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STUDY QUESTION Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis? SUMMARY ANSWER Women with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis. WHAT IS KNOWN ALREADY It has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%. STUDY DESIGN, SIZE, DURATION This population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case–control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970–2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls. MAIN RESULTS AND THE ROLE OF CHANCE The prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison's disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years. LIMITATIONS, REASONS FOR CAUTION This study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher. WIDER IMPLICATIONS OF THE FINDINGS Severe autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives. STUDY FUNDING/COMPETING INTEREST(S) This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

This article presents the findings of a population-based case-control study on risk factors for lichen planus (LP) in women. The study found that certain conditions such as hepatitis C, oral candidiasis, periodontitis, Sjögren's syndrome, and vitiligo increased the odds of LP, while autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, and Graves' disease decreased the odds. Cardiometabolic and psychiatric conditions were associated with reduced odds of LP. The study emphasized the importance of considering the temporal order of diagnoses when examining comorbidities and called for further research on the pathogenetic process of LP and its associated conditions. The study did not find any significant association between LP and urbanicity level or socioeconomic status. [Extracted from the article]

Background: Fragile X syndrome is a common inheritable cause of intellectual disability (ID) and is characterised by a large number of CGG repeats at the gene "FMR1" located on the X-chromosome. It has been reported that this genetic mechanism may protect against malignant transformations. Methods: We extracted from the Finnish registry on persons with ID a cohort of 302 persons with a fragile X diagnosis during 1982-1986. Follow-up for cancer incidence was performed in the Finnish Cancer Registry until the end of the year 2005. Results: There were 11 reported cancers during the mean follow-up of 21.4 years per person. The expected number of cancers based on the average Finnish population was 13.8 and no statistically significant protective effect was detected [standardised incidence ratios (SIR) 0.80, confidence interval (CI) 95% 0.40-1.4]. An increased risk for lip cancer was found (SIR 23, CI 95% 2.8-85). Conclusions: Confirmation of hypotheses about the mechanisms linking FXS and cancer needs further research.

STUDY QUESTION Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? SUMMARY ANSWER A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. WHAT IS KNOWN ALREADY POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7–15% of POI cases. STUDY DESIGN, SIZE, DURATION This population-based study included 5011 women diagnosed with POI in 1988–2017. The data were collected from various national registries and covers women with POI nationwide. PARTICIPANTS/MATERIALS, SETTING, METHODS We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. MAIN RESULTS AND THE ROLE OF CHANCE Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1–1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1–39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2–43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10–14 years old, OR 24.1, 95% CI 15.1–38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. LIMITATIONS, REASONS FOR CAUTION Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. WIDER IMPLICATIONS OF THE FINDINGS GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. STUDY FUNDING/COMPETING INTEREST(S) Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Sie Sie Siew,1,2 Timo Kauppinen,1 Pentti Kyyrönen,3 Pirjo Heikkilä,1 Eero Pukkala2,31Finnish Institute of Occupational Health, Helsinki, Finland; 2School of Health Sciences, University of Tampere, Tampere, Finland; 3Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, FinlandAbstract: Controversy exists over whether or not occupational inhalation exposure to wood dust and/or formaldehyde increases risk for respiratory cancers. The objective of this study was to examine the risk of nasal, nasopharyngeal, and lung cancer in relation to occupational exposure to wood dust and formaldehyde among Finnish men. The cohort of all Finnish men born between the years 1906 and 1945 and in employment during 1970 was followed up through the Finnish Cancer Registry for cases of cancers of the nose (n = 292), nasopharynx (n = 149), and lung (n = 30,137) during the period 1971–1995. The subjects' occupations, as recorded in the population census in 1970, were converted to estimates of exposure to wood dust, formaldehyde, asbestos, and silica dust through the Finnish job-exposure matrix. Cumulative exposure (CE) was calculated based on the prevalence, average level, and estimated duration of exposure. The relative risk (RR) estimates for the CE categories of wood dust and formaldehyde were defined by Poisson regression, with adjustments made for smoking, socioeconomic status, and exposure to asbestos and/or silica dust. Men exposed to wood dust had a significant excess risk of nasal cancer overall (RR, 1.59; 95% confidence interval [CI], 1.06–2.38), and specifically nasal squamous cell carcinoma (RR, 1.98; 95% CI, 1.19–3.31). Workers exposed to formaldehyde had an RR of 1.18 (95% CI, 1.12–1.25) for lung cancer. There was no indication that CE to wood dust or formaldehyde would increase the risk of nasopharyngeal cancer. Occupational exposure to wood dust appeared to increase the risk of nasal cancer but not of nasopharyngeal or lung cancer. The slight excess risk of lung cancer observed for exposure to formaldehyde may be the result of residual confounding from smoking. In summary, this study provides further evidence that exposure to wood dust in a variety of occupations may increase the risk of nasal cancer.Keywords: job-exposure matrix, inhalation exposure, cumulative exposure, cancer risk

Ahmed Ibrahim1, Arja R Aro1, Vibeke Rasch2, Eero Pukkala3,41Unit for Health Promotion Research, University of Southern Denmark, Esbjerg, Denmark; 2Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark; 3Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland; 4School of Public Health, University of Tampere, Tampere, FinlandObjective: To determine the feasibility of visual inspection with the use of acetic acid (VIA) as a screening method for cervical cancer, an alternative to the Pap smear used in primary health care setting in Sudan, and to compare sensitivity, specificity, positive and negative predictive values, and histological diagnosis of positive cases of both tests.Methods: A cross-sectional study of 934 asymptomatic women living in Khartoum, Sudan, was conducted during 2009–2010. A semi-structured questionnaire containing socio-economic and reproductive variables was used to collect data from each participant. Methods of screening used were VIA and conventional Pap smear, followed by colposcopy and biopsy for confirmation of the positive results of both screening tests.Results: The tests identified altogether 119 (12.7%) positive women. VIA detected significantly more positive women than Pap smear (7.6% versus 5.1%; P = 0.004), with an overlap between the two screening tests in 19% of positive results. There was no significant difference between VIA and Pap smear findings and sociodemographic and reproductive factors among screened women. Use of colposcopy and biopsy for positive women confirmed that 88/119 (73.9%) were positive for cervical intraepithelial neoplasia. VIA had higher sensitivity than Pap smear (74.2% versus 72.9%; P = 0.05) respectively. Out of 88 confirmed positive cases, 22 (25.0%) cases were invasive cervical cancer in stage 1, of which 19 versus three were detected by VIA and Pap smear respectively (P = 0.001). VIA had higher sensitivity and lower specificity than Pap smear (60.2% versus 47.7%) and (41.9% versus 83.8%) respectively. The combination of VIA/Pap has better sensitivity and specificity than each independent test (82.6% and 92.2%).Conclusion: The findings of this study showed that VIA has higher sensitivity and lower specificity compared to Pap smear, but a combination of both tests has greater sensitivity and specificity than each test independently. It indicates that VIA is useful for screening of cervical cancer in the primary health care setting in Sudan, but positive results need to be confirmed by colposcopy and biopsy.Keywords: cervical, cancer, screening, VIA, Pap smear, colposcopy, sensitivity, specificity, predictive value, primary health care setting

Ahmed Ibrahim1, Vibeke Rasch2, Eero Pukkala3, Arja R Aro1 1Unit for Health Promotion Research, University of Southern Denmark, Esbjerg, Denmark; 2Department of Obstetrics and Gynaecology, Odense University Hospital, Odense, Denmark; 3Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland Background: Cervical cancer is the second most common cancer among women in Sudan, with more than two-thirds of all women with invasive cervical cancer being diagnosed at an advanced stage (stages III and IV). The lack of a screening program for cervical cancer in Sudan may contribute to the late presentation of this cancer, but other factors potentially associated with advanced stages of cervical cancer at diagnosis are unknown. The purpose of this research was to investigate the relationship between age, marital status, ethnicity, health insurance coverage, residence in an urban vs a rural setting, and stage (at diagnosis) of cervical cancer in Sudan. Methods: This was a cross sectional study of 197 women diagnosed with different stages of cervical cancer. Data was obtained from the cancer registry unit at the Radiation and Isotopes Centre in Khartoum for all women diagnosed with cervical cancer in 2007. Results: There was an association between older age and advanced stage (at diagnosis) of cervical cancer (odds ratio [OR]: 1.03, 95% confidence interval [CI]: 1.01–1.05). Being of African ethnicity was associated with 76% increased odds (OR: 1.76, 95% CI: 1.01–3.05), living in a rural area was associated with 13% increased odds (OR: 1.13, 95% CI: 1.78–5.50), and being uninsured was associated with an almost eight-fold increase in odds (OR: 7.7, 95% CI: 3.76–15.38). Marital status and education level were not associated with an advanced stage of cervical cancer at diagnosis. Conclusion: Women with cervical cancer who are elderly, not covered by health insurance, of African ethnicity, and living in a rural area are more likely to be diagnosed at an advanced stage of cervical cancer in Sudan. These women should be targeted for cervical cancer screening and a health education program, and encouraged to have health insurance. Keywords: predictors, cervical cancer, diagnosis, advanced, health insurance, Sudan

Ahmed Ibrahim1, Vibeke Rasch2, Eero Pukkala3, Arja R Aro11Unit for Health Promotion Research, University of Southern Denmark, Esbjerg, Denmark; 2Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark; 3Institute for Statistical and Epidemiological Cancer Research, Finnish Cancer Registry, Helsinki, FinlandObjectives: To assess the risk factors of cervical cancer and the feasibility and acceptability of a visual inspection with acetic acid (VIA) screening method in a primary health center in Khartoum, Sudan.Methods: A cross-sectional prospective pilot study of 100 asymptomatic women living in Khartoum State in Sudan was carried out from December 2008 to January 2009. The study was performed at the screening center in Khartoum. Six nurses and two physicians were trained by a gynecologic oncologist. The patients underwent a complete gynecological examination and filled in a questionnaire on risk factors and feasibility and acceptability. They were screened for cervical cancer by application of 3%–5% VIA. Women with a positive test were referred for colposcopy and treatment.Results: Sixteen percent of screened women were tested positive. Statistically significant associations were observed between being positive with VIA test and the following variables: uterine cervix laceration (odds ratio [OR] 18.6; 95% confidence interval [CI]: 4.64–74.8), assisted vaginal delivery (OR 13.2; 95% CI: 2.95–54.9), parity (OR 5.78; 95% CI: 1.41–23.7), female genital mutilation (OR 4.78; 95% CI: 1.13–20.1), and episiotomy (OR 5.25; 95% CI: 1.15–23.8). All these associations remained statistically significant after adjusting for age, educational level, employment, and potential confounding factors such as smoking, number of sexual partners, and use of contraceptive method. Furthermore, the VIA screening method was found to be feasible and acceptable to participants.Conclusion: This pilot study showed that women who have uterine cervix laceration, assisted vaginal delivery, female genital mutilation, or episiotomy are at an increased risk of cervical cancer. It also showed that VIA is a feasible and acceptable cervical cancer screening method in a primary health care setting.Keywords: cervical cancer, screening, visual inspection, acetic acid, feasibility

Study Question: What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women?Summary Answer: The incidence of POI increased among females aged 15-19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased.What Is Known Already: So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause.Study Design, Size, Duration: Population-based study with 5011 women diagnosed with POI in 1988-2017. The data were collected from national registries and covers POI subjects in entire Finland.Participants/materials, Setting, Methods: Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model.Main Results and the Role Of Chance: The incidence was highest in the 35-39 age group, ranging from 73.8/100 000 women-years in 1993-1997 to 39.9/100 000 women-years in 2013-2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015-2017. Cumulative incidence of POI for women under 40 years in 1988-2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3-6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls.Limitations, Reasons For Caution: For some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria.Wider Implications Of the Findings: The risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis.Study Funding/competing Interest(s): This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]