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To investigate differences in bacterial distribution and resistance patterns of relevant pathogens in skin and tissue infections among migrants compared to nonmigrants.The population is based on a cohort of migrants who obtained residence as refugees or family-reunited migrants in Denmark between January 1993 and December 2015. The cohort was linked to positive swabs and tissue cultures collected from hospitals and general practitioners between the years 2000 and 2016 at the Department of Microbiology, University Hospital Hvidovre, Denmark. We calculated odds ratios for pathogen distribution and resistance patterns using logistic regression by comparing migrants with nonmigrants.In total, 43,770 pathogens from 37,276 individuals were included, with Staphylococcus aureus being the most common bacterium. Migrants had higher odds of infections with Enterobacterales than nonmigrants (OR 1.42, 95% CI: 1.23-1.63) and lower odds of beta-haemolytic Streptococci (OR 0.79, 95% CI: 0.73-0.86). Family-reunited migrants and refugees had higher odds of methicillin-resistant S. aureus (MRSA) than nonmigrants (OR 5.01, 95% CI: 3.73-6.73 and OR 3.66, 95% CI: 2.61-5.13). This was more pronounced in female migrants. The odds of ciprofloxacin-resistant Enterobacterales were higher in both family-reunited migrants and refugees than in nonmigrants (OR 2.21, 95% CI: 1.34-3.64 and OR 2.17, 95% CI: 1.34-3.52).The prevalence of MRSA and ciprofloxacin-resistant Enterobacterales was higher among family-reunited migrants and refugees than in nonmigrants. Our findings suggest an increased awareness for AMR in migrants.

To evaluate whether optimized and standardized diagnostic procedures would improve detection of germ cell neoplasia in situ (GCNIS) in the contralateral testis of patients with testicular germ cell tumour (TGCT) and decrease the rate of metachronous tumours, which in a nationwide Danish study was estimated to be 1.9%.This was a retrospective analysis of outcomes in 655 patients with TGCT who underwent contralateral biopsies (1996-2007) compared with those in 459 non-biopsied TGCT controls (1984-1988). The biopsies were performed using a standardized procedure with immunohistochemical GCNIS markers and assessed by experienced evaluators. Initial histopathology reports were reviewed, and pathology and survival data were retrieved from national Danish registers. In 604/608 patients diagnosed as GCNIS-negative (four were lost to follow-up), the cumulative incidence of metachronous TGCT was estimated in a competing risk setting using the Grey method. All cases of metachronous TGCT were re-examined using immunohistochemistry.Germ cell neoplasia in situ was found in 47/655 biopsied patients (7.2%, 95% confidence interval [CI] 5.4-9.5%). During the follow-up period (median 17.3 years) five of the 604 GCNIS-negative patients developed a TGCT. In 1/5 false-negative biopsies, GCNIS was found on histological revision using immunohistochemistry and 2/5 biopsies were inadequate because of too small size. The estimated cumulative incidence rate of second tumour after 20 years of follow-up was 0.95% (95% CI 0.10%-1.8%) compared with 2.9% (95% CI 1.3%-4.4%) among the non-biopsied TGCT patients (P = 0.012). The estimates should be viewed with caution due to the small number of patients with metachronous TGCT.Optimized diagnostic procedures improved the detection rate of GCNIS in patients with TGCT and minimized their risk of developing metachronous bilateral cancer. Urologists should be aware of the importance of careful tissue excision (to avoid mechanical compression) and the need of adequate biopsy size. Performing contralateral biopsies is beneficial for patients' care and should be offered as a part of their management.

Background Immigrants and ethnic minorities have been shown to be at increased risk of hospitalization from COVID-19. Our aim was to analyse the contribution of socioeconomic and demographic risk factors on hospital admissions for COVID-19 among immigrants and ethnic minorities compared to the majority population. Methods We used nationwide register data on all hospitalized COVID-19 cases between February and June 2020 (N = 2232) and random controls from the general population (N = 498 117). We performed logistic regression analyses and adjusted for age, sex, comorbidity, and socioeconomic and demographic factors. The main outcome measure was hospitalization with COVID-19 and was estimated using odds ratios (OR) and 95% confidence intervals (95% CI). Results Among 2232 COVID-19 cases, the OR of hospitalization with COVID-19 among immigrants and descendants of non-Western origin was 2.5 times higher (95% CI: 2.23–2.89) compared with individuals of Danish origin with most pronounced results among individuals from Iraq, Morocco, Pakistan and Somalia. The OR was largely attributed to comorbidity and socioeconomic factors, especially household size, occupation, and population density. Conclusion There is a significantly higher OR of hospitalization with COVID-19 among non-Western immigrants and ethnic minorities compared with ethnic Danes. This knowledge is crucial for health policymakers and practitioners in both the current and future pandemics to identify more vulnerable groups and target prevention initiatives.

Background Infertility is a common problem globally and impaired semen quality is responsible for up to 40% of all cases. Almost all infertile couples are treated with either insemination or assisted reproductive techniques (ARTs) independent of the etiology of infertility because no medical treatment exists. Denosumab is an antibody that blocks RANKL signaling and inhibition of testicular RANKL signaling has been suggested to improve semen quality in a pilot study. This RCT aims to assess whether treatment with denosumab can improve spermatogenesis in infertile men selected by serum AMH as a positive predictive biomarker. This paper describes the design of the study. Methods/design FITMI is a sponsor-investigator-initiated, double-blinded, placebo-controlled 1:1, single-center, randomized clinical trial. Subjects will be randomized to receive either a single-dose denosumab 60 mg subcutaneous injection or placebo. The study will be carried out at the Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen. The primary outcome of the study is defined as the difference in sperm concentration (millions pr. mL) one spermatogenesis (80 days) after inclusion. Discussion We describe a protocol for a planned RCT aimed at evaluating whether treatment with denosumab can improve the semen quality in infertile men selected by using serum AMH as a positive predictive biomarker. The results will provide evidence crucial for future treatment in a patient group where there is a huge unmet need. Trial registration Clinical Trials.gov NCT05212337. Registered on 14 January 2022. EudraCT 2021–003,451-42. Registered on 23 June 2021. Ethical committee H-21040145. Registered on 23 December 2021.

BACKGROUND Pubertal timing is closely linked to growth regulated by the growth hormone/insulin-like factor (GH/IGF) axis that includes IGF-regulating factors such as pregnancy-associated plasma protein-A/A2 (PAPP-A/PAPP-A2) and stanniocalcin 2 (STC2). We investigated the association between height, IGF-I concentration, and PAPPA, PAPPA2, and STC2 genotypes on the timing of female pubertal milestones. METHODS Height, IGF-I, and genotypes were analyzed in 1382 Danish girls from the general population, 67 patients with tall stature (height ≥2 SD), and 124 patients with short stature (height ≤-2 SD). The main outcomes were breast stage and menarche. RESULTS Thelarche occurred significantly earlier in patients with tall stature (mean age 9.37 years [95% confidence interval (CI) 8.87-9.87]) and later in patients with short stature (11.07 years [95% CI 10.7-11.43]) compared with girls within the normal range (9.96 years [95% CI 9.85-10.07]) (p = 0.02 and p

To investigate the psychiatric healthcare utilisation of refugees vis-a-vis their peers in Denmark during the ages 15–22. This paper utilises comprehensive full-population registry data from 1995 to 2016 to explore the psychiatric healthcare utilisation during the transition from childhood to adulthood for refugees (N = 13,027), a comparison group of children of labour migrants from Morocco, Pakistan, and Turkey (N = 13,413), and the majority population (N = 693,043) in Denmark. To test for population differences in types of admission for particular types of disorders, odds ratios for a first contact during ages 15–22 were calculated using logistic regression. For those with at least one diagnosis-specific hospital contact, differences in the amount and type of treatment were tested using negative binomial regression to estimate means ratios of days hospitalised, days in outpatient care, number of outpatient contacts, consultations with psychiatrists in private practice, and prescribed medicine purchases. Refugees and the comparison group were generally less likely than the majority population to have a first contact for most disorders (adjusted ORs 0.03–0.88), but not for schizophrenia for boys (adjusted ORs 0.92–2.13). Among those who did have a first contact, youths from the ethnic minority groups tended to have more or similar inpatient and emergency room contacts (MRs 0.89–2.10), hospitalisations of refugee girls being an exception (MR 0.46; CI [0.23–0.94]), but fewer outpatient contacts, consultations with psychiatrists in private practice, and prescribed medicine purchases (MRs 0.23–0.94). The results suggest that refugee and other ethnic minority groups may face barriers both to initial contact and to completing adequate treatment beyond the first contact.

Background Due to the circumstances of their early lives, young refugees are at risk of experiencing adverse labour market and health outcomes. The post-settlement environment is thought to play a decisive role in determining how this vulnerability plays out. This study compared trends in labour market marginalisation in young refugees and their majority peers during early adulthood in two national contexts, Denmark and Sweden, and explored the mediating role of common mental disorders and secondary school completions. Methods Using registry data, 13,390/45,687 refugees were included in Denmark/Sweden and 1:5 matched to majority peers. Inequalities in labour market marginalisation were investigated during 2012–2015 in each country using linear probability models and mediation analysis. Country trends were standardised to account for differences in observed population characteristics. Results The risk of marginalisation was 2.1–2.3 times higher among young refugees compared with their majority peers, but the risk decreased with age in Sweden and increased in Denmark for refugees. Birth-cohort differences drove the increase in Denmark, while trends were consistent across birth-cohorts in Sweden. Differences in population characteristics did not contribute to country differences. Common mental disorders did not mediate the inequality in either country, but secondary school completions did (77–85% of associations eliminated). Conclusions The findings document both the vulnerability of young refugees to labour market marginalisation and the variability in this vulnerability across post-settlement contexts. While the contrast in policy climates in Denmark and Sweden sharpened over time, the risk of marginalisation appeared more similar in younger cohorts, pointing to the importance of factors other than national immigration and integration policies. Institutional efforts to assist young refugees through secondary education are likely to have long-lasting consequences for their socio-economic trajectories.

Context It remains unknown how the postnatal activation of the hypothalamic-pituitary-gonadal axis in infancy, also known as “minipuberty”, relates to adult testis function. Objective To investigate how markers of reproductive function in 3-month-old boys correlate with adult reproductive health parameters. Methods This population-based birth cohort study (the Copenhagen Mother-Child cohort), conducted at Copenhagen University Hospital, Denmark, included 259 boys examined once around 3 months of age and again at 18 to 20 years. Reproductive hormones, penile length, testis volume, and semen quality were analyzed. Minipubertal markers of testis function (by tertiles, T1–T3) were explored as predictors of adult semen quality using linear regression models. Associations between reproductive outcomes in infancy and young adulthood were estimated by intraclass correlation coefficients (ICCs), describing how well measurements in infancy correlate with those in adulthood. Results Serum testosterone concentration in infancy was positively associated with adult total sperm count. Median (IQR) total sperm count was 84 (54-138) million spermatozoa for boys in T1, 141 (81-286) million spermatozoa in T2, and 193 (56-287) million spermatozoa in T3. We found the highest ICC for FSH (0.41; 95% CI, 0.26–0.57), while ICCs for inhibin B, SHBG, penile length, and testis volume ranged between 0.24 and 0.27. ICCs for LH and for total and free testosterone were lower and statistically nonsignificant. Conclusion Serum testosterone in infancy was a predictor of adult total sperm count. Other reproductive hormones and genital measures showed good correlation between infancy and adulthood, suggesting that an individual’s reproductive setpoint starts shortly after birth in boys and persists until adulthood.

BackgroundQuarterly intramuscular injections with long-acting testosterone undecanoate (TU) provide stable serum testosterone concentrations over time and are therefore preferred by many testosterone-deficient patients. However, the use of long-acting TU in elderly patients is limited due to lack of safety and feasibility studies.ObjectiveTo investigate long-acting TU pharmacokinetics and assess differences in treatment regimens and risk of adverse outcomes in younger versus elderly testosterone-deficient patients.Materials and methodsSingle-center longitudinal observational study. Patients who initiated long-acting TU treatment between 2005 and 2010 were included. Elderly patients were born before 1956 and younger patients between 1965 and 1985. TU dose was adjusted yearly through shortening or prolongation of time between injections. Treatment targets were as follows: (1) free testosterone between 0 and −1 SD from the age-adjusted mean, (2) no symptoms of testosterone deficiency, and (3) hematocrit within the normal range.ResultsThe study population consisted of 63 elderly and 63 younger patients. Median follow-up time during testosterone replacement was 12.1 years. Increasing intervals between TU injections were performed 44% more often in the elderly compared to younger patients and time between TU injections were prolonged 4% more in the elderly patients. The hematocrit, as well as the hematocrit for a given serum testosterone (hematocrit: testosterone ratio), increased with treatment time but did not differ between age groups. During follow-up, 40% of patients—both elderly and younger—experienced polycythemia. Risk of polycythemia did not differ with age.Discussion and conclusionAn increased number of adjustments of TU dose are necessary in elderly patients in order to reach treatment targets. TU treatment in elderly testosterone-deficient patients is not associated with an increased risk of polycythemia compared to younger patients if age-adjusted treatment targets are reached.

OBJECTIVES: To investigate bloodstream infection (BSI) related to migrant status by comparing the incidence and mortality in migrants with that in non-migrants.METHODS: In this register-based cohort study we linked a cohort of migrants and non-migrants with a bacteraemia database covering two regions in Denmark. We included first-time BSI between January 2000 and December 2015 in individuals ≥18 years. Migrants were categorized according to status: refugees or family-reunified migrants. Incidence rate ratio and mortality rate ratio were analysed using Poisson regression.RESULTS: We identified 493 080 non-migrants, of which 3405 had BSI, and 80 740 migrants with 576 cases; of the latter, 40 222 were family-reunified migrants with 226 cases and 40 518 were refugees with 350 cases. Refugees had a higher risk of BSI than non-migrants (adjusted IRR 1.19, 95%CI 1.01-1.40). Family-reunified migrants and refugees had a higher risk of Gram-negative BSIs (adjusted IRR 1.23, 95%CI 1.00-1.51 and 1.57, 95%CI 1.32-1.86), respectively, and a lower risk of Gram-positive BSIs (adjusted IRR 0.65, 95%CI 0.51-0.83 and 0.77, 95%CI 0.63-0.95), respectively, compared to non-migrants. Originating from Southeast Asia and the Pacific was associated with an increased risk of BSI compared to non-migrants (adjusted IRR 1.26, 95%CI 1.07-1.49). We found no differences in the adjusted 30-day or 90-day mortality according to migrant status.CONCLUSIONS: Vulnerability towards BSI differs according to migrant status. Refugees had a higher risk of BSI overall. Both refugees and family-reunified migrants had a higher incidence of Gram-negative BSI than non-migrants. Similarly, migrants from Southeast Asia and the Pacific had a higher risk of BSI than non-migrants.

The incidence of many hormone-dependent diseases, including testicular cancer, has sharply increased in all high-income countries during the 20th century. This is not fully explained by established risk factors. Concurrent, increasing exposure to antiandrogenic environmental endocrine disrupting chemicals (EDCs) in fetal life may partially explain this trend. This systematic review assessed available evidence regarding the association between environmental EDC exposure and risk of testicular cancer (seminomas and nonseminomas). Following PRISMA guidelines, a search of English peer-reviewed literature published prior to December 14, 2020 in the databases PubMed and Embase® was performed. Among the 279 identified records, 19 were eligible for quality assessment and 10 for further meta-analysis. The completeness of reporting was high across papers, but over 50% were considered subject to potential risk of bias. Mean age at diagnosis was 31.9 years. None considered effects of EDC multipollutant mixtures. The meta-analyses showed that maternal exposure to combined EDCs was associated with a higher risk of testicular cancer in male offspring [summary risk ratios: 2.16, (95% CI:1.78-2.62), 1.93 (95% CI:1.49-2.48), and 2.78 (95% CI:2.27-3.41) for all, seminoma, and nonseminoma, respectively]. Similarly, high maternal exposures to grouped organochlorines and organohalogens were associated with higher risk of seminoma and nonseminoma in the offspring. Summary estimates related to postnatal adult male EDC exposures were inconsistent. Maternal, but not postnatal adult male, EDC exposures were consistently associated with a higher risk of testicular cancer, particularly risk of nonseminomas. However, the quality of studies was mixed, and considering the fields complexity, more prospective studies of prenatal EDC multipollutant mixture exposures and testicular cancer are needed.

Context IGF-I is important for postnatal growth and may be of diagnostic value in infants suspected of pituitary disease; however, little is known about the impact of IGF-I and its determinants on infant growth. Importantly, detailed reference ranges for IGF-I and IGF binding protein-3 (IGFBP-3) concentrations during infancy are lacking. Objective To evaluate the rapid changes in weight and length as well as their determinants in healthy infants, and to establish age- and sex-specific reference curves for IGF-I and IGFBP-3 in children aged 0 to 1 years. Design Prospective longitudinal study. Setting Cohort study. Participants A total of 233 healthy children (114 girls) with repeated blood samples during the first year of life. Main Outcome Measure(s) Serum concentrations of IGF-I and IGFBP-3, length velocity, weight velocity, and PAPPA2 (rs1325598) genotype. Results Individual trajectories of length and weight velocities were sex specific. We provide detailed reference curves based on longitudinal data for IGF-I and IGFBP-3 during infancy. In both girls and boys, IGF-I decreased during infancy, whereas IGFBP-3 remained stable. IGF-I and IGFBP-3, but not PAPPA2 genotype, were positively associated with weight gain, but not with longitudinal growth. When stratified by sex, the association between weight gain and IGF-I only remained significant in girls. Conclusions Interestingly, we found a significant association between IGF-I and infant weight gain in girls, but not with longitudinal growth in the first year of life. Our findings highlight the role of IGF-I as an important anabolic hormone that is not limited to linear growth.

Background The high prevalence of psychiatric disorders among resettled refugees necessitates identification of factors that reduce the risk of mental illness. In this 22-year longitudinal cohort study, we assessed whether the length of asylum-decision waiting periods is associated with resettled refugees’ risk of being diagnosed with a psychiatric disorder. Methods We used full-population data from the Danish Civil Registration System to establish a cohort of 46 104 refugees resettled in Denmark during 1995–2016. Hazard ratios (HRs) for first-time psychiatric hospital contact (ICD-10) after residence permit issuance across varying lengths of asylum-decision waiting periods were estimated by cross-linkage with the Danish National Patient Register. Results Long asylum-decision waiting periods were associated with an increased risk of psychiatric disorders. Compared with refugees who waited 0–6 months for their asylum decision, the HRs of any psychiatric diagnosis were 1.22 [95% confidence interval (CI): 1.12–1.33] for those who waited 13–24 months and 1.46 (95% CI: 1.27–1.69) for those who waited 25–71 months. Associations varied across diagnoses and length of follow-up: whereas the risk of nervous disorders increased with longer asylum-decision waiting periods in the follow-ups of 0–2.9, 3–5.9 and 6–11.9 years, the risk of psychotic disorders was associated with longer asylum-decision procedures only in the 0–2.9-year follow-up. Conclusion Resettled refugees who waited longer than 1 year for an asylum decision face an increased risk of psychiatric disorders. Host countries should consider that long asylum-decision waiting periods could lead to mental illness among refugees.

Background Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. Methods This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. Results In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1–13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of −0.8 ± 0.2 with an annual slope of −0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin–creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. Conclusions ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

Background: The filaggrin gene (FLG) encodes an epidermal protein, filaggrin, which is important for normal skin barrier functions. We previously showed that FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals such as certain phthalates and parabens, suggesting increased trans-epidermal penetration. Several groups of non-persistent chemicals are suspected endocrine disrupters with potential to affect testicular function. Objectives: To investigate associations between exposure to non-persistent chemicals and testicular function in young Danish men with and without FLG mutations. Methods: We measured urinary concentrations of bisphenol A (BPA) and other simple phenols, parabens, and UV filters including benzophenones (BP-1, BP-3 and 4-HBP) in men genotyped for FLG R501X, 2282del4, and R2447X loss-of-function mutations; in total 65 mutation carriers and 130 non-carriers (controls) were included. Outcomes were markers of testicular function, assessed by serum reproductive hormones and semen quality. Results: We found that associations between urinary chemical concentrations and outcomes were different in cases and controls. Within the group of FLG mutation carriers, higher urinary concentrations of BPA, BP-1 and BP-3 were associated with higher testosterone and estradiol serum levels and lower FSH. Similar trends in hormone levels were observed for FLG mutation carriers with measurable levels of 4-HBP compared to those who had no detectable levels of urinary 4-HBP. Furthermore, those in the highest urinary BPA quartile had lower sperm motility than those in the lower quartiles. None of these associations were evident in the control group. In the control group, however, lower sperm motility and sperm concentration were observed in the men with detectable urinary 4-HBP compared to the men non-detectable urinary 4-HBP. We found no association between any parabens and outcomes, nor for the other measured phenols or UV filters. Conclusions: Associations between male reproductive health parameters and urinary levels of BPA and benzophenones such as BP-3, BP-1 and 4-HBP were observed in FLG mutation carriers but not in controls from the same study population. This difference between FLG mutation carriers and non-carriers is not explained solely by differences in exposure levels of the examined compounds as e.g. BPA and 4-HBP urinary levels did not differ between the two groups. We hypothesise that effects of exposure to these compounds may be modulated in FLG mutation carriers by either different levels of co-exposures or by route of uptake, with a higher fraction of the uptake by dermal uptake. Keywords: Endocrine disrupting chemicals, Bisphenol A, Benzophenone-3, Testicular function, Filaggrin gene

Purpose To examine whether family separation caused by prolonged waiting for family reunification is associated with the risk of mental disorders among refugee fathers. Method Based on full-population Danish registry data covering 1995–2015, we mapped arrival patterns among nuclear refugee family members resettled in Denmark (n = 76,776) and established a cohort of refugee fathers (n = 6176) who all arrived alone and later obtained family reunification with their wife and children. The fathers were followed for up to 24 years, from the day their residence permit was issued until their first psychiatric diagnosis, emigration, death, or study end, whichever came first. Using Cox proportional hazard regression, we estimated hazard ratios (HRs) of being diagnosed with a mental disorder (i) for the period while the fathers were still separated from their family and (ii) across varying lengths of family separation. Results The HR of any mental disorder was 2.10 (95% confidence interval (CI): 1.57–2.81) for fathers still separated from their family compared with those who had obtained family reunification. The HR increased with longer family separation. Compared with fathers separated for Conclusion Fathers waiting for their wives and children face an increased risk of mental disorders. Countries receiving refugees should be aware that delaying family reunification can lead to adverse mental health effects.

Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC-MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS).This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC-MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated.In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01).The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.

This study aimed at examining psychiatric morbidity in the perinatal period among refugees and family-reunified immigrants compared to Danish-born women, including predictors of psychiatric morbidity according to migration history. Inclusion criteria were women who had a residence permit in Denmark and gave birth to a live child between 1 April 1998 and 31 December 2014. The study included 7804 refugee women, 21,257 family-reunified women, and 245,865 Danish-born women. We estimated Odds Ratios (ORs) of having a first-time perinatal psychiatric episode (PPE) and specific risk for affective, psychotic, and neurotic disorders. Compared with Danish-born women, women family-reunified with immigrants had lower (aOR 0.37, 95% CI 0.22–0.64) and refugees had higher ORs of PPE (OR 1.46, 95% CI 1.22–1.76). In fully adjusted models, refugees no longer presented increased risk of PPE (OR 1.16, 95% CI 0.95–1.42) but showed higher ORs for psychotic (aOR 4.72, 95% CI 2.18–9.84) and neurotic disorders (aOR 1.31, 95% CI 1.01–1.72). Women family-reunified with refugees and to Nordic citizens had higher ORs of psychotic disorders. Among migrants, refugees had higher ORs of PPE. Results suggest that elevation in risk of PPE among refugees compared to Danish-born may be related to higher likelihood of poverty and single-parenting among refugees. Still, refugees appear to have increased risk for neurotic and psychotic disorders. In contrast, family-reunified to immigrants may have lower risk of PPE. Maternal health programs need to focus on promotion of mental health and tackle social risks that disproportionately affect immigrant women, particularly refugees.

STUDY QUESTION What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0–80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the healthy males (n = 3144) and females (n = 3273) aged 0–80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S) M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER NA DATE OF FIRST PATIENT’S ENROLMENT June 1990 (the launch of the department from which this project stems).

Context The use of anogenital distance (AGD) in clinical and epidemiological settings is increasing; however, sex-specific reference data on AGD and data on longitudinal changes in AGD in children is scarce. Objective To create age-, sex-, and method-related reference ranges of AGD in healthy boys and girls aged 0–24 months, to assess the age-related changes in AGD and to evaluate the 2 predominantly used methods of AGD measurement. Design The International AGD consortium comprising 4 centers compiled data from 1 cross-sectional and 3 longitudinal cohort studies (clinicaltrials.gov [NCT02497209]). Setting All data were collected from population-based studies, recruiting from 4 maternity or obstetric centers (United States, Cambridge [United Kingdom], Odense, and Copenhagen [Denmark]). Subjects This study included a total of 3705 healthy, mainly Caucasian children aged 0–24 months on whom 7295 measurements were recorded. Main Outcome Measures AGDAS (ano-scrotal), AGDAF (ano-fourchette), AGDAP (ano-penile), AGDAC (ano-clitoral), AGD body size indices (weight, body mass index [BMI], body surface area, and length), and intra- and interobserver biases. Results We created age-specific reference ranges by centers. We found that AGD increased from birth to 6 months of age and thereafter reached a plateau. Changes in AGD/BMI during the first year of life were minor (0–6% and 0–11% in boys and girls, respectively). Conclusions Reference ranges for AGD can be used in future epidemiological research and may be utilized clinically to evaluate prenatal androgen action in differences-in-sex-development patients. The increase in AGD during the first year of life was age-related, while AGD/BMI was fairly stable. The TIDES and Cambridge methods were equally reproducible.

BACKGROUND: Male infertility is associated with a higher long-term morbidity and mortality risk. However, it is not clear which diseases are contributing to this risk. Osteoporosis is a possible factor, as it is a frequent disease and sex steroids regulate both fertility and bone health. Furthermore, there are data indicating that high FSH levels in women are related to low bone mineral density (BMD), independent of estradiol levels. As infertile men often have increased FSH, already from a young age, this could be a risk factor for impaired bone health in later life. METHODS: One hundred and thirty-seven men with a history of male factor infertility due to spermatogenic failure (SgF men) as well as a control group of 70 men from couples treated with IVF for female factor infertility (non-SgF men) were included in a long-term follow-up study. Men with explained infertility, including testosterone deficiency, were not included. Data from baseline fertility investigations were retrieved from the patient files of the SgF men. At follow-up hormonal and semen analysis were performed and axial, femoral and total body BMD was measured by dual X-ray absorptiometry in all men. Multiple linear regression was used to assess differences between SgF and non-SgF men and to study associations between FSH levels and BMD. RESULTS: Median follow-up time was 14.8 years (5th-95th percentile 11.3-18.2) after fertility assessment for SgF men and 15.6 years (12.1-18.5) for non-SgF men (p = 0.033). When comparing the two groups, no significant differences in total T, free T or E2 levels were apparent at follow-up. As expected, LH and FSH were higher in SgF men ((median (5th-95th percentile)) for LH (IU/L): 4.3 (2.2-13.6) for SgF men and 3.0 (1.4-5.8) for non-SgF men (p

Background Spermatogenesis depends on stimulation by follicle-stimulating hormone (FSH) which binds to FSH receptors (FSHR) on testicular Sertoli cells. Three FSH-related single nucleotide polymorphisms (SNPs); FSHB -211G>T (rs10835638), FSHR -29G>A (rs1394205) and FSHR 2039A>G (rs6166) affect FSH action, and have been suggested to affect testicular function, but the evidence is uncertain. Objective To describe the associations between the three SNPs and testicular function in a large and well-characterised cohort of men from the general population. Materials and methods A cross-sectional study of 2,020 Danish men unselected regarding testicular function. Outcome variables were semen parameters, reproductive hormones and testis size. Genotyping was done by competitive allele-specific quantitative PCR. Differences in genotype frequencies were tested by Chi-square test and associations between genotypes and outcomes were assessed by multivariate linear regressions. Results The SNPs affected serum FSH; carriers of the variant affecting FSH secretion (FSHB -211G>T) had lower FSH levels while carriers of variants affecting receptor expression (FSHR -29G>A) and receptor sensitivity (FSHR 2039A>G) had higher FSH levels. Carriers of FSHB -211G>T had lower calculated free-Testosterone/LH ratio. Although both FSHB -211G>T and FSHR 2039A>G were associated with smaller testis size, no clear association was detected in relation to any semen parameters, except a lower total number of morphologically normal spermatozoa in the heterozygous carriers of the FSHB -211G>T DISCUSSION AND CONCLUSION: The studied polymorphisms have only minor modulating influence on testis size and function in healthy men. We detected subtle effects of the three SNPs on FSH levels, but also effects of FSHB -211G>T on calculated free-Testosterone/LH ratio, compatible with altered Leydig cell function. Thus, the role of these FSH-related polymorphisms is complex and modest in men with normal testicular function, but the possible importance of FSH polymorphisms in men with impaired testicular function should be evaluated in future studies in more detail.

Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease predominantly caused by 21-hydroxylase deficiency. Clinical management in children includes glucocorticoid and often mineralocorticoid treatment alongside monitoring outcomes such as an­thro­po­metry, pubertal status, blood pressure, and biochemistry. Objective: The objective of this pilot study was to present the use of 17-hydroxyprogesterone (17-OHP) and androgen metabolites expressed as standard deviation (SD) scores rather than actual concentrations as a tool in the management of children with CAH as well as in research settings. Methods: The study was a retrospective, longitudinal study that took place in a single, tertiary center and included 38 children and adolescents aged 3–18 years with CAH due to 21-hydroxylase deficiency. Biochemical measurements of 17-OHP, androstenedione, dehydroepiandrosterone-sulphate (DHEAS), and testosterone using liquid chromatography-tandem mass spectrometry were expressed as SD scores, and outcomes such as genotype, height, bone maturation, blood pressure, and treatment doses were extracted from patient files. Results: The majority (86%) of CAH patients had 17-OHP measurements above +2 SD during standard hydrocortisone therapy, receiving an average daily hydrocortisone dose of 12.6 mg/m2. Androstenedione concentrations were mostly within ±2 SD, whereas DHEAS values were below –2 SD in 47% of patients. Conclusions: Applying sex- and age-related SD scores to 17-OHP and androgen metabolite concentrations allows for monitoring of hydrocortisone treatment independent of age, sex, assay, and center. We propose that 17-OHP and androgen metabolites expressed as SD scores be implemented as a unifying tool that simplifies research and, in the future, also optimal management of treatment.

Background:Lower semen quality is associated with increased mortality and morbidity, which may include osteoporosis.Objective:To assess whether infertile men have a lower bone mineral density (BMD) compared with fertile men at the time of fer-tility workup.Methods:A total of 146 men from infertile couples with unexplained impaired semen quality, characterized by sperm concentra-tion

Importance The initial clinical sign of pubertal onset in girls is breast gland development (thelarche). Although numerous studies have used recalled age at menarche (first menstruation) to assess secular trends of pubertal timing, no systematic review has been conducted of secular trends of thelarche. Objectives To systematically evaluate published data on pubertal timing based on age at thelarche and evaluate the change in pubertal onset in healthy girls around the world. Data Sources A systematic literature search was performed in PubMed and Embase of all original peer-reviewed articles published in English before June 20, 2019. Study Selection Included studies used clinical assessment of breast development in healthy girls and used adequate statistical methods, including the reporting of SEs or CIs. The quality of the articles was evaluated by assessing study design, potential sources of bias, main characteristics of the study population, and methods of statistical analysis. Data Extraction and Synthesis In accordance with PRISMA guidelines, all articles were assessed for eligibility independently by 2 authors. Weighted regression analysis was performed using a random-effects model. Main Outcomes and Measures Studies examining age at thelarche (development of Tanner breast stage 2) in healthy girls. Results The literature search resulted in a total of 3602 studies, of which 30 studies fulfilled the eligibility criteria. There was a secular trend in ages at thelarche according to race/ethnicity and geography. Overall, the age at thelarche decreased 0.24 years (95% CI, −0.44 to −0.04) (almost 3 months) per decade from 1977 to 2013 (P = .02). Conclusions and Relevance The age at thelarche has decreased a mean of almost 3 months per decade from 1977 to 2013. A younger age at pubertal onset may change current diagnostic decision-making. The medical community needs current and relevant data to redefine “precocious puberty,” because the traditional definition may be outdated, at least in some regions of the world.

Context The lack of sensitive and robust analytical methods has hindered the reliable quantification of estrogen metabolites in subjects with low concentrations. Objective To establish sex-specific reference ranges for estrone (E1) and estradiol (E2) throughout life and to evaluate sex-differences using the state-of-the-art liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of E1, E2, and estriol (E3). Design LC-MS/MS method development and construction of estrogen reference ranges. Settings Population-based cross-sectional cohorts from the greater Copenhagen and Aarhus areas. Participants Healthy participants aged 3 months to 61 years (n = 1838). Results An isotope diluted LC-MS/MS method was developed and validated for measurements of serum E1, E2, and E3. Limits of detections (LODs) were 3 pmol/L (E1), 4 pmol/L (E2), and 12 pmol/L (E3), respectively. This sensitive method made it possible to differentiate between male and female concentration levels of E1 and E2 in children. In girls, E2 levels ranged from Conclusion Reference ranges of simultaneous quantification of E1 and E2 by this novel specific and highly sensitive LC-MS/MS method provide an invaluable tool in clinical practice and in future research studies.

Background The peptide hormone insulin-like factor 3 (INSL3) is a marker for Leydig cell function and the clinical use of serum INSL3 measurements has been suggested by several groups. Aim (1) To establish a reference range for liquid chromatography–tandem mass spectrometry (LC-MS/MS) of serum INSL3 in healthy boys and men; and (2) to compare the associations of serum INSL3 and testosterone (T) to pubertal stage, lifestyle factors, diurnal variation, body composition, and human chorionic gonadotropin (hCG) stimulation. Results In a reference range based on LC-MS/MS analysis of serum from 1073 boys and men, INSL3 increased from levels close to the detection limit (0.03 µg/L) in prepubertal boys to a maximum mean level of 1.3 µg/L (95% CI, 0.9-2.7) in young men (19-40 years of age) and decreased slightly in older men (0.1 µg/L per decade). Serum T, but not INSL3, was associated with body mass index or body fat percentage and with alcohol consumption. Smoking was positively associated with serum T, but negatively associated with INSL3. There were significant diurnal variations in both INSL3 and T in men (P Conclusion Measurement of serum INSL3 by LC-MS/MS has promise as a marker of testicular disorders.

Background Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide resulting in multi-organ dysfunction e.g. cerebral, cardiac, renal and audiologic complications. The audiologic involvement in FD has often been neglected; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life. Objectives To investigate baseline hearing status of the Danish Fabry cohort prior to treatment, compared to sex- and age-expected hearing levels and correlating hearing to renal and cerebral findings. Material and methods Retrospective study of baseline hearing status of the Danish Fabry cohort (n = 83, 9–72 years). Air conduction and speech discrimination scores were assessed at 6 frequencies between 0.25–8 kHz bilaterally. Data were collected between 2001–2014 and compiled in STATA using multilinear mixed modelling for statistical evaluation. Results Hearing thresholds at all frequencies deviated from the expected thresholds of an otologically normal cohort (p

PURPOSE:Migrants represent a considerable proportion of HIV diagnoses in Europe and are considered a group at risk of late presentation. This study examined the incidence of HIV diagnoses and the risk of late presentation according to migrant status, ethnic origin and duration of residence.METHODS:We conducted a historically prospective cohort study comprising all adult migrants to Denmark between 1.1.1993 and 31.12.2010 (n = 114.282), matched 1:6 to Danish born by age and sex. HIV diagnoses were retrieved from the National Surveillance Register and differences in incidence were assessed by Cox regression model. Differences in late presentation were assessed by logistic regression.RESULTS:Both refugees (HR = 5.61; 95% CI 4.45-7.07) and family-reunified immigrants (HR = 10.48; 95% CI 8.88-12.36) had higher incidence of HIV diagnoses compared with Danish born and the incidence remained high over time of residence for both groups. Migrants from all regions, except Western Asia and North Africa, had higher incidence than Danish born. Late presentation was more common among refugees (OR = 1.87; 95% CI 1.07-3.26) and family-reunified immigrants (OR = 2.30; 95% CI 1.49-3.55) compared with Danish born. Southeast Asia and Sub-Saharan Africa were the only regions with a higher risk of late presentation. Late presentation was only higher for refugees within 1 year of residence, whereas it remained higher within 10 years of residence for family-reunified immigrants.CONCLUSIONS:This register-based study revealed a higher incidence of HIV diagnoses and late presentation among migrants compared with Danish born and the incidence remained surprisingly high over time. Purpose: Migrants represent a considerable proportion of HIV diagnoses in Europe and are considered a group at risk of late presentation. This study examined the incidence of HIV diagnoses and the risk of late presentation according to migrant status, ethnic origin and duration of residence. Methods: We conducted a historically prospective cohort study comprising all adult migrants to Denmark between 1.1.1993 and 31.12.2010 (n = 114.282), matched 1:6 to Danish born by age and sex. HIV diagnoses were retrieved from the National Surveillance Register and differences in incidence were assessed by Cox regression model. Differences in late presentation were assessed by logistic regression. Results: Both refugees (HR = 5.61; 95% CI 4.45–7.07) and family-reunified immigrants (HR = 10.48; 95% CI 8.88–12.36) had higher incidence of HIV diagnoses compared with Danish born and the incidence remained high over time of residence for both groups. Migrants from all regions, except Western Asia and North Africa, had higher incidence than Danish born. Late presentation was more common among refugees (OR = 1.87; 95% CI 1.07–3.26) and family-reunified immigrants (OR = 2.30; 95% CI 1.49–3.55) compared with Danish born. Southeast Asia and Sub-Saharan Africa were the only regions with a higher risk of late presentation. Late presentation was only higher for refugees within 1 year of residence, whereas it remained higher within 10 years of residence for family-reunified immigrants. Conclusions: This register-based study revealed a higher incidence of HIV diagnoses and late presentation among migrants compared with Danish born and the incidence remained surprisingly high over time.

Background: The prevalence of multimorbidity, defined by having two or more chronic diseases, is increasing in many Western countries. Simultaneously, the migrant population in Western countries has increased, making up a growing proportion of European populations. This study aims i) to determine the quantity and quality of multimorbidity patterns among refugees and family reunification immigrants from non-Western countries compared to Danish-born, and ii) to compare the mortality burden among those with multimorbidity in the two groups. Methods: Through the Danish Immigration Service, we conducted a historically prospective cohort study. We identified a total of 101,894 adult migrants who were sub-categorised into refugees and family reunification immigrants, and matched them to a Danish-born comparison group 1:6 on age and sex. Through the Danish National Patient Registry, we obtained information on all in- and outpatient data on hospitalised and ambulatory patients. To assess multimorbidity we used Charlson Comorbidity Index based on ICD-10 codes, together with ICD-10 diagnostic categories for psychiatric disease. We used Cox regression analysis to calculate risk of multimorbidity and risk of mortality in people with multimorbidity. Results: Overall refugees had higher risk of multimorbidity compared to Danish-born, while family reunification immigrants had a lower risk. When adjusting for civil status and mean income, the risk was lower for all migrant groups compared to Danish-born. Risk of mortality in people with multimorbidity, was lower for all migrant groups, compared to Danish-born. Conclusion: Refugees are an at-risk group for multimorbidity, however, mortality among those with multimorbidity is lower in all migrant groups compared to Danish-born.

Context: The early activation of the hypothalamic-pituitary-gonadal axis during infancy can be used in the evaluation of infants suspected of disorders of sex development (DSD). However, few data exist on sex-specific reference ranges for these hormones during early life. Objective: To evaluate sex differences in reproductive hormone concentrations in serum from healthy infants to define sex-specific cutoff values and to apply these in infants with DSD. Design: A cross-sectional study. Setting: A tertiary center for pediatric endocrinology at the University Hospital of Copenhagen. Patients or Other Participants: Healthy infants (1840) and patients with DSD (27), aged 2 to 5 months. Main Outcome Measures: Serum concentrations of LH, FSH, testosterone (T), estradiol, sex hormone-binding globulin (SHBG), inhibin B, anti-Mullerian hormone (AMH), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, and LH/FSH ratio. Results: LH and FSH concentrations showed overlap between sexes, with LH being highest in boys and FSH being highest in girls. The LH/FSH ratio separated infant boys from girls with minimal overlap at a cutoff value of 0.32. Inhibin B and AMH concentrations were markedly higher in boys compared with girls, with minimal or no overlap. In infants with Klinefelter syndrome, 45,X/46,XY mosaicism and male phenotype, and Turner syndrome, the LH/FSH ratio matched the gender of rearing. However, infants with complete androgen insensitivity syndrome had LH/FSH ratios within the male range. Conclusions: Reference ranges for reproductive hormones and LH/FSH ratio during mini-puberty were established in this study. The classifiers that best separated sex in mini-puberty were AMH, LH/FSH ratio, and T. Use of the LH/FSH ratio may add valuable information in the workup of infants suspected of DSD. (J Clin Endocrinol Metab 103: 3028-3037, 2018)

BACKGROUND: Anogenital distance (AGD) has been suggested to represent a phenotypic signature reflecting in utero androgen action. However, it is not known whether an individual's AGD at birth correlates to AGD later in life. We investigate correlations of AGD between 3 and 18 months and asses reproducibility of measurements.METHODS: We measured AGD from anus to scrotum (AGDas) and penis (AGDap) in 407 boys, and to posterior fourchette (AGDaf) and clitoris (AGDac) in 282 girls. Each measure was repeated three times at 3 and 18 months and some children were furthermore examined by two different examiners. We assessed age related changes and reproducibility of measurements.RESULTS: AGD increased between the two examinations and correlated within the child. A large proportion of the observed variation in AGD was due to true differences between the children (AGDas: 62%, AGDap: 40%, AGDaf: 30%, AGDac: 21%), and measurement error due to between- and within-examiner variation was low.CONCLUSIONS: Our study showed that measures of AGD within a child correlated during infancy, especially in boys and particularly for AGD measured as the distance between anus and scrotum. A planned cohort follow-up through childhood and puberty will reveal whether AGD represents a phenotypic signature throughout life.Pediatric Research accepted article preview online, 20 November 2017. doi:10.1038/pr.2017.287.

Impaired semen quality is frequent in Western countries and is the main reason or contributing reason in up to 50% of cases of couple infertility. Male factor infertility is mainly determined by examination of semen samples according to the World Health Organization's 2010 guidelines. AMH has both autocrine and paracrine properties through a direct effect via the AMH type II receptor and is therefore thought to be involved in spermatogenesis. We aimed to study the association between the serum concentration of AMH and semen quality in a cross-sectional study including 970 young Danish men from the general population. All participants provided a semen sample, had a blood sample drawn, underwent a physical examination, and answered a questionnaire including information on lifestyle and medical history. Serum concentrations of reproductive hormones [AMH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free T, oestradiol (E2) and inhibin B] and semen parameters (semen volume, sperm concentration, and percentages of motile and morphologically normal spermatozoa) were determined. We found no association between serum AMH and semen quality, except for a significant (p = 0.011) trend for lower percentage of normal morphology with higher AMH. AMH quartile was positively associated with serum inhibin B (p

Aims: A number of aspects of the health status of migrants who return to their country of origin have been explored in the literature; however, a more general description of the incidence of disease and demographic characteristics is lacking. The aim of this research was to contribute such a description. Methods: A nationwide cohort study was conducted of 114,331 migrants who obtained residence in Denmark between 1 January 1993 and 31 December 2010. Demographic characteristics and ten disease groups were included as explanatory variables and hazards ratios for the association between return migration and disease incidence, as well as demographic characteristics, were estimated using Cox regressions. Results: The tendency to return-migrate when ill was not the same among younger and elderly migrants; migrants

Background: Filaggrin is an epidermal protein that is important for normal skin barrier functions. Up to 10% of Europeans and Asians carry filaggrin gene (FLG) loss-of function mutations that appear to facilitate trans-epidermal penetration of certain chemicals. We previously showed that mutation carriers have higher internal exposure to certain phthalates, compared to controls, and hypothesized that they could have increased trans-epidermal penetration of other chemicals. Objectives: We investigated exposure to non-persistent chemicals in young Danish men with and without FLG mutations. Methods: Concentrations of eight simple phenols, six parabens and nine UV filters were analysed in urine from 65 FLG loss-of-function mutation carriers and 130 non-carriers (controls). Regression analyses, controlling for urinary dilution and confounders, were performed to estimate associations between FLG mutation status and chemical concentrations in urine. Results: FLG mutation carriers had 80% (13–180%) higher urinary concentrations of methyl paraben (MeP) and 91% (13–219%) higher concentrations of n-propyl paraben (n-PrP) than controls. For 13 compounds, levels were higher in FLG mutation carriers, although differences were only statistically significant for MeP and n-PrP. Combined statistical analysis of concentrations of all the 18 compounds that were detectable in >10% of subjects, suggested that concentrations were generally higher in mutation carriers (p=0.03). Conclusion: FLG loss-of-function mutation carriers have a higher internal exposure to some non-persistent chemicals, independently of atopic dermatitis. This may be due to increased trans-epidermal absorption and/or higher exposure, and mutation carriers may constitute a group susceptible to increased absorption of chemicals and topical medication. Keywords: Endocrine disrupting chemicals, Phenols, UV filters, Parabens, Filaggrin, Dermal exposure

In patients with Fabry disease (FD), left ventricular hypertrophy and arrhythmias are frequently observed and cardiac involvement is the leading cause of death. Long-term efficacy of enzyme replacement therapy (ERT) on cardiac involvement is unclear. We assessed and compared long-term progression of cardiac involvement according to ERT and non-ERT.We retrospectively assessed and compared long-term progression of cardiac involvement in adult patients with FD in the nationwide Danish cohort. We followed clinical signs, symptoms and findings by echocardiography, electrocardiography and Holter-monitoring.We included 66 patients; 47 patients (27 women) received ERT (ERT group) and 19 patients (15 women) did not (non-ERT group). The groups were followed for a median of 8 [0-12] years and 6 [0-13] years, respectively. Comparison between ERT and non-ERT receiving patients by left ventricular mass (echocardiographic assessment) and Sokolow-Lyon voltage- and Cornell product criteria (electrocardiographic assessment) revealed no significant differences. In the ERT group, we observed no change in left ventricular mass but a decrease in Sokolow-Lyon voltage- and Cornell product criteria from baseline to follow-up; 30 mm [15-53] vs. 25 mm [3-44], p 0.005 and 1710 mm·ms [480-3740] vs. 1520 mm·ms [550-5740], p .05, respectively. There were no changes within the non-ERT group. During follow-up, cardiac symptoms and use of cardiovascular procedures and -medication increased significantly in the ERT group, whereas no differences were observed within the non-ERT group.We raise concerns regarding the efficacy and benefit of ERT on cardiac involvement in Fabry disease and stress the need for further research.

Sperm concentration is an essential parameter in the diagnostic evaluation of men from infertile couples. It is usually determined by manual counting using a hemocytometer, and is therefore both laborious and subjective. We have earlier shown that a newly developed image cytometry (IC) method may be used to determine sperm concentration. Here we present a validation of the IC method by analysis of 4010 semen samples. There was high agreement between IC and manual counting at sperm concentrations above 3mill/ml and in samples with concentrations above 12mill/ml the two methods can be used interchangeable. However, we found substantial differences in samples below 3mill/ml. We also assessed the accuracy of the two methods by repeated measurements of 248 samples, which revealed that IC measurements seemed more accurate. Moreover, based on ten samples counted by several operators the IC method had a lower coefficient of variation than the manual method (5% vs 10%), indicating a better precision of the IC method. In conclusion, measurement of sperm concentration by IC can be used at concentrations above 3mill/ml and seems more accurate and precise than manual counting, making it an attractive option in the daily clinical practice.

Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.

Objective The aim of this study was to evaluate an individualised gonadotrophin starting dose regimen for women with anovulatory infertility. Study design We included 71 normogonadotrophic anovulatory infertile women in a prospective, observational study. All underwent one ovulation induction cycle in a flexible, low-dose step-up protocol. The gonadotrophin starting dose (75–150 IU/day) was individualised according to a nomogram incorporating menstrual cycle pattern (oligo- or amenorrhoea), BMI, and mean ovarian volume. The number of women who fulfilled the criteria for human chorionic gonadotrophin (hCG) administration (one follicle ≥17 mm or 2–3 follicles ≥15 mm) was assessed. Results Of the 50 women (70.4%) who fulfilled the hCG criteria and underwent intrauterine insemination, 34 (47.9%) achieved monofollicular growth and 16 (22.5%) developed 2–3 mature follicles. Seventeen (23.9%) cycles were converted to in vitro fertilisation (IVF) due to the development of >3 mature follicles, and one (1.4%) cycle was cancelled due to risk of ovarian hyperstimulation syndrome. Baseline total antral follicle count was found to be significantly associated with fulfillment of the hCG criteria (OR 0.96, 95% CI: 0.92–0.99, P = 0.01). Conclusions The nomogram-based dose regimen was not considered suitable for ovulation induction due to a tendency to overestimate the gonadotrophin starting dose. However, the model may serve as a mild IVF regimen, especially in women prone to excessive follicle growth.

Context: Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed. Objective: To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche. Design: A prospective, longitudinal population-based study. Patients or Other Participants: Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms. Intervention(s): None. Main Outcome Measure(s): Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth. Results: Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche. Conclusion: TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms.

Summary Background Children of refugees are often exposed to the consequences of parental post-traumatic stress disorder (PTSD), potentially leaving them vulnerable to intergenerational transmission of psychopathology. The present study aimed to determine whether parental PTSD is associated with childhood psychiatric morbidity among children of refugees. Methods This study is a two-generation nationwide cohort study using the Danish Immigration Services database. We followed up children younger than 18 years with at least one refugee parent until psychiatric contact, end of the study, their 18th birthday, emigration, or death. We excluded children if their parents were diagnosed only with psychiatric diagnoses other than PTSD or if they had received a psychiatric contact before parental PTSD diagnosis. Information on parental PTSD and offspring psychiatric morbidity was obtained from the Danish Psychiatric Central Research Register. We used Cox proportional hazards regression models to assess the risk of psychiatric contacts among children of refugees with PTSD compared with children of refugees with no psychiatric diagnosis. Findings Between Jan 1, 1995, and Dec 31, 2015, 102 010 refugees obtained residency permission in Denmark and 62 239 biological children of refugees were born in Denmark before Dec 31, 2015. 51 793 were eligible and included in the study (median follow-up 7·15 years [IQR 3·37–11·78]); of these, 1307 (2·5%) children had a psychiatric contact. 7486 (14·5%) children of refugees were exposed to parental PTSD. Parental PTSD significantly increased the risk of psychiatric contact in offspring (hazard ratio 1·49 [95% CI 1·17–1·89] for paternal PTSD, p=0·0011; 1·55 [1·20–2·01] for maternal PTSD, p=0·00084) after adjustment for sociodemographic variables. Interpretation Children of refugees exposed to parental PTSD are at increased risk of psychiatric morbidity. Targeted screening and interventions are necessary to prevent psychiatric morbidity and ensure access to adequate care. Funding Section for Immigrant Medicine, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre.

Background: Biobank serum samples from longitudinal mother-child cohorts have been used to estimate prenatal exposures to endocrine disrupting chemicals (EDCs). However, the knowledge about variations in serum concentrations of non-persistent chemicals during pregnancy is limited. Objective: To describe the within- and between-person variations in serum concentrations of non-persistent chemicals and changes over trimesters, including phthalate metabolites, parabens, phenols, and UV filters. Design: Longitudinal study with repeated blood samples from 128 healthy pregnant women during pregnancy. Setting: Population based study at a University Hospital in Copenhagen 1999–2001. Methods: 503 repetitive prenatal serum samples from 128 pregnant women taken at approximately gestational week 12, 20, 30 and 40 were analyzed for 7 UV filters, 32 metabolites of 15 phthalate diesters, 8 phenols and 7 parabens by LC-MS/MS. Results: Ten of 32 phthalate metabolites from six out of 15 phthalate diesters, two of seven parabens, two of eight phenols and three of seven UV filters were measurable in more than half of the serum samples. Of these chemicals, mono‑ethyl phthalate (MEP), mono‑iso‑nonyl phthalate (MiNP), mono‑iso‑decyl phthalate (MiDP), 4‑methylbenzophenone (4‑MBP), 4‑hydroxybenzoephenone (4‑HBP) and n‑propyl paraben (nPrP) had intra-class correlation coefficients (ICC) above 0.4 in both adjusted and unadjusted analyses (0.427–0.795), indicating low within-person variation. The serum concentration of UV filters 4‑MBP and 4‑HBP significantly increased throughout pregnancy, also after adjusting for seasonal variation (4‑HBP: effect estimates 0.142–0.437, p 50% of serum samples and showed low within-person variation. Thus, it is possible with acceptable accuracy to evaluate maternal exposure during pregnancy for these non-persistent chemicals using one or more biobank serum samples. The here presented adjusted ICC values can in addition be applied as adjustment of residual variation in future studies that evaluate outcomes related to prenatal exposures. Keywords: Serum, Pregnancy, Phthalates, Parabens, Phenols, UV-filters, Non-persistent EDC

STUDY QUESTION Is the Leydig cell function of young European men associated with semen quality? SUMMARY ANSWER Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. WHAT IS ALREADY KNOWN Semen quality of young European men shows a heterogeneous pattern. Many have sperm counts below and in the lower WHO reference where there nevertheless is a significant risk of subfecundity. Little is known about differences in Leydig cell function between men with semen quality below and within the WHO reference range. STUDY DESIGN, SIZE AND DURATION A coordinated, cross-sectional population-based study of 8182 men undertaken in 1996-2010. PARTICIPANTS, SETTING AND METHOD Young men (median age 19.1 years) were investigated in centres in Denmark, Estonia, Finland, Germany Latvia, Lithuania, and Spain. The men originated from the general populations, all were young, almost all were unaware of their fecundity and each provided a semen and blood sample. Associations between semen parameters and serum levels of testosterone and luteinising hormone (LH), calculated free testosterone, and ratios between serum testosterone and LH were determined. MAIN RESULT AND ROLE OF CHANCE Serum testosterone levels were not associated with sperm concentrations, total sperm counts, or percentage of motile or morphologically normal spermatozoa. There was an inverse association between the semen parameters and serum LH levels, and accordingly a positive association to testosterone/LH ratio and calculated-free-testosterone/LH ratio. LIMITATIONS, REASON FOR CAUTION The size of the study mitigates the intra-individual variability concern. The distinction between different sub-categories of sperm motility and sperm morphology is subjective despite training. However, inter-observer variation would tend towards non-differential misclassification and would decrease the likelihood of detecting associations between reproductive hormone levels and semen variables, suggesting that the presented associations might in reality be even stronger than shown. Although we adjusted for confounders, we cannot of course exclude that our results can be skewed by selection bias or residual confounding. WIDER IMPLICATIONS OF THE FINDINGS Compensated reduction in Leydig cell function, defined as increased LH concentration combined with adequate testosterone production is associated with lower semen quality. This is apparent even within the WHO reference range of semen quality. It is unknown whether impaired Leydig cell function in young men may confer an increased risk of acquired testosterone deficiency later in life. STUDY FUNDING/COMPETING INTERESTS Support from The Research Fund of Rigshospitalet (grant no. R42-A1326) to N.J. made this study possible. The background studies of young men have been supported economically by several grants. ITALIC! Denmark: The European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603 and most recently FP7/2007-2013, DEER Grant agreement no. 212844), The Danish Research Council (grants nos. 9700833 2107-05-0006), The Danish Agency for Science, Technology and Innovation (Grant no. 271070678), Rigshospitalet (Grant no. 961506336), The University of Copenhagen (Grant no. 211-0357/07-3012), The Danish Ministry of Health and the Danish Environmental Protection Agency, A.P. Moller and wife Chastine McKinney Mollers foundation, and Svend Andersens Foundation. ITALIC! Finland: European Union (contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT- 2002-00603 and most recently FP7/2008-2012, DEER Grant agreement no. 212844), The Academy of Finland, Turku University Hospital Funds, Sigrid Juselius Foundation. ITALIC! Estonia, Latvia and Lithuania: European Union (QLRT-2001-02911), the Estonian Science Foundation, grant number 2991, Lithuanian Foundation for Research, Organon Agencies B.V. and the Danish Research Council, grant no. 9700833. ITALIC! Germany: European Union (contract numbers QLK4-CT-2002-00603). ITALIC! Spain: European Commission QLK4-1999-01422. M.F. received support from the Spanish Ministry of Science and Innovation (Program Ramon y Cajal). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors have any competing interests to declare.

We report reference ranges based on LC-MS/MS for testosterone (T), free testosterone (FT) and its precursors, i.e. 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) and androstenedione (Adione), in relation to different health markers and lifestyle factors. The study was based on 304 healthy men aged 30-61 years participating in a population-based cross-sectional study (Health2008). Examination program consisted of a clinical examination, completion of a self-administered questionnaire and blood sampling. Steroid metabolites were measured by a validated and sensitive LC-MS/MS method. Older age-groups were significantly associated with decreased concentrations of DHEA, DHEAS, Adione, and FT, while no significant associations with age were shown for 17-OHP or T. Participants with BMI≥30 kg/m(2) had lower age-related steroid metabolite z-scores compared to participants with BMI

Background Immigrants may face problems with accessing the Danish healthcare system due to, for example, lack of knowledge of how to navigate it, which may cause inappropriate healthcare-seeking. Danish municipalities provide a mandatory introduction and language programme for newly arrived immigrants, but no information on the healthcare system is offered. This study investigated what effects information about the Danish healthcare system may have on the hypothetical healthcare-seeking behaviour of newly arrived immigrants and their actual healthcare use. Methods A prospective intervention study of 1572 adult immigrants attending two language schools in Copenhagen was carried out. Two intervention groups received either a course or written information on the Danish healthcare system, respectively, while the control group received neither. Survey data included three case vignettes on healthcare-seeking behaviour (flu-like symptoms, chest pain and depression) and were linked to registry data on sociodemographic characteristics and healthcare use in the year to follow. Logistic regression and binomial regression analyses were performed. Results Appropriate hypothetical healthcare-seeking behaviour was reported by 61.8–78.8% depending on the vignette. Written information showed no effect on immigrants’ hypothetical healthcare-seeking behaviour, while the course showed a positive effect on hypothetical healthcare-seeking behaviour for flu-like symptoms (adjusted odds ratio [AOR] = 1.71, 95% confidence interval [CI] = 1.01–2.91, p-value = 0.0467), but not on chest pain or depression. The interventions did not affect immigrants’ actual healthcare use; all groups made lower use of health care services in the following year compared with the year where the study took place, except for the use of dental care which remained stable. Conclusions Information on the healthcare system embedded in the language school programme has the potential to facilitate immigrants’ access to healthcare. Yet, the results underscore the need for further refinement and development of educational interventions, as well as ensuring adequate utilisation of healthcare services by other means. Multi-dimensional and multi-sectional efforts are important for integration issues within healthcare in Europe. Trial registration Health-seeking behaviour among newly arrived immigrants in Denmark ISRCTN24905314, May 1, 2015 (Retrospectively registered).

Study question Are infertile men with reduced semen quality at risk of a further decrease in testicular function? Summary answer Infertile men with severely reduced semen quality risk further deterioration of semen quality 15 years after treatment for infertility, and a lower baseline sperm concentration was associated with a more pronounced increase in LH and decrease in testosterone/LH ratio at follow-up. What is known already Male factors account for up to 50% of human infertility. The most common finding is spermatogenic failure (SgF) yet the life course of semen quality and testosterone production in such men has not been described. Study design, size, duration A follow-up study of men with SgF was performed 15 years after the initial infertility assessment between January 1995 and December 2000. Participants/materials, setting, methods Hospital records were used to identify potential participants in the study. A total of 137 men with primary male infertility due to SgF and 70 controls with good semen quality from couples with female factor infertility who attended a tertiary referral centre were included: the participation rate was 31% and 26%, respectively. The men provided semen samples and underwent a physical examination. Blood samples were taken to measure levels of reproductive hormones (FSH, LH, testosterone, sex hormone-binding globulin, estradiol and inhibin B). Current results were compared with results from the initial assessments. Main results and the role of chance At the time of follow up the SgF men had significantly lower Leydig cell capacity than the control group as well as much lower semen quality. For the SgF men, between baseline sampling and follow up, the median sperm concentration decreased from 1.9 to 0.6 mill/ml and total sperm count from 7.7 to 2.0 million (P = 0.019 and 0.012, respectively), and 10% developed azoospermia. Calculated free testosterone (cFT), but not total testosterone (tT) decreased in the SgF group by ~0.6% (95% CI 0.1-1.2%) per year. In the SgF group, LH increased by 1.6% (CI 0.9-2.3%) annually, and consequently tT/LH and cFT/LH ratios had decreased by 1.3% (CI 0.5-2.1) and 2.1% (CI 1.2-3.0%), respectively. The increase in LH and the decreases in tT/LH and cFT/LH ratios were more pronounced in men with lower baseline sperm concentrations. Limitations, reasons for caution We consider the case group as representative of infertile men not in need of testosterone treatment at baseline investigation, but do not have information on those that chose not to participate in the follow-up study. There were alterations in some hormone analysis methods during the follow-up period that may introduce uncertainty in interpretation of long-term changes in hormone levels despite rigorous quality control. The validity of the control group suffers from a lack of hormone values at baseline. Also, at follow-up, for practical reasons only one semen sample could be obtained, which makes the effect estimate more uncertain and there is a risk of non-differential misclassification. Wider implications of the findings Without being able to predict individual outcomes, it is prudent to consider sperm cryopreservation or advise not to postpone fertility treatment when men present with infertility due to impaired semen quality. Whether partly compensated Leydig cell insufficiency in men with SgF will eventually develop into overt testosterone deficiency cannot be determined from our study. Study funding/competing interest(s) Aase and Einar Danielsen (Grant no. 10-001053), Nordic Research Committee (Grant no. 5109), The Kirsten and Freddie Johansen Fund, and Rigshospitalet's Research Fund (grant no. R24-A812). There are no competing interests.

Background: 'Remigration bias' is often referred to when explaining low mortality outcomes among migrants compared with local-born. The hypothesis suggests that severely ill migrants tend to return to their country of origin, but it has hitherto not been tested in a large-scale epidemiological study. Consequently, we studied whether migrants with severe disease were more likely to emigrate compared with migrants without severe disease. Methods: A historic prospective cohort study was conducted based on all adult refugees and family reunification immigrants (n = 114,331) who obtained residence permission in Denmark between 1 January 1993 and 31 December 2010. Migrants with severe disease were identified through the Danish National Patient Register. Emigrations during follow-up (1 January 1993 to 31 December 2011) were identified using the Danish Civil Registration System. Hazard ratios were calculated for emigration among migrants with different levels of disease severity, adjusting for sex, age and income. Results: Results showed progressively fewer emigrations with increasing disease severity. Migrants with low (HR = 0.92; 95% CI: 0.80-1.06), moderate (HR = 0.84; 95% CI: 0.67-1.06) and high (HR = 0.70; 95% CI: 0.55-0.90) disease severity had fewer emigrations to 'country of origin' compared with migrants without disease. For emigration to 'any country', results likewise showed fewer emigrations among migrants with low (HR = 0.86; 95% CI: 0.78-0.95), moderate (HR = 0.73; 95% CI: 0.62-0.87) and high (HR = 0.64; 95% CI: 0.53-0.76) disease severity. This tendency was also observed by nationality and migrant status. On the disease-specific level, no uniform tendencies in emigration patterns were identified. Conclusion: The results do not generally support the hypothesis of 'remigration bias' but rather suggest the opposite. Accordingly, remigration bias does not appear to explain lower mortality of migrants.

Individuals with newly diagnosed tuberculosis (TB) were screened for diabetes (DM) with fasting plasma glucose (FPG) in Pakistan. A significant decrease in FPG was observed when TB was treated. Of those with newly diagnosed DM, 46% and 62% no longer had hyperglycemia after 3 and 6 months, respectively. Individuals with known DM also showed a significant decrease in fasting plasma levels when treated for TB, but after 3 months none had normoglycemia, and after 6 months 9.2% were normoglycemic. Thus, TB-related DM may abate when the stress terminates, as is the case in gestational DM. However, because stress hyperglycemia may be associated with subsequent risk of developing DM, follow-up is recommended.

Context Results of animal models and cross-sectional cohort studies have suggested a beneficial role for vitamin D in male reproduction. Objective Determine the effect of vitamin D and calcium supplementation on semen quality in infertile men with serum 25-hydroxyvitamin-D (25OHD) levels ≤50 nmol/L. Design A single-center, triple-blinded, randomized clinical trial. Participants A total of 1427 infertile men were screened to include 330; 1002 men did not meet inclusion criteria and 95 did not wish to participate. Intervention The active group received cholecalciferol 300,000 IU initially, then 1400 IU cholecalciferol and 500 mg of calcium daily for 150 days; the other group received placebo. Results Serum concentrations of 25OHD and 1,25-dihydroxyvitamin D3 were significantly higher in men in the treatment group compared with the placebo group. Vitamin D supplementation was not associated with changes in semen parameters, although spontaneous pregnancies tended to be higher in couples in which the man was in the treatment group [7.3% vs 2.4%, Δ5.0% (-0.6%; 10.5%)]. Vitamin D treatment in a subgroup of oligozoospermic men increased the chance for a live birth compared with placebo [35.6% vs 18.3%, Δ17.3% (1.6%; 32.9%)]. Moreover, serum inhibin B levels were higher in men deficient in vitamin D who were randomly assigned to receive high-dose vitamin D [193 pg/mL vs 143 pg/mL, Δ49 pg/mL (8; 91 pg/mL)]; however, the increase in sperm concentration was not significantly higher than in the placebo group (P = 0.07). Conclusion High-dose vitamin D supplementation did not improve semen quality in vitamin D-insufficient infertile men. The positive impact of vitamin D supplementation on live birth rate and serum inhibin B in oligozoospermic and vitamin D-deficient men may be of clinical importance and warrant verification by others.

We present a model-based approach to the analysis of agreement between different raters in a situation where all raters have supplied ordinal ratings of the same cases in a sample. It is assumed that no "gold standard" is available. The model is an ordinal regression model with random effects-a so-called rating scale model. The model includes case-specific parameters that allow each case his or hers own level (disease severity). It also allows raters to have different propensities to score a given set of individuals more or less positively-the rater level. Based on the model, we suggest quantifying the rater variation using the median odds ratio. This allows expressing the variation on the same scale as the observed ordinal data. An important example that will serve to motivate and illustrate the proposed model is the study of breast cancer diagnosis based on screening mammograms. The purpose of the assessment is to detect early breast cancer in order to obtain improved cancer survival. In the study, mammograms from 148 women were evaluated by 110 expert radiologists. The experts were asked to rate each mammogram on a 5-point scale ranging from "normal" to "probably malignant."