Predictors of therapeutic treatment outcome in adolescent chronic tic disorders.

BACKGROUND: Chronic tic disorders may have a major impact on a child's function. A significant effect has been shown for combined habit reversal training (HRT) and exposure response prevention (ERP) treatment delivered in an individual and group setting. AIMS: The present study examines predictors and moderators of treatment outcome after an acute therapeutic intervention. METHOD: Fifty-nine children and adolescents were randomised to manualised treatment combining HRT and ERP as individual or group training. Age, gender, baseline tic severity, Premonitory Urge for Tics Scale (PUTS) scores, Beliefs about Tic Scale (BATS) scores, hypersensitivity and comorbid psychiatric symptoms were analysed as predictors of outcome. The same characteristics were examined as moderators for individual versus group treatment. Outcome measures included the change in total tic severity (TTS) score and functional impairment score (as measured by the Yale Global Tic Severity Scale (YGTSS)). RESULTS: Internalising symptoms predicted a lesser decrease in functional impairment. The occurrence of obsessive-compulsive symptoms predicted a larger decrease in TTS. Baseline hypersensitivity and high scores on depressive symptoms favoured individual treatment. High baseline PUTS scores favoured group therapy. CONCLUSIONS: This is the first study examining factors predicting and moderating perceived functional impairment following a therapeutic intervention. The study adds to the knowledge on predictors and moderators of TTS. Furthermore, this is the first study examining the effect of the BATS score. The study points towards factors that may influence treatment outcome and that require consideration when choosing supplemental treatment. This applies to comorbid anxiety and depressive symptoms, and to the child's belief about their tics and premonitory urge. DECLARATION OF INTEREST: None.

Reproduction after the loss of a child: a population-based matched cohort study.

STUDY QUESTION: Is the death of a child associated with higher subsequent fertility? SUMMARY ANSWER: Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the child's age at the time of death. WHAT IS KNOWN ALREADY: Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior. STUDY DESIGN, SIZE, DURATION: The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522). MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the child's death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up. LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant ERC-2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.

Diagnostic validity of early-onset obsessive-compulsive disorder in the Danish Psychiatric Central Register: findings from a cohort sample.

OBJECTIVES: Employing national registers for research purposes depends on a high diagnostic validity. The aim of the present study was to examine the diagnostic validity of recorded diagnoses of early-onset obsessive-compulsive disorder (OCD) in the Danish Psychiatric Central Register (DPCR). DESIGN: Review of patient journals selected randomly through the DPCR. METHOD: One hundred cases of OCD were randomly selected from DPCR. Using a predefined coding scheme based on the Children's Yale Brown Obsessive Compulsive Scale (CYBOCS), experienced research nurse or child and adolescent psychiatrists assessed each journal to determine the presence/absence of OCD diagnostic criteria. The detailed assessments were reviewed by two senior child and adolescent psychiatrists to determine if diagnostic criteria were met. PRIMARY OUTCOME MEASUREMENTS: Positive predictive value (PPV) was used as the primary outcome measurement. RESULTS: A total of 3462 children/adolescents received an OCD diagnosis as the main diagnosis between 1 January 1995 and 31 December 2015. The average age at diagnosis was 13.21±2.89 years. The most frequent registered OCD subcode was the combined diagnosis DF42.2. Of the 100 cases we examined, 35 had at least one registered comorbidity. For OCD, the PPV was good (PPV 0.85). Excluding journals with insufficient information, the PPV was 0.96. For the subcode F42.2 the PPV was 0.77. The inter-rater reliability was 0.94. The presence of the CYBOCS in the journal significantly increased the PPV for the OCD diagnosis altogether and for the subcode DF42.2. CONCLUSION: The validity and reliability of International Classification of Disease 10th revision codes for OCD in the DPCR is generally high. The subcodes for predominant obsessions/predominant compulsions are less certain and should be used with caution. The results apply for both children and adolescents and for both older and more recent cases. Altogether, the study suggests that there is a high validity of the OCD diagnosis in the Danish National Registers.

A framework for the etiology of running-related injuries.

The etiology of running-related injury is important to consider as the effectiveness of a given running-related injury prevention intervention is dependent on whether etiologic factors are readily modifiable and consistent with a biologically plausible causal mechanism. Therefore, the purpose of the present article was to present an evidence-informed conceptual framework outlining the multifactorial nature of running-related injury etiology. In the framework, four mutually exclusive parts are presented: (a) Structure-specific capacity when entering a running session; (b) structure-specific cumulative load per running session; (c) reduction in the structure-specific capacity during a running session; and (d) exceeding the structure-specific capacity. The framework can then be used to inform the design of future running-related injury prevention studies, including the formation of research questions and hypotheses, as well as the monitoring of participation-related and non-participation-related exposures. In addition, future research applications should focus on addressing how changes in one or more exposures influence the risk of running-related injury. This necessitates the investigation of how different factors affect the structure-specific load and/or the load capacity, and the dose-response relationship between running participation and injury risk. Ultimately, this direction allows researchers to move beyond traditional risk factor identification to produce research findings that are not only reliably reported in terms of the observed cause-effect association, but also translatable in practice.

Prenatal maternal bereavement and mortality in the first decades of life: a nationwide cohort study from Denmark and Sweden.

BACKGROUND: The loss of a close relative is one of the most stressful life events. In pregnancy, this experience has been associated with a higher risk of fetal death and under-five mortality, but little is known about potential effects on long-term mortality in offspring. We examined the association between prenatal maternal bereavement and mortality in a cohort of 5.3 million children followed until up to 37 years of age. METHOD: The population-based cohort study included 5 253 508 live singleton births in Denmark (1973-2004) and Sweden (1973-2006). Children born to mothers who lost a child, spouse, sibling, or parent during or 1 year before pregnancy were categorized as exposed. RESULTS: Prenatal maternal bereavement was associated with a 10% increased all-cause mortality risk in offspring [mortality rate ratio (MRR) 1.10, 95% confidence interval (CI) 1.03-1.18]. The association was the most pronounced for children of mothers who lost a child/spouse (MRR 1.28, 95% CI 1.14-1.44) and was stronger during the first 10 years of life. Prenatal maternal bereavement may have stronger effects on natural causes of death in offspring, including infectious/parasitic disease (MRR 1.86, 95% CI 1.07-3.23), endocrine/nutritional/metabolic diseases (MRR 3.23, 95% CI 2.02-5.17), diseases of nervous system (MRR 3.36, 95% CI 2.47-4.58), and congenital malformations (MRR 1.39, 95% CI 1.08-1.80). No excess mortality risk in offspring was observed for unnatural causes of death. CONCLUSION: Prenatal maternal bereavement was associated with an increased long-term mortality risk in offspring, particularly for selected natural causes of diseases and medical conditions. Our results support the fetal programming hypothesis that prenatal stress may contribute to ill health from physical diseases later in life.

Survival after traumatic spinal cord injury in Denmark: a hospital-based study among patients injured in 1990-2012.

STUDY DESIGN: Hospital-based cohort study at Spinal Cord Injury Centre of Western Denmark (VCR). OBJECTIVE: To examine the overall survival and mortality over time adjusted for age at the time of injury and gender. METHODS: Review of medical records of traumatic spinal cord injury (TSCI) patients admitted at VCR between 1990 and 2012. The patients were followed up until death, emigration or end of study (December 2014). Survival and mortality rate ratios (MRRs) with 95% confidence intervals (CI) were estimated for sub-groups defined by year of injury (1990-1994, 1995-1999, 2000-2004, 2005-2009 and 2010-2012). Mortality was analysed using Cox proportional hazard regression. Adjustment for gender and age at injury was performed (restricted cubic splines). RESULTS: In total, 665 patients (males 82%) were followed; 136 (20%) patients died during the observation period. Two-year survival varied from 93% in 2005-2009 to 98% in 2000-2004. Using 1990-1994 as a reference, the adjusted MRRs varied between 1.22 (CI: 0.43; 3.42) and 0.48 (CI: 0.13; 2.71). The 5- and 10-year survival varied between 85% (2005-2009) and 95% (1990-1994), and between 77% (2005-2009) and 91% (1990-1994), respectively. No trend over time was observed either for 2-, 5- or 10-year survival. Men's mortality did not differ consistently from that of women. Except for the most recent time period, the overall survival after TSCI was higher among those aged <60 years at time of injury. CONCLUSION: Survival after TSCI in Denmark did not change considerably from 1990 to 2014, and there seemed to be no gender difference. Mortality was highest among patients above 60 years of age at injury.

Gestational Age and Autism Spectrum Disorder: Trends in Risk Over Time.

Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder. Several previous studies have identified preterm birth as a risk factor for ASD but none has studied whether the association between gestational age and ASD has changed over time. This is a Danish population-based follow-up study including live-born singletons born in Denmark between 1980 and 2009, identified in the Danish Medical Birth Registry, a study population of 1,775,397 children. We used a Cox regression model combined with spline to study the risk for ASD by gestational age across three decades of birth cohorts. We included 19,020 children diagnosed with ASD. Across all birth year cohorts, we found that the risk of being diagnosed with ASD increased with lower gestational age (P-value: <0.01). Across all gestational weeks, we found a statistically significant higher risk estimates in birth cohort 1980 to 1989, compared to birth cohorts 1990 to 1999 and 2000 to 2009, respectively. No statistically significant difference in risk estimates was observed between birth cohort 1990 to 1999 and 2000 to 2009. The observed time trend in risk of ASD after preterm birth may reflect: (1) a change in the risk profile of persons with ASD due to the broadening of ASD diagnostic criteria over time; or (2) improved neonatal care for low GA infants, which has reduced risk of adverse outcomes like ASD in preterm children.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

Maternal stress before and during pregnancy and subsequent infertility in daughters: a nationwide population-based cohort study.

STUDY QUESTION: Is maternal stress following the death of a close relative before or during pregnancy associated with the risk of infertility in daughters? SUMMARY ANSWER: Compared with unexposed women, women whose mothers had experienced bereavement stress during, or in the year before, pregnancy had a similar risk of infertility overall, but those exposed to maternal bereavement during the first trimester had a higher risk of infertility. WHAT IS KNOWN ALREADY: Animal studies have shown that prenatal maternal stress results in reduced offspring fertility. In humans, there is evidence that girls who have been prenatally exposed to stress have a more masculine behaviour and a slight delay in having their first child. STUDY DESIGN, SIZE AND DURATION: This population-based cohort study, included 660 099 females born in Denmark between 1 January 1973 and 31 December 1993 to mothers of Danish origin and with at least one living relative in the exposure window, and followed the women through 31 December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 13 334 women (2.0%) were considered prenatally exposed to stress because their mother had lost a spouse/partner, a child, a parent, or a sibling during pregnancy or in the year before conception. Infertility was defined as any record of infertility treatment or diagnosis of female infertility. We considered the date of onset as the date of the first appearance of any such record. The association between exposure and outcome was examined using hazard ratios (HR) with 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Based on our definition, 40 052 (6.5%) women were infertile in the follow-up period (median age at the end of follow-up: 26.7 years, maximum age: 39 years). Overall, prenatal exposure to maternal stress was not associated with risk of infertility (adjusted HR = 1.04 [CI: 0.95-1.14]). However, women prenatally exposed during the first trimester had a higher estimated risk (adjusted HR = 1.40 [CI: 1.05-1.86]). These findings were consistent in subgroups defined by the relationship of the mother to the deceased and in several sensitivity analyses, including a sibling-matched analysis, and in analyses restricted to women who were married or cohabitating with a man, or to women born at term. LIMITATIONS, REASONS FOR CAUTION: We did not have a direct measure of stress, but bereavement due to death of a close relative is likely to be very stressful. We based the timing of exposure on the date of the death of the family member, although the stress may well have started earlier. Infertility was also defined indirectly, and many women in the cohort were too young at the end of the follow-up to have been diagnosed. However, misclassification of the outcome was most likely non-differential, and the similar results from all sensitivity analyses suggest that it is unlikely that the effect observed in first trimester exposure would be due to chance. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal exposure to maternal stress in the first trimester may affect the later fecundity of daughters. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the European Research Council (ERC-2010-StG-260242-PROGEURO) to the ProgEuro project (http://progeuro.au.dk). O.P.-R. is partly supported by a fellowship from Aarhus University and a travel grant from Oticon Fonden. The authors report no conflict of interests.

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

Mortality in mothers after perinatal loss: a population-based follow-up study.

OBJECTIVE: To assess whether mothers who lost a child from stillbirth or in the first week of life have an increased overall mortality and cause-specific mortality. DESIGN: A population based follow-up study. SETTING: Data from Danish national registers. POPULATION: All mothers in Denmark were included in the cohort at time of their first delivery from 1 January 1980 to 31 December 2008 and followed until 31 December 2009 or death, whichever came first. METHODS: The association between perinatal loss and total and cause-specific mortality in mothers was estimated with hazard ratios (HR) and 95% confidence intervals (95% CI) calculated using Cox proportional hazards regression analyses. MAIN OUTCOME MEASURES: Overall mortality and cause-specific mortality. RESULTS: During the follow-up period, 838,331 mothers in the cohort gave birth to one or more children and 7690 mothers (0.92%) experienced a perinatal loss. During follow-up, 8883 mothers (1.06%) died. There was an increased overall mortality for mothers who experienced a perinatal loss adjusted for maternal age and educational level, hazard ratio (HR) 1.83 [95% confidence interval (CI) 1.55-2.17]. The strongest association was seen in mortality from cardiovascular diseases (CVD) with an HR of 2.29 (95% CI 1.48-3.52) adjusted for CVD at time of delivery. We found no association between a perinatal loss and mortality from traumatic causes. CONCLUSIONS: Mothers who experience a perinatal loss have an increased mortality, especially from CVD.

A Descriptive Study on the Neonatal Morbidity Profile of Autism Spectrum Disorders, Including a Comparison with Other Neurodevelopmental Disorders.

The aim of this study was to describe the profile of specific neonatal morbidities in children later diagnosed with autism spectrum disorder (ASD), and to compare this profile with the profile of children with hyperkinetic disorder, cerebral palsy, epilepsy or intellectual disability. This is a Danish population based cohort study, including all children born in Denmark from 1994, through 2010, and surviving the first year of life. Children with ASD as a whole have significantly elevated rates of a range of neurologic, respiratory, inflammatory, and metabolic problems in the neonatal period compared to the general population, but there are few if any indicators of a distinctive neonatal morbidity profile in ASD compared to other neurodevelopmental outcomes.

No association between q-angle and foot posture with running-related injuries: a 10 week prospective follow-up study.

BACKGROUND/PURPOSE: There is a paucity of knowledge on the association between different foot posture quantified by Foot Posture Index (FPI) and Quadriceps angle (Q-angle) with development of running-related injuries. Earlier studies investigating these associations did not include an objective measure of the amount of running performed. Therefore, the purpose of this study was to investigate if kilometers to running-related injury (RRI) differ among novice runners with different foot postures and Q-angles when running in a neutral running shoe. METHODS: A 10 week study was conducted including healthy, novice runners. At baseline foot posture was evaluated using the foot posture index (FPI) and the Q-angle was measured. Based on the FPI and Q-angle, right and left feet / knees of the runners were categorized into exposure groups. All participants received a Global Positioning System watch to allow them to quantify running volume and were instructed to run a minimum of two times per week in a conventional, neutral running shoe. The outcome was RRI. RESULTS: Fifty nine novice runners of mixed gender were included. Of these, 13 sustained a running-related injury. No significant difference in cumulative relative risk between persons with pronated feet and neutral feet was found after 125 km of running (Cumulative relative risk = 1.65 [0.65; 4.17], p = 0.29). Similarly, no difference was found between low and neutral Q-angle (Cumulative relative risk = 1.25 [0.49; 3.23], p = 0.63). CONCLUSION: Static foot posture as quantified by FPI and knee alignment as quantified by Q-angle do not seem to affect the risk of injury among novice runners taking up a running regimen wearing a conventional neutral running shoe. These results should be interpreted with caution due to a small sample size. LEVEL OF EVIDENCE: 2a.

Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm: a controlled national cohort study.

STUDY QUESTION: Does neonatal outcome including congenital malformations in children born after ICSI with epididymal and testicular sperm [testicular sperm extraction (TESE)/percutaneous epididymal sperm aspiration (PESA)/testicular sperm aspiration (TESA) (TPT)] differ from neonatal outcome in children born after ICSI with ejaculated sperm, IVF and natural conception (NC)? SUMMARY ANSWER: Children born after TPT have similar neonatal outcome, including total malformation rates, as have children born after ICSI and IVF with ejaculated sperm. Testing for variance over the four groups may indicate smaller differences in specific malformation rates with TPT as the highest risk group. WHAT IS KNOWN ALREADY: Regarding neonatal outcome as well as congenital malformations in children born after TPT, studies are few, with limited sample size, heterogeneous and often performed without relevant control groups. STUDY DESIGN, SIZE, DURATION: Population-based cohort study including all Danish children born after TPT and fresh embryo transfer in Denmark from 1995 to 2009. Children born after transfer of frozen-thawed embryos were excluded. Control groups of children conceived by ICSI with ejaculated sperm, IVF and NC were identified by cross-linkage of the Danish IVF Register, Medical Birth Register (MBR) and National Hospital Discharge Register (HDR). PARTICIPANTS/MATERIALS, SETTING: The study group consisted of 466 children born after TPT, while the control groups consisted of 8967 (ICSI with ejaculated sperm), 17 592 (IVF) and 63 854 (NC) children. Neonatal outcomes and congenital malformations were analysed for singletons and twins separately. Risk estimates for low birthweight (LBW, <2500 g) and preterm birth (PTB, <37 gestational weeks) were adjusted for maternal age, parity, child gender and year of childbirth. The study group was identified from the Danish national database on children born after TPT. Control groups were obtained from the IVF register and the MBR. All information included in the study was retrieved from the national registers. MAIN RESULTS AND THE ROLE OF CHANCE: Considering singletons and twins as one group, the sex ratio (♂/♀) was significantly lower for children born after TPT (0.89) compared with conventional IVF (1.11; P = 0.017) but did not differ significantly when compared with ICSI with ejaculated sperm (0.94) and NC (1.05). The mean birthweight (BW) for singletons did not differ significantly between groups when including only first-born children. The mean gestational age (GA) in the TPT singletons (279 ± 12 days) was significantly higher compared with IVF (276 ± 18 days; P = 0.02), but similar to ICSI with ejaculated sperm and NC singletons when including only first-born children (277 ± 16 days and 279 ± 14 days, respectively). Rate of stillbirths, perinatal and neonatal mortality in the group of TPT singletons did not differ significantly from any of the control groups. Comparable results were found for the TPT twin group, except for perinatal mortality, which was significantly lower in the TPT group compared with naturally conceived twins. The adjusted risk of LBW was significantly higher for TPT versus NC singletons [adjusted odds ratio (AOR) = 0.67 (0.48-0.93)]; however AOR for PTB was similar in the two groups. Regarding twins, similar adjusted risks were observed for PTB and LBW between the TPT and all three control groups. Significantly more Caesarean sections were performed after IVF (27.3% for singletons) and ICSI (25.1% for singletons) with ejaculated sperm compared with the TPT group (16.4% for singletons). The total rate of congenital malformations in the TPT group was 7.7% and did not differ significantly from any of the control groups. However, singleton TPT boys showed an increased rate of cardiac malformations (3.6%) compared with singleton boys after IVF (1.4%; P = 0.04) and NC (1.1%; P = 0.02). Considering the level of male infertility as a continuum over the four groups, tests for variance in the rate of cardiac malformations in singleton boys, and undescended testicles for singleton as well as twin boys were each significantly increased from NC to IVF to ICSI to TPT (P < 0.001). The rate of hypospadias showed the same pattern, but the TPT group did not differ significantly compared with the control groups. LIMITATIONS, REASONS FOR CAUTION: One of the limitations is that the TPT group could not be classified according to testicular or epididymal sperm, as these data were not available in the IVF register. Another limitation is that registry-based studies are encumbered with the risk of reporting or coding errors or missing data due to insufficient coding. However, the quality of data on congenital malformations in HDR has, in other studies, been validated and found acceptable for epidemiological research, and furthermore, recordings on study and control groups are performed similarly. WIDER IMPLICATIONS OF THE FINDINGS: Accumulating data show that TPT treatment is equally safe as conventional ICSI and IVF treatment and as NC with regard to neonatal outcome including congenital malformation. STUDY FUNDING/POTENTIAL COMPETING INTERESTS: This study is supported by Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital. No competing interests declared.

Male-mediated infertility in sons of building painters and gardeners: a nationwide register-based follow-up study.

AIM: To investigate whether sons of gardeners and building painters have increased risk of infertility in comparison with sons of bricklayers, carpenters and electricians. METHODS: Participants were men born 1965-1984 in Denmark whose fathers the year before birth had worked as gardeners, painters, bricklayers, carpenters or electricians (N=22,978). Cases of infertility were identified by Danish registers, and participants were followed-up for up to 24 years after their 20th birthday. RESULTS: Sons of gardeners did not have increased risk of infertility. Hazard ratios for sons of painters fluctuated around the null in main analyses but were 1.6 (98% CI: 1.0-2.5) and 1.7 (95% CI: 0.9-3.2) in the subset of participants with smallest risk of paternal exposure misclassification. CONCLUSIONS: Working as gardener or building painter was not related to increased risk of infertility among the next generation of males in main analyses. However, inherent limitations in data may have attenuated true associations.

Preventive home visits to home-dwelling older people and hospital admissions: a municipality-randomised intervention trial.

Preventive home visits to older home-dwelling people have been part of national policy in Denmark since 1996. The aim was to evaluate whether education of home visitors and GPs was associated with hospital admission rates. In a population-based prospective controlled intervention trial in 34 municipalities, intervention municipality visitors received regular education during 3 years and GPs were introduced to a short assessment programme. Participation totalled 4,034 75- and 80-year-old home-dwelling persons, of which 3,132 (78%) had no mobility disability at baseline. Complete data on hospital services were obtained for all participants. No difference was observed in time to first admission between older people living in the intervention municipalities compared with people living in the control municipalities, HR 0.93 (95%CI: 0.85, 1.02, P = 0.17). Duration of first hospital stay was the same in the two groups (7.3 days). The mean number of admissions was not associated with intervention. Accepting and receiving home visits was associated with a reduced risk of hospital admission, HR 0.84 (95%CI: 0.76, 0.92), especially among the initially disabled. Hospital admission rates were associated with functional decline patterns. Persons experiencing catastrophic and progressive decline had the highest risk. Persons experiencing reversible functional decline were more often hospitalised in the intervention municipalities, and fewer persons living in the intervention municipalities experienced progressive decline. Education of primary care professionals was not associated with risk for first hospital admission among all older people living in the community, but may be associated with older people's different functional decline patterns.

Preventive home visits to older home-dwelling people and different functional decline patterns.

A preventive home visitation scheme has been part of Danish legislation since 1996. The aim of this study was to describe functional trajectories of older home-dwelling people, and to identify whether education of the preventive home visitation staff and individual risk factors were related to specific functional decline patterns. The study is a secondary analysis of a population-based prospective controlled cohort study. Participation totalled 3,129 non-disabled 75- and 80-year-old men and women without mobility disability at baseline living in 34 municipalities. Self-reported functional ability was measured at baseline and after 1½, 3 and 4½ years follow-up. No functional decline was seen in 58% of the participants. A total of 17% developed catastrophic decline, 6% progressive and 7% showed a reversible decline pattern. The remaining 12% showed mixed patterns. Education of the preventive home visitation staff was associated with a reduced risk of progressive decline, RR = 0.66 (CI 95% 0.50-0.86, p = 0.002). Not receiving home visits and living alone were associated with increased risk of catastrophic decline. Younger age (75 at baseline) was less associated with all decline patterns compared with older age (80 at baseline). Men had less risk of developing progressive, reversible and mixed decline patterns than women, but an increased risk of developing catastrophic decline. A feasible educational preventive staff intervention was associated with a reduced risk of progressive functional decline but not with other functional decline patterns. Early signs of functional decline may serve as an important trigger for when to intensify the search for and actively seek to ameliorate preventable conditions.

Effect of preventive health screening on long-term primary health care utilization. A randomized controlled trial.

BACKGROUND: Regular preventive health screenings are a feature of primary health care in several countries. Studies of the effect of regular preventive health checks have reported different results regarding primary health care utilization. OBJECTIVE: To analyse the effect of preventive health screening and health discussions on contacts to general practice. METHODS: A randomized controlled trial with all GPs in the district of Ebeltoft, Denmark. All middle-aged residents registered with a GP in the district of Ebeltoft were included (n = 3464). A random sample of 2030 subjects was selected for invitation to participate in health screening or health screening and discussions. The remaining 1434 subjects were never contacted and served as an external control group. Main outcome measure was number of daytime consultations in general practice. RESULTS: The annual rate ratios for daytime consultations showed a very clear time trend (P < 0.0001) with a high rate of contacts among invited compared with non-invited subjects during the first year (P = 0.001) followed by a gradual decrease to a lower level after eight years (P = 0.037). The total rate ratio for daytime consultations was 1.01 (95% CI 0.93 to 1.10). CONCLUSION: We observed no differences between the invited group and the non-invited group in any type of contact to general practice when the entire follow-up period was considered. There was a significant trend in rate ratios for daytime consultations with an initial rise followed by a gradual decrease in rate ratios. More investigations are needed to confirm and explore reasons for this trend.

Biological interpretation of the correlation of emergence times of permanent teeth.

The eruption mechanism is not fully understood. It is known that the dental follicle is essential and that experimentally provoked denervation influence the process of eruption. Accordingly, the purpose of this study was to elucidate the eruption pattern in a human population and relate this pattern to the pattern of jaw innervation. The eruption pattern was evaluated from the correlation between the emergence times of different teeth in the permanent dentition based on longitudinal data from a large national registry (12,642 boys and 12,095 girls). Correlations coefficients were generally high (>0.5) and higher between teeth within the same tooth groups (i.e. incisors, canines and premolars, and molars) than between teeth from different tooth groups. It was shown that the correlation in emergence of teeth closely followed the pattern of innervation of the jaws. Thus the study supported the hypothesis concerning a possible association between eruption and innervation.

Lipid solubility- and concentration-dependent attenuation of in vitro natural killer cell cytotoxicity by local anesthetics.

BACKGROUND: Natural killer (NK) cells constitute an essential component of the innate immune system in the defence against infected and malignant cells. In this study the in vitro effect on NK cell activity of three different local anesthetics with different lipid solubility was investigated. METHODS: Venous blood from seven healthy volunteers was incubated with three amide local anesthetics with three different concentrations of lipid solubility: lidocaine 0.50, 1.00 and 2.00 mg/ml, ropivacaine 0.375, 0.75 and 1.50 mg/ml, and bupivacaine 0.25, 0.50 and 1.00 mg/ml. After 1 h of incubation, mononuclear cells were isolated and cryopreserved until tested for NK cell cytotoxicity in a 4-h 51Cr-release assay against K-562 target cells. Natural killer cell cytotoxicity of mononuclear cells incubated with isotonic saline was used as the control. RESULTS: A significant suppression in NK cell cytotoxicity was demonstrated for all three local anesthetic agents when the NK cell cytotoxicity was compared with the cytotoxicity estimated after incubation with the isotonic saline (P<0.004). Moreover a significant lipid solubility-dependent effect (P=0.0001) as well as an overall concentration-dependent effect (P<0.0001) on the NK cell cytotoxicity was found. CONCLUSION: The results of the present in vitro study suggest a negative association between the estimated NK cell cytotoxicity and the lipid solubility as well as the concentrations of the three local anesthetic agents tested.