in middle adulthood (>40 years old) tended to have a higher incidence risk (3.44, 2.28-5.19) and mortality (3.67, 1.80-7.46) than those diagnosed at younger ages. Conclusions: Our findings on the association of CVD diagnosis, especially heart and vascular disease, with increased risk of lung cancer incidence and mortality suggest that CVD contributes to the development and worsening of lung cancer survival. In particular, people with CVD diagnosed in middle adulthood (>40 years old) would benefit from early preventive evaluation and screening for lung cancer.

Mammography radiomics features at diagnosis and progression-free survival among patients with breast cancer.

BACKGROUND: The associations between mammographic radiomics and breast cancer clinical endpoints are unclear. We aimed to identify mammographic radiomics features associated with breast cancer prognosis. METHODS: Nested from a large breast cancer cohort in our institution, we conducted an extreme case-control study consisting of 207 cases with any invasive disease-free survival (iDFS) endpoint <5 years and 207 molecular subtype-matched controls with >5-year iDFS. A total of 632 radiomics features in craniocaudal (CC) and mediolateral oblique (MLO) views were extracted from pre-treatment mammography. Logistic regression was used to identify iDFS-associated features with multiple testing corrections (Benjamini-Hochberg method). In a subsample with RNA-seq data (n = 96), gene set enrichment analysis was employed to identify pathways associated with lead features. RESULTS: We identified 15 iDFS-associated features from CC-view yet none from MLO-view. S(1,-1)SumAverg and WavEnLL_s-6 were the lead ones and associated with favourable (OR 0.64, 95% CI 0.42-0.87, P = 0.01) and poor iDFS (OR 1.53, 95% CI 1.31-1.76, P = 0.01), respectively. Both features were associated with eight pathways (primarily involving cell cycle regulation) in tumour but not adjacent normal tissues. CONCLUSION: Our findings suggest mammographic radiomics features are associated with breast cancer iDFS, potentially through pathways involving cell cycle regulation.

Genome-wide association study of posttraumatic stress disorder among childhood cancer survivors: results from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Genetic influence shapes who develops posttraumatic stress disorder (PTSD) after traumatic events. However, the genetic variants identified for PTSD may in fact be associated with traumatic exposures (e.g., interpersonal violence), which appear heritable as well. Childhood cancer survivors (CCS) are at risk for PTSD, but genetic influences affecting cancer are unlikely to overlap with those affecting PTSD. This offers a unique opportunity to identify variants specific to PTSD risk. In a genome-wide association study (GWAS), 3984 5-year survivors of childhood cancer of European-ancestry from the Childhood Cancer Survivor Study (CCSS) were evaluated for discovery and 1467 survivors from the St. Jude Lifetime (SJLIFE) cohort for replication. Childhood cancer-related PTSD symptoms were assessed using the Posttraumatic Stress Diagnostic Scale in CCSS. GWAS was performed in CCSS using logistic regression and lead markers were replicated/meta-analyzed using SJLIFE. Cross-associations of identified loci were examined between CCS and the general population. PTSD criteria were met for 671 participants in CCSS and 161 in SJLIFE. Locus 10q26.3 was significantly associated with PTSD (rs34713356, functionally mapped to ECHS1, P = 1.36 × 10-8, OR 1.57), and was replicated in SJLIFE (P = 0.047, OR 1.37). Variants in locus 6q24.3-q25.1 reached marginal significance (rs9390543, SASH1, P = 3.56 × 10-6, OR 0.75) in CCSS and significance when meta-analyzing with SJLIFE (P = 2.02 × 10-8, OR 0.75). Both loci were exclusively associated with PTSD in CCS rather than PTSD/stress-related disorders in general population (P-for-heterogeneity < 5 × 10-6). Our CCS findings support the role of genetic variation in PTSD development and may provide implications for understanding PTSD heterogeneity.

Neuroendocrine pathways and breast cancer progression: a pooled analysis of somatic mutations and gene expression from two large breast cancer cohorts.

BACKGROUND: Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue. METHODS: We conducted an extreme case-control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively. RESULTS: In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07-2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2-35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA. CONCLUSION: Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer.

Demographics, clinical features, and prognosis of rare lymphoepithelioma-like carcinoma across different anatomic sites.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is an unusual histological malignancy type. Due to the rarity of this disease, we used the Surveillance, Epidemiology, and End Results (SEER) database to investigate comprehensively and systematically the prognosis factor of LELC. METHODS: We identified 2079 patients diagnosed with LELC during 1973-2015 from the SEER database. LELC was classified according to the tumor site. We analyzed the clinical characteristics and estimated the hazard ratio (HR) of overall mortality of LELC at each site. RESULTS: The nasopharynx was the most frequent site where LELC (58%) occurred. A large percentage of nasopharyngeal and pulmonary LELC patients were of Asian descent (44.5 and 32.56%, respectively). Furthermore, the majority of LELC patients were rather young when diagnosed. However, urinary bladder LELC and digestive system LELC (mean age: 69.03 and 68.05 years, respectively) were mainly to be found in older patients. Then according to Kaplan-Meier survival analysis, we found that patients with pulmonary LELC had worse survival. After adjusting for clinical tumor characteristics, pulmonary LELC patients were at increased risk of overall mortality compared with nasopharyngeal LELC either at the localized stage (HR 3.12, 95% confidence interval [CI], 1.55-6.26. P < 0.01) or at the regional stage (HR 1.72, 95% CI 1.03-2.88 P = 0.04). CONCLUSIONS: In conclusion, we found that urinary bladder and digestive system LELCs mainly were diagnosed in old people and different from other LELCs. Pulmonary LELC patients might have a bad prognosis. The origination site may represent a predictive factor for determining survival in patients with LELC.

Associations of parental and perinatal factors with subsequent risk of stress-related disorders: a nationwide cohort study with sibling comparison.

Little is known about the contribution of pregnancy-related parental and perinatal factors to the development of stress-related disorders. We aimed to investigate whether parental/perinatal adversities entail higher risks of stress-related disorders in the offspring, later in life, by accounting for genetic and early environmental factors. Based on the nationwide Swedish registers, we conducted a population-based cohort study of 3,435,747 singleton births (of which 2,554,235 were full siblings), born 1973-2008 and survived through the age of 5 years. Using both population- and sibling designs, we employed Cox regression to assess the association between parental and perinatal factors with subsequent risk of stress-related disorders. We identified 55,511 individuals diagnosed with stress-related disorders in the population analysis and 37,433 in the sibling analysis. In the population-based analysis we observed increased risks of stress-related disorders among offspring of maternal/paternal age <25, single mothers, parity ≥4, mothers with BMI ≥ 25 or maternal smoking in early pregnancy, gestational diabetes, and offspring born moderately preterm (GA 32-36 weeks), or small-for-gestational-age. These associations were significantly attenuated toward null in the sibling analysis. Cesarean-section was weakly associated with offspring stress-related disorders in population [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.12] and sibling analyses (HR 1.10, 95% CI 1.02-1.20). Our findings suggest that most of the observed associations between parental and perinatal factors and risk of stress-related disorders in the population analysis are driven by shared familial environment or genetics, and underscore the importance of family designs in epidemiological studies on the etiology of psychiatric disorders.

Increased Risk of Suicide among Cancer Survivors Who Developed a Second Malignant Neoplasm.

BACKGROUND: Cancer diagnosis entails substantial psychological distress and is associated with dramatically increased risks of suicidal behaviors. However, little is known about the suicide risk among cancer survivors who developed a second malignant neoplasm (SMN). METHODS: Using the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study involving 7,824,709 patients with first malignant neoplasm (FMN). We measured the hazard ratios (HRs) of suicide death after receiving a SMN diagnosis using Cox proportional hazard models, as compared with patients with FMN. The comparison with the US population was achieved by calculating standardized mortality ratios (SMRs). RESULTS: Totally 685,727 FMN patients received a diagnosis of SMN during follow-up, and we in total identified 10,930 and 937 suicide deaths among FMN and SMN patients, respectively. The HR of suicide deaths was 1.23 (95% confidence interval (CI), 1.14-1.31) after a SMN diagnosis, compared with FMN patients, after adjusting for sociodemographic factors, tumor characteristics, and cancer treatment. As compared with the general population, while both SMN and FMN patients suffered an increased risk of suicide deaths, the excess risk was higher among SMN patients than FMN patients (age-, sex-, and calendar-year-adjusted SMR 1.65 (95% CI 1.54-1.75) vs. 1.29 (95% CI 1.26-1.31); P difference < 0.0001). Notably, across different time periods, we observed the greatest risk elevation during the first 3 months after a cancer diagnosis. CONCLUSIONS: Compared with either patients with FMN or the general population, cancer survivors who received a SMN diagnosis were at increased risk of suicide death. The risk elevation was most prominent soon after the cancer diagnosis, highlighting the necessity of providing timely psychological support to cancer survivors with a SMN.

Maternal Polycystic Ovary Syndrome and Offspring Birth Weight: A Mendelian Randomization Study.

CONTEXT: Observational associations between maternal polycystic ovary syndrome (PCOS) and offspring birth weight (BW) have been inconsistent and the causal relationship is still uncertain. OBJECTIVE: We conducted a 2-sample Mendelian randomization (MR) study to estimate the causal effect of maternal PCOS on offspring BW. METHODS: We constructed genetic instruments for PCOS with 14 single nucleotide polymorphisms (SNPs) which were identified in a genome-wide association study (GWAS) meta-analysis including 10 074 PCOS cases and 103 164 controls of European ancestry from 7 cohorts. The genetic associations of these SNPs with the offspring BW were extracted from summary statistics estimated by the Early Growth Genetics consortium (n = 406 063 European ancestry individuals) using the weighted linear model, an approximation method of structural equation model, which separated maternal genetic effects from fetal genetic effects. We used a 2-sample MR design to examine the causal relationship between maternal PCOS and offspring BW. Sensitivity analyses were conducted to assess the robustness of the MR results. RESULTS: We found little evidence for a causal effect of maternal PCOS on offspring BW (-6.1 g, 95% CI -16.8 g, 4.6 g). Broadly consistent results were found in the sensitivity analyses. CONCLUSION: Despite the large scale of this study, our results suggested little causal effect of maternal PCOS on offspring BW. MR studies with a larger sample size of women with PCOS or more genetic instruments that would increase the variation of PCOS explained are needed in the future.

Novel disease associations with schizophrenia genetic risk revealed in ~400,000 UK Biobank participants.

Schizophrenia is a serious mental disorder with considerable somatic and psychiatric morbidity. It is unclear whether comorbid health conditions predominantly arise due to shared genetic risk or consequent to having schizophrenia. To explore the contribution of genetic risk for schizophrenia, we analysed the effect of schizophrenia polygenic risk scores (PRS) on a broad range of health problems in 406 929 individuals with no schizophrenia diagnosis from the UK Biobank. Diagnoses were derived from linked health data including primary care, hospital inpatient records, and registers with information on cancer and deaths. Schizophrenia PRS were generated and tested for associations with general health conditions, 16 ICD10 main chapters, and 603 diseases using linear and logistic regressions. Higher schizophrenia PRS was significantly associated with poorer overall health ratings, more hospital inpatient diagnoses, and more unique illnesses. It was also significantly positively associated with 4 ICD10 chapters: mental disorders; respiratory diseases; digestive diseases; and pregnancy, childbirth and the puerperium, but negatively associated with musculoskeletal disorders. Thirty-one specific phenotypes were significantly associated with schizophrenia PRS, and the 19 novel findings include several musculoskeletal diseases, respiratory diseases, digestive diseases, varicose veins, pituitary hyperfunction, and other peripheral nerve disorders. These findings extend knowledge of the pleiotropic effect of genetic risk for schizophrenia and offer insight into how some conditions often comorbid with schizophrenia arise. Additional studies incorporating the genetic basis of hormone regulation and involvement of immune mechanisms in the pathophysiology of schizophrenia may further elucidate the biological mechanisms underlying schizophrenia and its comorbid conditions.

Optimal communication associated with lower risk of acute traumatic stress after lung cancer diagnosis.

PURPOSE: The aim of this study was to assess the role of the patient's background and perceived healthcare-related factors in symptoms of acute stress after lung cancer diagnosis. METHODS: The study population consisted of 89 individuals referred for diagnostic work-up at Landspitali National University Hospital in Iceland and subsequently diagnosed with lung cancer. Before diagnosis, the patients completed questionnaires on sociodemographic characteristics, pre-diagnostic distress (Hospital Anxiety and Depression Scale), social support, and resilience. At a median of 16 days after diagnosis, the patients reported symptoms of acute stress on the Impact of Event Scale-Revised (IES-R) and experience of communication and support from healthcare professionals and family during the diagnostic period. RESULTS: Patients were on average 68 years and 52% reported high levels of post-diagnostic acute stress (IES-R > 23) while 24% reported symptoms suggestive of clinical significance (IES-R > 32). Prior history of cancer (ß = 6.7, 95% CI: 0.1 to 13.3) and pre-diagnostic distress were associated with higher levels of post-diagnostic acute stress (ß = 8.8, 95% CI: 2.7 to 14.9), while high educational level (ß = - 7.9, 95% CI: - 14.8 to - 1.1) was associated with lower levels. Controlling for the abovementioned factors, the patients' perception of optimal doctor-patient (ß = - 9.1, 95% CI: - 14.9 to - 3.3) and family communication (ß = - 8.6, 95% CI: - 14.3 to - 2.9) was inversely associated with levels of post-diagnostic acute stress after lung cancer diagnosis. CONCLUSIONS: A high proportion of patients with newly diagnosed lung cancer experience high levels of acute traumatic stress of potential clinical significance. Efforts to improve doctor-patient and family communication may mitigate the risk of these adverse symptoms.