Factors associated with teenage pregnancy in the Scandinavian countries.

AIMS: Teenage pregnancy may have negative consequences for the mother and the infant. The aim of the study was to examine whether selected individual factors occurring early in life were associated with teenage pregnancy. METHODS: In a population-based, cross-sectional questionnaire study among 34,455 women from Denmark, Norway, and Sweden aged 20-45 years, who had first sexual intercourse (FSI) at age 13-19 years, we assessed the association between early smoking and drinking initiation (i.e., before the age of 13), contraceptive use at FSI, and teenage pregnancy. Log-linear binary regression models were fitted to estimate the relative risk (RR) with 95% confidence intervals (CIs) of teenage pregnancy according to the three exposure variables, overall and by age at FSI. Furthermore, the outcomes of the teenage pregnancies were examined according to age at FSI. RESULTS: Teenage pregnancy occurred in 11% of the population. Both early smoking initiation (RR: 1.6; 95% CI: 1.4-1.8), early drinking initiation (RR: 1.2; 95% CI: 1.0-1.4), and non-use of contraceptives at FSI (RR: 1.9; 95% CI: 1.8-2.0) were associated with teenage pregnancy. The associations for early smoking initiation and non-use of contraceptives remained when analyses were stratified by age at FSI. Almost 60% of all teenage pregnant women had an induced abortion and less than 30% gave birth. CONCLUSIONS: Individual factors, including early smoking and drinking initiation, and non-use of contraceptives at FSI, were associated with teenage pregnancy regardless of age at FSI. This emphasizes the necessity of focusing on early risk-taking behavior as a potential modifier to prevent teenage pregnancy.

Spontaneous preterm birth risk among HPV-vaccinated and -unvaccinated women: a nationwide retrospective cohort study of over 240 000 singleton births.

OBJECTIVE: To determine whether prior human papillomavirus (HPV) vaccination contributes to preterm birth risk. DESIGN: Population-based retrospective cohort study. SETTING: Denmark. POPULATION: A cohort of 243 136 primiparous females born in the period 1961-2004 who had a singleton delivery at >22 weeks of gestation occurring from October 2006 to December 2018. METHODS: High-quality nationwide registries were linked to provide information on demographics, birth outcomes, HPV vaccination status, smoking, body mass index (BMI), and cervical lesions and treatment history. MAIN OUTCOME MEASURES: We assessed the association between HPV vaccination status and spontaneous preterm birth using logistic regression. To address age at vaccination, we performed a stratified analysis by vaccination before and after 17 years of age. RESULTS: In age-adjusted and fully adjusted models, there was a nonsignificant difference in the odds of spontaneous preterm birth between vaccinated and unvaccinated women (OR 1.05 (95% CI 0.99-1.12) and OR 1.04 (95% CI 0.98-1.10), respectively). There was no difference in the odds of spontaneous preterm birth in relation to time between vaccination and pregnancy. In contrast, compared with unvaccinated women, the odds of preterm birth were lower among women vaccinated before the age of 17 years (fully adjusted OR 0.87, 95% CI 0.75-1.00). This association was not present for women vaccinated at ≥17 years of age. CONCLUSIONS: In this large, population-based cohort, we found reduced odds of spontaneous preterm birth among women vaccinated against HPV at an early age compared with women who were unvaccinated. It seems conceivable that HPV vaccination may not only reduce the incidence of cervical cancer and severe precursors, but also reduce the risk of preterm birth related to HPV infection.

Human Papillomavirus Infection Among Pregnant Women Living With HIV: A Systematic Review and Meta-Analysis.

BACKGROUND: In the general population, human papillomavirus (HPV) prevalence is reportedly increased during pregnancy, and emerging evidence suggests that it may be associated with adverse pregnancy outcomes. Women living with HIV (WLWH) experience higher rates of both HPV infection and certain adverse pregnancy outcomes, yet there are no prior reviews of HPV infection during pregnancy in WLWH. METHODS: We conducted a systematic review and meta-analysis of pooled and type-specific HPV prevalence and associated pregnancy outcomes among pregnant WLWH and, if available, within-study comparators of women without HIV. Subgroup analyses were performed according to polymerase chain reaction primers used and geographic location. RESULTS: Ten studies describing HPV prevalence in 1594 pregnant WLWH were included. The pooled HPV prevalence in pregnant WLWH was 75.5% (95% confidence interval: 50.2 to 90.4) but ranged widely (23%-98%) between individual studies. Among studies that also assessed HPV prevalence in pregnant women without HIV, the pooled prevalence was lower at 48.1% (95% confidence interval: 27.1 to 69.8). Pregnant WLWH had 54% higher odds of being HPV positive compared with pregnant women without HIV. The most common HPV type detected in pregnant WLWH was HPV16. No studies reported pregnancy outcomes by the HPV status. CONCLUSIONS: High prevalence of HPV was documented in pregnant WLWH, exceeding the prevalence among pregnant women without HIV. The limited research on this topic must be addressed with further studies to inform the use of HPV testing as a screening modality for this population as well as the role of HPV in adverse pregnancy outcomes.

A nationwide longitudinal study on risk factors for progression of anal intraepithelial neoplasia grade 3 to anal cancer.

Little is known about risk factors for progression of high-grade anal intraepithelial neoplasia (AIN) to anal squamous cell carcinoma (ASCC). In this large, population-based study, we assess the role of factors related to immune status for the risk of ASCC among individuals from the general population with a diagnosis of AIN3. Individuals diagnosed with AIN3 during 1985-2016 were identified in the Danish Pathology Registry and followed for subsequent development of ASCC. The study population was linked to the National Patient Registry, the Danish Prescription Registry and the Danish HIV Cohort Study for information on autoimmune disease, genital warts and HIV status. To study the progression rate, Cox regression models with hazard ratios (HR) and 95% confidence intervals (CI) were applied with time since AIN3 as the underlying time scale and with adjustment for age at AIN3 diagnosis, year of AIN3 diagnosis and sex. The study population comprised 1222 individuals with AIN3 contributing 12 824 person-years of follow-up. Ninety-seven individuals (7.9%) developed ASCC. Individuals registered with an autoimmune disease or genital warts before and/or after the AIN3 diagnosis had an increased rate of progression to ASCC compared to individuals without these conditions. People living with HIV had a higher progression rate than HIV-negative individuals (HR = 4.25; 95% CI: 1.87-9.65) with the highest progression rate among those with CD4 count ≤200 cells/µL. These associations may be caused by an interplay between HPV infection and immunosuppression.

Determinants of Human Papillomavirus Vaccine Uptake by Adult Women Attending Cervical Cancer Screening in 9 European Countries.

INTRODUCTION: Human papillomavirus-vaccinated cohorts, irrespective of age, will likely reduce their subsequent screening requirements, thus opening opportunities for global cost reduction and program sustainability. The determinants of uptake and completion of a 3-dose human papillomavirus vaccination program by adult women in a European context were estimated. STUDY DESIGN: This was an intervention study. SETTING/PARTICIPANTS: Study participants were women aged 25-45 years, attending opportunistic or population-based cervical cancer screening in Belgium, Denmark, Finland, France, Germany, Slovenia, Spain, Sweden, and the United Kingdom between April 2016 and May 2018. INTERVENTION: Study participants completed a questionnaire on awareness and attitudes on adult female human papillomavirus vaccination and were invited to receive free human papillomavirus vaccination. MAIN OUTCOME MEASURES: Main outcome measures were acceptance, uptake, and completion of vaccination schedule. Determinants of vaccine uptake were explored using multilevel logistic models in 2019. RESULTS: Among 3,646 participants, 2,748 (range by country=50%-96%) accepted vaccination, and 2,151 (range=30%-93%) received the full vaccination course. The factors associated with higher vaccine acceptance were previous awareness of adult female (OR=1.22, 95% CI=1.00, 1.48) and male (OR=1.59, 95% CI=1.28, 1.97) vaccination. Women in stable relationships (OR=0.56, 95% CI=0.45, 0.69) or with higher educational level (OR=0.76, 95% CI=0.63, 0.93) were more likely to refuse vaccination. Recruitment by postal invitation versus personal invitation from a healthcare professional resulted in lower vaccine acceptance (OR=0.13, 95% CI=0.02, 0.76). Vaccination coverage of >70% of adolescent girls in national public programs was of borderline significance in predicting human papillomavirus vaccine uptake (OR=3.23, 95% CI=0.95, 10.97). The main reasons for vaccine refusal were vaccine safety concerns (range=30%-59%) and the need for more information on human papillomavirus vaccines (range=1%-72%). No safety issues were experienced by vaccinated women. CONCLUSIONS: Acceptance and schedule completion were largely dependent on recruitment method, achieved coverage of national vaccination programs, and personal relationship status. Knowledge of benefits and safety reassurance may be critical to expanding vaccination target ages. Study results suggest that there are no major opinion barriers in adult women to human papillomavirus vaccination, especially when vaccination is offered face to face in healthcare settings. TRIAL REGISTRATION: EudraCT Number 2014-003177-42.

Borderline ovarian tumors in Denmark 1997-2018: Time trends in incidence by histology, age and educational level.

INTRODUCTION: After some decades with an increasing incidence of borderline ovarian tumors, more recent studies have observed that the incidence rate seems to be leveling off or declining. In this study, we describe the incidence of borderline ovarian tumors in Denmark 1997-2018 by histology, age at diagnosis and educational level. MATERIAL AND METHODS: All borderline ovarian tumors registered in the Danish Pathology Registry during 1997-2018 were identified and individual-level educational information was retrieved from nationwide registers. Age-standardized incidence rates were estimated according to histology, age at diagnosis and educational level. To investigate incidence trends over time, the average annual percentage change and corresponding 95% confidence intervals (CIs) were estimated using Poisson regression. RESULTS: We identified 3927 women with borderline ovarian tumors during the study period, of which 1997 (50.9%) were serous and 1743 (44.4%) were mucinous. The age-standardized incidence rate of serous borderline ovarian tumors did not change significantly over calendar time (average annual percentage change = -0.13, 95% confidence interval [CI] -1.13 to 0.88). For mucinous tumors, the age-standardized incidence rate was also relatively stable during the first half of the study period, followed by a decrease from 2.56 to 1.25 per 100 000 person-years between 2007-2011 and 2017-2018. Over the entire study period, the incidence rate of mucinous borderline tumors declined on average by 2.91% (95% CI -4.24 to -1.51) per year. The incidence of both types of borderline ovarian tumors seemed to be highest among women with a low educational level. Over calendar time, the incidence of mucinous tumors decreased in all educational groups, whereas the incidence of serous tumors decreased exclusively in women with a high educational level. Time trends did not differ markedly by age at diagnosis. CONCLUSIONS: In Denmark, the incidence of serous borderline ovarian tumors was stable during 1997-2018, whereas the incidence of mucinous borderline ovarian tumors decreased. The incidence rates of both types of borderline ovarian tumors tended to be highest among women with a low educational level throughout the study period.

Risk of Anal Cancer Following Benign Anal Disease and Anal Cancer Precursor Lesions: A Danish Nationwide Cohort Study.

BACKGROUND: Human papillomavirus (HPV) is associated with the majority of anal high-grade intraepithelial neoplasia (AIN) and anal cancers. Little is known about the risk of anal cancer following a diagnosis of benign anal disease and AIN. METHODS: Using data from nationwide, population-based Danish registries, a cohort of 126,174 individuals with either non-neoplastic anal disease or AIN 1 to 3 during 1970 to 2016 was followed until first occasion of anal cancer. Information on HIV status was obtained from the Danish HIV Cohort Study. The absolute risk of anal cancer was estimated using the Aalen-Johansen estimator taking into account censoring at emigration and end of follow-up and competing risk at time of death. Standardized incidence ratios (SIR) for anal cancer among individuals with non-neoplastic anal disease, including inflammatory lesions, hemorrhoids, and polyps, were estimated in Poisson models. Sex-, age-, and calendar period-specific national population rates were estimated using the Danish National Pathology Registry. RESULTS: Anal cancer risk increased with increasing severity of lesions, reaching 4% 5 years after diagnosis of AIN3. Even among those with non-neoplastic anal lesions, particularly inflammatory lesions, anal cancer risk was significantly higher than expected from Danish national anal cancer rates (SIR = 2.8; 95% confidence intervals, 2.3-3.2). The absolute 5-year risk of anal cancer following AIN3 was considerably higher among HIV-positive (14.1%) than HIV-negative (3.2%) individuals. CONCLUSIONS: Anal cancer risk increases with increasing severity of lesions and is especially high among HIV-positive individuals. IMPACT: Vaccination against HPV is important in the prevention of both high-grade AIN and anal cancer.

Prevalence, type distribution and risk factors for oral HPV in Danish renal transplant recipients.

OBJECTIVE: To assess the prevalence and type distribution of oral human papillomavirus (HPV) among renal transplant recipients (RTRs) and healthy controls and to examine risk factors for oral HPV among RTRs. MATERIALS AND METHODS: During 2016-2017 we recruited 250 RTRs and 250 controls. Oral samples were tested for HPV DNA with INNO-LiPA HPV Genotyping Extra II. All participants answered a questionnaire on lifestyle and sexual behaviour, and characteristics of RTRs were obtained from medical files. We assessed prevalence and type distribution of oral HPV. Using logistic regression, the risk of oral HPV and risk factors for oral HPV among RTRs were estimated as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Overall, 30 RTRs (12.1%) and 26 controls (10.4%) were oral HPV positive (OR = 1.14; 95% CI: 0.64-2.05). Female RTRs tended to have a higher oral HPV prevalence than controls (OR = 1.73; 95% CI: 0.63-4.77), while no difference was observed among men. HPV51 was the commonest genotype. Sexual behaviour tended to be associated with oral HPV among RTRs. CONCLUSIONS: There was no overall difference in oral HPV prevalence between RTRs and controls, but female RTRs tended to have a higher prevalence of oral HPV than controls.

Prevalence and type distribution of human papillomavirus in squamous cell carcinoma and intraepithelial neoplasia of the vulva.

In this updated systematic review and meta-analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta-regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1-44.4%). Overall, 76.3% (95% CI: 70.1-82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5-95.5%) and 2.0% (95% CI: 0-10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases, the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.

Prevalence of human papillomavirus in epithelial ovarian cancer tissue. A meta-analysis of observational studies.

OBJECTIVE: The role of human papillomavirus (HPV) in the pathogenesis of ovarian cancer is controversial, and conflicting results have been published. We conducted a systematic review and meta-analysis to estimate the prevalence of HPV in epithelial ovarian cancer tissue. MATERIAL AND METHODS: Observational studies published until 4 March 2013 were identified in PubMed and Embase. We adhered to MOOSE guidelines and included 22 studies (case-control, cross-sectional studies). A pooled estimate of the HPV prevalence with corresponding 95% confidence interval (CI) was calculated based on a random effect model. In a meta-regression analysis we examined the contribution of different factors to heterogeneity. Furthermore, publication bias was evaluated. RESULTS: The pooled HPV prevalence in ovarian cancer tissue was 15.5%, but wide variation was found (0-66.7%). After stratification by geographical region, publication year, tissue type and method of HPV detection, we found that the prevalence of HPV varied most markedly by geographical area, the prevalence being 45.6% (95% CI, 31.0-60.3) in Asia, 18.5% (95% CI, 8.5-28.6) in Eastern Europe, 1.1% (95% CI, -1.6 to 3.8) in Western Europe and zero in North America. A meta-regression analysis revealed that the difference between geographical regions could not be explained by HPV detection method or type of tissue. CONCLUSIONS: Great geographical variation exists in HPV prevalence in ovarian cancer tissue, which is not explained by different HPV detection methods. The results suggest that HPV is unlikely to play an important role in Western European and American women, but cannot reject a role of HPV in other populations.

Pelvic inflammatory disease and risk of invasive ovarian cancer and ovarian borderline tumors.

PURPOSE: The aim of the study was to examine the potential association between a history of pelvic inflammatory disease (PID) and risk of epithelial ovarian cancer or ovarian borderline tumors. METHODS: In a population-based case-control study in Denmark, we included 554 women with invasive ovarian cancer, 202 with ovarian borderline tumors, and 1,564 controls aged 35-79 years. The analyses were performed in multiple logistic regression models. RESULTS: We found a significantly increased risk of ovarian borderline tumors among women with a history of PID (OR = 1.50; 95% CI 1.08-2.08) but no apparent association between PID and risk of invasive ovarian cancer (OR = 0.83; 95% CI 0.65-1.05). We found no effect of age at time of first PID or time since first PID on the risk for either condition. CONCLUSION: Our results suggest that a history of PID is associated with an increased risk of ovarian borderline tumors, which may support the hypothesis that inflammation is an etiological factor. The lack of an association between previous PID and invasive ovarian cancer may indicate an etiological difference between ovarian borderline tumors and invasive ovarian cancer. However, an important limitation of the study is the use of self-reported PID.

Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies.

PURPOSE: The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology. METHODS: We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model. RESULTS: Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer. CONCLUSIONS: Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

Nonsteroidal anti-inflammatory drugs and risk of ovarian cancer: systematic review and meta-analysis of observational studies.

OBJECTIVE: Several observational studies have investigated the association between nonsteroidal anti-inflammatory drug (NSAID) use and ovarian cancer risk, but with conflicting results. We performed a systematic review and meta-analysis of the association between NSAID use and ovarian cancer risk. DESIGN: Systematic review and meta-analysis of observational studies published until September 2012. SETTING: Studies were identified from the PubMed database. POPULATION: Fourteen case-control and seven cohort studies were included. METHODS: Pooled relative risks (RRs) with corresponding 95% confidence intervals (CI) for aspirin and non-aspirin NSAIDs, separately, were calculated. Both fixed and random effect models were applied, but only random effect pooled RRs are presented. Risk estimates for invasive and borderline ovarian tumors combined and for invasive ovarian tumors only were calculated. Furthermore, heterogeneity and publication bias were evaluated. MAIN OUTCOME MEASURES: Ovarian cancer. RESULTS: In the combined analysis, a slight inverse association between use of aspirin (RR 0.93; 95% CI 0.84-1.02) and non-aspirin NSAIDs (RR 0.94; 95% CI 0.84-1.06) and ovarian cancer risk was found, although it was not statistically significant. However, the risk of invasive ovarian cancer was significantly reduced with use of aspirin (RR 0.88; 95% CI 0.79-0.98). A similar tendency was observed for non-aspirin NSAIDs, but the results were not significant. CONCLUSIONS: This meta-analysis showed a slight inverse association between NSAIDs and risk of ovarian cancer. However, data suggest that a chemopreventive effect of NSAIDs may be restricted to invasive ovarian tumors. Further research on NSAIDs and ovarian cancer is needed before definite conclusions can be drawn.

Use of analgesic drugs and risk of ovarian cancer: results from a Danish case-control study.

OBJECTIVE: The role of analgesic drug use in development of ovarian cancer is not fully understood. We examined the association between analgesic use and risk of ovarian cancer. In addition, we examined whether the association differed according to histological types. DESIGN: Population-based case-control study. SETTING: Denmark in the period 1995-1999. POPULATION: We included 756 women with epithelial ovarian cancer and 1564 randomly selected control women aged 35-79 years. METHODS: Information on analgesic drug use was collected from personal interviews. Analgesic drugs were divided into the following categories: any analgesics; aspirin; non-aspirin non-steroidal anti-inflammatory drugs; paracetamol; and other analgesic drugs. The association between analgesic drug use and ovarian cancer risk was analysed using multiple logistic regression models. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. MAIN OUTCOME MEASURES: Epithelial ovarian cancer. RESULTS: Women with a regular use of any analgesics (OR = 0.79; 95% CI 0.62 - 1.01) or aspirin (OR = 0.68; 95% CI 0.46 - 1.02) had a decreased risk of ovarian cancer, although not statistically significant. Regular use of non-aspirin non-steroidal anti-inflammatory drugs, paracetamol or other analgesics did not decrease ovarian cancer risk. Use of any analgesics (OR = 0.72; 95% CI 0.53-0.98) or aspirin (OR = 0.60; 95% CI 0.36-1.00) resulted in a statistically significant decreased risk of serous ovarian cancer but not mucinous or other ovarian tumors. CONCLUSION: In accordance with most previous studies, our results indicate a possible inverse association between analgesic use, particularly aspirin, and ovarian cancer risk.

Use of dairy products, lactose, and calcium and risk of ovarian cancer - results from a Danish case-control study.

BACKGROUND: A number of epidemiological studies have examined the association between use of dairy products and risk of ovarian cancer, but results are conflicting. Using data from a large Danish population-based case-control study we here further examined the association between dairy consumption, lactose, and calcium and risk of overall ovarian cancer and histological types of ovarian cancer. MATERIAL AND METHODS: In the period 1995-1999 we included 554 women with epithelial ovarian cancer and 1554 randomly selected age-matched controls (35-79 years). All women participated in a detailed personal interview that included questions about dairy consumption. Data were analysed using multiple logistic regression models. RESULTS: Total dairy intake was associated with ovarian cancer risk (OR = 1.11; 95% CI: 1.07-1.15 per 100 ml/day). The association was strongest for milk [OR = 1.14; 95% CI: 1.03-1.27 per glass (200 ml)/day], soured milk products [OR = 1.49; 95% CI: 1.22-1.81 per portion (250 ml)/day] and yoghurt [OR = 1.65; 95% CI: 1.22-2.23 per portion (250 ml)/day]. In contrast, intake of cheese was associated with a decreased risk [OR = 0.70; 95% CI: 0.55-0.89 for > 1 portion (100 ml)/day compared with no intake]. Intake of lactose, but not calcium, was also associated with an increased ovarian cancer risk (OR = 1.24; 95% CI: 1.10-1.40 per 10 g of lactose/day). Similar risk patterns were observed for the different histological types of ovarian cancer, indicating virtually identical aetiologies with regard to dairy intake, lactose, and calcium. CONCLUSIONS: Our results indicate that intake of dairy products is associated with a modest increased risk of ovarian cancer. In addition, ovarian cancer development was associated with lactose intake.