Predictors of non-drug psychiatric/psychotherapeutic treatment in children and adolescents with mental or behavioural disorders.

Children and adolescents with mental health problems need effective and safe therapies to support their emotional and social development and to avoid functional impairment and progress of social deficits. Though psychotropic drugs seem to be the preferential treatment, psychotherapy and psychosocial interventions are essential in mental health care. For Germany, current data on the utilization of psychotherapy and psychosocial interventions in children with mental health problems is lacking. To analyse why certain children and adolescents with mental or behavioural disorders do and others do not receive non-drug treatment, we assessed predictors associated with specific non-drug psychiatric/psychotherapeutic treatment including psychosocial interventions, psychotherapy and other non-drug treatments. The study is based on data of two large German health insurance funds, AOK and TK, comprising 30 % of the German child and adolescent population. Predictors of non-drug psychiatric/psychotherapeutic treatment were analysed for 23,795 cases and two controls for every case of the same age and sex in children aged 0-17 years following a new diagnosis of mental or behavioural disorder in 2010. Predictors were divided according to Andersen's behavioural model into predisposing, need and enabling factors. The most prominent and significant predictors positively associated with non-drug psychiatric/psychotherapeutic treatment were the residential region as predisposing factor; specific, both ex- and internalizing, mental and behavioural disorders, psychiatric co-morbidity and psychotropic drug use as need factors; and low area deprivation and high accessibility to outpatient physicians and inpatient institutions with non-drug psychiatric/psychotherapeutic department as enabling factors. In conclusion, the present study suggests that the residential region as proxy for supply of therapist and socioeconomic situation is an influencing factor for the use of psychotherapy. The analysis sheds further light on predisposing, need and enabling factors as predictors of non-drug psychotherapeutic/psychiatric treatment in children and adolescents with mental or behavioural health disorders in Germany. More research is needed to further understand the factors promoting the gap between the need and utilization of mental health care.

Psychopharmacological Prescriptions in Children and Adolescents in Germany.

BACKGROUND: In view of the well-known increase in prescriptions of stimulants for children and adolescents over the last 20 years, it is important to study trends in the prevalence and incidence of the use of other psychotropic drugs by this age group as well, to enable an early response to potential problems in the current care situation. METHODS: We used nationwide data from German statutory health insurance funds (Allgemeine Ortskrankenkasse [AOK], all insurees; Techniker Kranken - kasse [TK], a 50% randomized sample) concerning all insurees aged 0-17 years (5.0 million people in 2012) to study trends in the prevalence and incidence of psychotropic medication use as well as initially prescribing medical specialties over the period 2004-2012, both for the overall group of psychotropic drugs and for selected subgroups of drugs. RESULTS: From 2004 to 2012, the prevalence of psychotropic drug prescriptions (not including herbal and homeopathic substances) for children and adolescents rose from 19.6 to 27.1 per 1000 individuals. Marked rises were seen for stimulants (10.5 to 19.1 per 1000) and antipsychotic drugs (2.3 to 3.1 per 1000), while the prevalence of antidepressant prescriptions remained constant at about 2 per 1000. The rates of new prescriptions from 2006 to 2012 were generally constant or decreasing; for the overall group of (non-herbal, nonhomeopathic) psychotropic drugs, the rate of new prescriptions fell from 9.9 to 8.7 per 1000. There was a trend toward the issuance of new prescriptions by medical specialists, rather than by family physicians and pediatricians. CONCLUSION: The observed increased prevalence of psychotropic drug use among children and adolescents appears to be due not to an increased rate of initial prescriptions for these drugs, but rather to a rise in the number of patients who, once having received such drugs, were given further prescriptions for them in the years that followed.

Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort.

PURPOSE: Clinical trials and few observational studies report increased hyperkalemia risks in heart failure patients receiving aldosterone blockers in addition to standard therapy. The aim of this study is to assess the hyperkalemia risk and combined use of spironolactone and long-term ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB) therapy for heart failure in a real-life setting of a heterogeneous population. METHODS: Using claims data of the statutory health insurance fund AOK, covering 30% of the German population, we performed a nested case-control study in a cohort of heart failure patients receiving continuous ACE/ARB therapy (n = 1,491,894). Hyperkalemia risk associated with concurrent use of spironolactone and ACE/ARB was calculated by conditional logistic regression in 1062 cases and 10,620 risk-set-sampling-matched controls. RESULTS: Risk of hyperkalemia in heart failure patients was significantly associated with spironolactone use (odds ratio (OR) (95% confidence interval (CI)) = 13.59 (11.63-15.88) in all and 11.05 (8.67-14.08) in those with information on New York Heart Association (NYHA) stage of disease). In the NYHA subpopulation, higher risk estimates were observed in short-term as compared with long-term users (OR (95%CI) = 13.00 (9.82-17.21) and 9.12 (6.78-12.26), respectively). Moreover, the association was stronger in older (≥70 years of age) as compared with younger patients (<70 years of age) (OR (95%CI) = 12.32 (9.35-16.23) and 8.73 (5.05-15.08), respectively), although interaction was not significant (pinteraction = 0.07). CONCLUSIONS: Hyperkalemia risk associated with combined use of spironolactone and ACE/ARB is much stronger in real-life practice than observed in clinical trials. Careful potassium level monitoring in concomitant users of spironolactone and ACE/ARB is necessary.

Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort.

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenprocoumon users ≥ 18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20-2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84-2.38 and OR 1.34, 95% CI 1.03-1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62-3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08-4.84) and fluorquinolones (OR 3.13, 95% CI 2.74-3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01-8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics - particularly quinolones and cotrimoxazole - should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.

Dietary intake of vitamin D and calcium and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition.

Studies assessing the effects of vitamin D or calcium intake on breast cancer risk have been inconclusive. Furthermore, few studies have evaluated them jointly. This study is the largest so far examining the association of dietary vitamin D and calcium intake with breast cancer risk in the European Prospective Investigation into Cancer and Nutrition. During a mean follow-up of 8.8 yr, 7760 incident invasive breast cancer cases were identified among 319,985 women. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for pre- and postmenopausal breast cancer risk. Comparing the highest with the lowest quintile of vitamin D intake, HR and 95% CI were 1.07 (0.87-1.32) and 1.02 (0.90-1.16) for pre- and postmenopausal women, respectively. The corresponding HR and 95% CIs for calcium intake were 0.98 (0.80-1.19) and 0.90 (0.79-1.02), respectively. For calcium intake in postmenopausal women, the test for trend was borderline statistically significant (P(trend) = 0.05). There was no significant interaction between vitamin D and calcium intake and cancer risk (P(interaction) = 0.57 and 0.22 in pre- and postmenopausal women, respectively). In this large prospective cohort, we found no evidence for an association between dietary vitamin D or calcium intake and breast cancer risk.

The frequency of prescription of immediate-release nifedipine for elderly patients in Germany: utilization analysis of a substance on the PRISCUS list of potentially inappropriate medications.

BACKGROUND: Immediate-release nifedipine is on the PRISCUS list of drugs that should not be given to elderly patients. We studied the use of this calcium-channel blocker under real-life conditions. METHODS: In 2009, we carried out a cross-sectional study based on the Statutory Health Insurance Sample AOK Hesse/KV Hesse with a sample size of 260 672 insurees. We used an anatomic-therapeutic-chemical classification (C08) to identify prescriptions for calcium-channel blockers. We determined from brand names and dosage forms whether nifedipine was prescribed in an immediate-release or sustained-release formulation. RESULTS: Among insurees over age 65, the prevalence of treatment with immediate-release and sustained-release nifedipine was 0.9% and 1.0%, respectively. Immediate-release nifedipine was usually (75%) given in a single administration. 46% of patients receiving immediate-release nifedipine also received another calcium-channel blocker. Patients who received immediate-release nifedipine tended to take more cardiovascular drugs than those who received sustained-release nifedipine (6 or more cardiovascular drugs were taken by 30% and 16%, respectively). Among all medical diagnoses related to hypertension, two were significantly more common among patients taking immediate-release nifedipine than among those taking sustained-release nifedipine: hypertensive crisis (OR 4.26, 95% CI 2.45-7.40) and hypertensive heart disease (OR 1.82, 95% CI 1.04-3.19). CONCLUSION: Our analysis demonstrates that immediate-release nifedipine is being prescribed to elderly patients in Germany, albeit mostly in a single administration. In view of the risks and the availability of alternative drugs, stricter adherence to the PRISCUS recommendations in this case should be stressed in continuing medical education.

Association of long-term adherence to evidence-based combination drug therapy after acute myocardial infarction with all-cause mortality. A prospective cohort study based on claims data.

PURPOSE: To determine long-term adherence to evidence-based secondary preventive combination pharmacotherapy in survivors of acute myocardial infarction (AMI) and to investigate the association between adherence to recommended therapy and all-cause mortality in claims data. METHODS: Prospective cohort study based on claims data of an 18.75 % random sample of all persons insured with the local statutory health insurance fund AOK Hesse. Study population included patients with hospital discharge diagnoses of AMI between 2001 and 2005 excluding those who died within the first 30 days after AMI or who had been hospitalised with an AMI in the previous 2 years. A total of 3,008 patients were followed up until death, cancellation of insurance, or the end of the study period on 31 December 2007, whichever came first (median follow-up: 4.2 years). RESULTS: Drug adherence to single drug groups as determined by proportion of days covered ≥80 % was 21.8 % for antiplatelet drugs, 9.4 % for beta-blockers, 45.6 % for ACE inhibitors or angiotensin II receptor blockers and 45.1 % for lipid-lowering drugs. A total of 924 (39.7 %) patients met our definition of guideline adherence: Drugs available from three of four relevant drug groups on the same day for at least 50 % of the observation time. Of the patients adhering to the guidelines, 17.3 % died and of the non-adherents, 32.4 % died. All-cause mortality was 28 % lower for guideline-adherent patients than for the non-adherent group (adjusted HR 0.72, 95 % CI 0.60-0.86). CONCLUSIONS: In everyday practice, post AMI patients benefit from guideline-oriented treatment, but the percentage of adherent patients should be improved.

Estimation of disease incidence in claims data dependent on the length of follow-up: a methodological approach.

OBJECTIVE: To analyze the impact of the length of disease-free intervals on incidence estimation. DATA SOURCE: Statutory health insurance sample in Germany. STUDY DESIGN: Overestimation of the incidence in the first quarter of 2008 for three selected diseases, diabetes mellitus, colorectal cancer, and heart failure, depending on different lengths of preceding disease-free intervals. DATA COLLECTION/EXTRACTION METHODS: Continuously insured from 2000 until 2008 ≥ 18 years (N = 144,907). PRINCIPAL FINDINGS: Compared with an 8-year disease-free period, incidence overestimations for diabetes, colorectal cancer, and heart failure were 40, 23, and 43 percent defining a 1-year, and 5, 9, and 5 percent defining a 5-year disease-free period, respectively. CONCLUSIONS: Depending on the specific disease, caution has to be taken while using short disease-free periods because incidence estimates may be extremely overestimated.

Prevalence and incidence of diagnosed endometriosis and risk of endometriosis in patients with endometriosis-related symptoms: findings from a statutory health insurance-based cohort in Germany.

OBJECTIVE: The objectives were: (a) to determine the administrative prevalence and incidence of endometriosis and (b) to assess the risk of endometriosis associated with endometriosis-related symptoms. STUDY DESIGN: The study is based on inpatient and outpatient data from a statutory health insurance fund in Germany. For prevalence and incidence definition 62,323 women aged 15-54 continuously insured in 2007 were identified. The prevalence and incidence of endometriosis in 2007 were calculated standardized to the age distribution in Germany. In a further prospective cohort study based within the health insurance sample 2095 patients with endometriosis-related symptoms and 8380 age-matched asymptomatic controls were identified. Endometriosis follow-up was from 2004 to 2008. Cox proportional hazard regression was used to examine the risk of endometriosis associated with endometriosis-related symptoms, such as pelvic pain, dysmenorrhoea, dyspareunia, menorrhagia, post-coital bleeding, inter-menstrual pain and ovarian cysts. Relative risks (RR) and 95% confidence intervals (CI) were calculated. RESULTS: Standardized prevalence and incidence rates were 8.1 and 3.5 per 1000 women, respectively. The highest prevalence was observed in women aged 35-44 with 12.8 per 1000 women. Median follow-up was 4.5 years. Risk of endometriosis associated with endometriosis-related symptomatology was RR (95% CI)=4.95 (3.67-6.68); 4.5% of all symptomatic women were diagnosed with endometriosis in a median follow-up of 4.5 years. The highest risk was observed in women aged 35-44 [RR (95% CI)=6.29 (4.00-9.90)] with 7.6% of all symptomatic women receiving a diagnosis of endometriosis during the follow-up. CONCLUSION: Prevalence estimates based on population-based administrative data were lower than described in the literature. Risk of endometriosis was increased in women with endometriosis-related symptoms. However, those symptoms were of limited predictive value for endometriosis as only a small proportion of symptomatic patients were diagnosed with endometriosis in the follow-up.

Serum 25-hydroxyvitamin D and postmenopausal breast cancer survival: a prospective patient cohort study.

INTRODUCTION: Vitamin D has been postulated to be involved in cancer prognosis. Thus far, only two studies reported on its association with recurrence and survival after breast cancer diagnosis yielding inconsistent results. Therefore, the aim of our study was to assess the effect of post-diagnostic serum 25-hydroxyvitamin D [25(OH)D] concentrations on overall survival and distant disease-free survival. METHODS: We conducted a prospective cohort study in Germany including 1,295 incident postmenopausal breast cancer patients aged 50-74 years. Patients were diagnosed between 2002 and 2005 and median follow-up was 5.8 years. Cox proportional hazards models were stratified by age at diagnosis and season of blood collection and adjusted for other prognostic factors. Fractional polynomials were used to assess the true dose-response relation for 25(OH)D. RESULTS: Lower concentrations of 25(OH)D were linearly associated with higher risk of death (hazard ratio (HR) = 1.08 per 10 nmol/L decrement; 95% confidence interval (CI), 1.00 to 1.17) and significantly higher risk of distant recurrence (HR = 1.14 per 10 nmol/L decrement; 95%CI, 1.05 to 1.24). Compared with the highest tertile (≥ 55 nmol/L), patients within the lowest tertile (< 35 nmol/L) of 25(OH)D had a HR for overall survival of 1.55 (95%CI, 1.00 to 2.39) and a HR for distant disease-free survival of 2.09 (95%CI, 1.29 to 3.41). In addition, the association with overall survival was found to be statistically significant only for 25(OH)D levels of blood samples collected before start of chemotherapy but not for those of samples taken after start of chemotherapy (P for interaction = 0.06). CONCLUSIONS: In conclusion, lower serum 25(OH)D concentrations may be associated with poorer overall survival and distant disease-free survival in postmenopausal breast cancer patients.

Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium.

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.

Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study.

Laboratory and epidemiological data have linked vitamin D to breast cancer prevention. Beside dietary intake, endogenous production of vitamin D substantially contributes to a subject's vitamin D status. Most studies, however, have assessed dietary intake only. Although differential effects of vitamin D on premenopausal and postmenopausal breast cancer have been discussed, this is the first study to investigate the association of plasma 25-hydroxyvitamin D [25(OH)D], as indicator of the overall vitamin D status, with breast cancer risk with restriction to premenopausal women only. We used data of a population-based case-control study comprising 289 cases and 595 matched controls. Information on sociodemographic and breast cancer risk factors was collected by questionnaire and plasma 25(OH)D was measured by enzyme immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. We observed a significant inverse association between breast cancer risk and plasma 25(OH)D concentrations. Compared with the lowest category (<30 nmol/L), the ORs (95% CI) for the upper categories (30-45, 45-60, >or=60 nmol/L) were 0.68 (0.43-1.07), 0.59 (0.37-0.94) and 0.45 (0.29-0.70), respectively (p(trend) = 0.0006). The association was shown to be nonlinear (p(nonlinearity) = 0.06) in fractional polynomial analysis with a stronger effect in women at low plasma 25(OH)D levels, providing some evidence of a threshold effect (at circa 50 nmol/L). The association was stronger in progesterone receptor negative tumors, with suggestive evidence of effect heterogeneity (p(heterogeneity) = 0.05, case-only model). Our findings support a protective effect of vitamin D for premenopausal breast cancer.

The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status.

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (P(trend) < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer.

Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk.

INTRODUCTION: Vitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined. METHODS: We assessed the effects of two frequently analyzed polymorphisms (FokI and TaqI) and two potentially functional variants (VDR-5132 and Cdx2) in the VDR gene, which thus far have not been analyzed with respect to breast cancer risk, on postmenopausal breast cancer risk in a population-based, case-control study including 1,408 patients (cases) and 2,612 control individuals (controls) matched for year of birth. Odds ratios (ORs) for breast cancer adjusted for potential confounders were calculated for genotypes and estimated haplotypes. RESULTS: No differences in serum 25(OD)D concentrations by VDR genotype were observed. None of the analyzed polymorphisms was associated with overall risk for postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk for oestrogen receptor positive tumours (OR = 1.18, 95% confidence interval [CI] = 1.00 to 1.38, comparing t allele carriers with noncarriers) but not for oestrogen receptor negative tumours (OR = 0.88, 95% CI = 0.69 to 1.13; P for interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A), which contains the TaqI t allele, to be associated with a significantly greater breast cancer risk as compared with the most frequent haplotype FTCG (OR = 1.43, 95% CI = 1.00 to 2.05). No significant interaction between VDR genotypes or haplotypes and 25(OH)D was observed. CONCLUSION: Our results support potential effects of VDR polymorphisms on postmenopausal breast cancer risk and possible differential effects of receptor status of the tumour. However, further studies focusing on the influence of polymorphisms and haplotypes on VDR functionality, activity and concentration are needed.

Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer--results of a large case-control study.

Various studies suggest that vitamin D may reduce breast cancer risk. Most studies assessed the effects of dietary intake only, although endogenous production is an important source of vitamin D. Therefore, the measurement of serum 25-hydroxyvitamin D [25(OH)D] better indicates overall vitamin D status. To assess the association of 25(OH)D serum concentrations with post-menopausal breast cancer risk, we used a population-based case-control study in Germany, which recruited incident breast cancer patients aged 50-74 between 2002 and 2005. Information on sociodemographic and breast cancer risk factors was collected by personal interview. For this analysis, we included 1394 cases and 1365 controls, matched on year of birth and time of blood collection. Conditional logistic regression was used to calculate odds ratios (ORs) for breast cancer adjusted for potential confounders. Serum 25(OH)D concentration was significantly inversely associated with post-menopausal breast cancer risk. Compared with the lowest category (<30 nM), OR [95% confidence intervals (CI)] for the higher categories of 25(OH)D (30-45, 45-60, 60-75 and >/=75 nM) were 0.57 (0.45-0.73), 0.49 (0.38-0.64), 0.43 (0.32-0.57) and 0.31 (0.24-0.42), respectively (P(trend) < 0.0001). Analysis using fractional polynomials indicated a non-linear association. The association was stronger in women never using menopausal hormone therapy (HT) compared with past and current users (P(interaction) < 0.0001). Our findings strongly suggest a protective effect for post-menopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D measurement, with a stronger inverse association in women with low serum 25(OH)D concentrations (<50 nM).

Dietary vitamin D and calcium intake and premenopausal breast cancer risk in a German case-control study.

Epidemiological studies and laboratory data suggest that vitamin D may protect against the development of cancer, including breast cancer. Vitamin D supply affects the bioavailability of dietary calcium, which might also have anticarcinogenic effects. However, few studies considered them jointly. We used a population-based case-control study in Germany to examine the independent and joint effects of dietary vitamin D and calcium on premenopausal breast cancer risk. Dietary information was assessed using a validated food frequency questionnaire from 278 premenopausal cases and 666 age-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate models adjusting vitamin D models for calcium intake and vice versa. Breast cancer risk was significantly inversely associated with vitamin D intake. The OR and 95% CI for the highest intake category (> or = 5 microg/day) was 0.50 (95% CI = 0.26-0.96) compared with the lowest (< 2 microg/day; P(trend) = 0.02). Dietary calcium intake was not associated with breast cancer (OR = 0.73, 95% CI = 0.41-1.29) for the highest (> or = 1,300 mg/day) versus the lowest category (< 700 mg/day), P(trend) = 0.29). No statistically significant interaction between the 2 nutrients was observed. Our data support a protective effect of dietary vitamin D on premenopausal breast cancer risk independent of dietary calcium intake.

A multiresistant clone of Shiga toxin-producing Escherichia coli O118:[H16] is spread in cattle and humans over different European countries.

Multiresistant Shiga toxin-producing Escherichia coli (STEC) O118:H16 and O118 nonmotile strains (designated O118:[H16]) were detected by examination of 171 STEC isolates for their antimicrobial sensitivity. Of 48 STEC O118:[H16] strains, 98% were resistant to sulfonamide, 96% were resistant to streptomycin, 79% were resistant to kanamycin, 75% were resistant to tetracycline, 67% were resistant to ampicillin, 60% were resistant to chloramphenicol, 48% were resistant to trimethoprim, and 10% each were resistant to gentamicin and nalidixic acid. Nalidixic acid resistance and reduced susceptibility to ciprofloxacin were associated with the mutation gyrA(LEU-83). The STEC O118:[H16] strains were found to belong to a single genetic clone as investigated by multilocus enzyme electrophoresis and by multilocus sequence analysis of E. coli housekeeping genes. The STEC O118:[H16] strains originated from humans and cattle and were isolated in seven different countries of Europe between 1986 and 1999. Strains showing multiresistance to up to eight different antimicrobials predominated among the more recent STEC O118:[H16] strains. The genes in parentheses were associated with resistance to kanamycin (aphA1-Ia), chloramphenicol (catA1), tetracycline [tet(A)], and ampicillin (bla(TEM-1)). Class 1 integrons containing sulI (sulfonamide resistance), aadA1a (streptomycin resistance), or dfrA1 (trimethoprim resistance)-aadA1a gene cassettes were detected in 28 strains. The bla(TEM-1b) gene was present in 18 of 21 strains that were examined by nucleotide sequencing. Class 1 integrons and bla(TEM) genes were localized on plasmids and/or on the chromosome in different STEC O118:[H16] strains. Hybridization of XbaI-digested chromosomal DNA separated by pulsed-field gel electrophoresis revealed that bla(TEM) genes were integrated at different positions in the chromosome of STEC O118:[H16] strains that could have occurred by Tn2 insertion. Our data suggest that strains belonging to the STEC O118:[H16] clonal group have a characteristic propensity for acquisition and maintenance of resistance determinants, thus contrasting to STEC belonging to other serotypes.