Cotinine concentrations in maternal serum and amniotic fluid during pregnancy and risk of testicular germ cell cancer in the offspring: A prospective nested case-control study.

Maternal smoking in pregnancy may increase the risk of testicular germ cell cancer (TGCC) in offspring, but current evidence remains inconclusive. We performed a nested case-control study using cotinine measurements in maternal serum and amniotic fluid as a biomarker for tobacco exposure during pregnancy. A total of 654 males with maternal serum (n = 359, ncases/controls = 71/288) and/or amniotic fluid (n = 295, ncases/controls = 66/229) samples were included. Data on TGCC diagnoses and relevant covariates were derived from nationwide Danish health registries. Cotinine was quantified by liquid chromatography tandem mass spectrometry. An adapted cox regression model estimated the risk of TGCC considering active and inactive tobacco use defined according to cotinine concentrations of <, ≥15 ng/ml. Overall, the concentrations of cotinine were comparable in maternal serum and amniotic fluid (medianserum/amniotic fluid : 2.1/2.6 ng/ml). A strong statistically significant correlation was detected in 14 paired samples (Spearman rho: 0.85). Based on maternal serum cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC in offspring (HR 0.88, 95% CI 0.51; 1.52). Similarly, based on amniotic fluid cotinine concentrations, exposure to active tobacco use was not associated with risk of TGCC (HR 1.11, 95% CI 0.64; 1.95). However, different risks were observed for seminomas and nonseminomas in both matrices, but none were statistically significant. Our findings did not provide convincing evidence supporting that exposure to tobacco during pregnancy is associated with TGCC.

Risk of long COVID and associated symptoms after acute SARS-COV-2 infection in ethnic minorities: A nationwide register-linked cohort study in Denmark.

BACKGROUND: Ethnic minorities living in high-income countries have been disproportionately affected by Coronavirus Disease 2019 (COVID-19) in terms of infection rates, hospitalisations, and deaths; however, less is known about long COVID in these populations. Our aim was to examine the risk of long COVID and associated symptoms among ethnic minorities. METHODS AND FINDINGS: We used nationwide register-based cohort data on individuals diagnosed with COVID-19 aged ≥18 years (n = 2,287,175) between January 2020 and August 2022 in Denmark. We calculated the risk of long COVID diagnosis and long COVID symptoms among ethnic minorities compared with native Danes using multivariable Cox proportional hazard regression and logistic regression, respectively. Among individuals who were first time diagnosed with COVID-19 during the study period, 39,876 (1.7%) were hospitalised and 2,247,299 (98.3%) were nonhospitalised individuals. Of the diagnosed COVID-19 cases, 1,952,021 (85.3%) were native Danes and 335,154 (14.7%) were ethnic minorities. After adjustment for age, sex, civil status, education, family income, and Charlson comorbidity index, ethnic minorities from North Africa (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] [1.12,1.79], p = 0.003), Middle East (aHR 1.38, 95% CI [1.24,1.55], p < 0.001), Eastern Europe (aHR 1.35, 95% CI [1.22,1.49], p < 0.001), and Asia (aHR 1.23, 95% CI [1.09,1.40], p = 0.001) had significantly greater risk of long COVID diagnosis than native Danes. In the analysis by largest countries of origin, the greater risks of long COVID diagnosis were found in people of Iraqi origin (aHR 1.56, 95% CI [1.30,1.88], p < 0.001), people of Turkish origin (aHR 1.42, 95% CI [1.24,1.63], p < 0.001), and people of Somali origin (aHR 1.42, 95% CI [1.07,1.91], p = 0.016). A significant factor associated with an increased risk of long COVID diagnosis was COVID-19 hospitalisation. The risk of long COVID diagnosis among ethnic minorities was more pronounced between January 2020 and June 2021. Furthermore, the odds of reporting cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) and any long COVID symptoms were higher among people of North African, Middle Eastern, Eastern European, and Asian origins than among native Danes in both unadjusted and adjusted models. Despite including the nationwide sample of individuals diagnosed with COVID-19, the precision of our estimates on long COVID was limited to the sample of patients with symptoms who had contacted the hospital. CONCLUSIONS: Belonging to an ethnic minority group was significantly associated with an increased risk of long COVID, indicating the need to better understand long COVID drivers and address care and treatment strategies in these populations.

Prenatal phthalate exposure and pubertal development in 16-year-old daughters: reproductive hormones and number of ovarian follicles.

STUDY QUESTION: Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? SUMMARY ANSWER: Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. WHAT IS KNOWN ALREADY: Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. STUDY DESIGN, SIZE, DURATION: This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother-Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. MAIN RESULTS AND THE ROLE OF CHANCE: In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. LIMITATIONS, REASONS FOR CAUTION: Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. TRIAL REGISTRATION NUMBER: N/A.

Disparities with global standards about growth references of mid-upper arm circumference-for-age for Pakistani children aged 6-60 months.

AIM: Growth reference values about mid-upper arm circumference (MUAC) are vital for assessing children's nutritional status. However, Pakistan lacks these reference values and growth charts. This study aims to develop these for children aged 6-60 months and compare them with global standards. METHODS: The data were acquired from the 2018 National Nutrition Survey of Pakistan, which was conducted by the United Nations Children's Fund (UNICEF) during 2018-2019. The final study cohort comprised 57 285 children, with 51% being boys. Percentile values and charts for MUAC-for-age were developed using generalised additive models for location, scale and shape with the Box-Cox power exponential distribution. RESULTS: The mean MUAC was 14.21 cm (±2.07 cm) and 14.13 cm (±2.12 cm) for the boys and girls, respectively. At 60 months of age, the P3 and P97 percentiles for girls were slightly higher than those for boys. The median percentiles of Pakistani children were smaller than the World Health Organisation 2007 standards and with international references. CONCLUSION: We observed disparities in MUAC-for-age growth references among Pakistani children compared to global standards, highlighting regional, age and gender variations. This underscores the need for developing countries like Pakistan to establish their growth references.

COVID-19 mortality and use of intensive care among ethnic minorities - a national register-based Danish population study.

Migrants and ethnic minorities are disproportionately affected by the Coronavirus Disease 2019 (COVID-19) pandemic compared to the majority population. Therefore, we studied mortality and use of mechanical ventilation (MV) by country of birth and migrant status in a nationwide cohort in Denmark. Nationwide register data on all cases hospitalized for > 24-hours with COVID-19 between February 2020 and March 2021. Main outcome measures were mortality and MV within 30 days of hospitalization for COVID-19. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by region of origin and migrant status using logistic regression analyses, adjusting for age, sex, comorbidity and sociodemographic factors. Of 6,406 patients, 977 (15%) died and 342 (5%) were treated with mechanical ventilation. Immigrants (OR:0.55;95%CI: 0.44-0.70) and individuals of non-Western origin had a lower odds (OR: 0.49; 95% CI: 0.37-0.65) of death upon admission with COVID-19 compared to Danish born individuals. Immigrants and descendants (OR: 1.62; 95% CI: 1.22-2.15) as well as individuals of non-Western origin (OR: 1.83; 95% CI: 1.35-2.47) had a significantly higher odds of MV compared to Danish born individuals. Outcomes of individuals with Western origin did not differ. Immigrants and individuals of non-Western origin had a significantly lower COVID-19 associated mortality compared to individuals of Danish origin after adjustment for sociodemographic factors and comorbidity. In contrast, the odds of MV was higher for immigrants and individuals of non-Western origin compared to individuals of Danish origin.

Socioeconomic inequities in mortality and functional outcome after stroke in Zanzibar: A prospective cohort study.

OBJECTIVES: To characterise mortality and functional outcome and their relationships with socioeconomic deprivation for women and men in Zanzibar. MATERIALS AND METHODS: Participants in ZanStroke, a prospective observational study of patients admitted to hospital with a diagnosis of acute stroke, were followed up until one year after the stroke. The modified National Institute of Health Stroke Scale was used to assess initial stroke severity, while modified Rankin Scale (mRS) was used to assess disability at 12 months post-stroke. A multidimensional poverty index was created using individual-level data. Kaplan-Meier analysis and Cox regression model were used to examine associations of socioeconomic deprivation and death at 28 days and 12 months after stroke onset, while logistic regression analysis was used to examine associations between deprivation and functional outcome. RESULTS: Overall mortality rate was 38.2% (CI 34.8-41.9) at 28 days, rising to 59.0% (CI 55.2-62.8) at 12 months. When adjusted for other variables, survival was higher among the least deprived (HR 0.60 CI 0.45-0.80), an association that was strongly significant for women (HR 0.46 CI 0.29-0.74). Among 12-month survivors 45.1% (n = 122) had no/low level of disability (mRS 0-2), while 22.9% (n = 62) were unable to walk independently or at all. No difference between socioeconomic deprivation and outcome was seen at one year. CONCLUSION: Case-fatality rates were high, and socioeconomic disparities were evident even during the acute stroke phase. Policies are needed to reduce significant health disparities, adapt evidence-based interventions, and promote equitable access to stroke care and rehabilitation.

Clinical assessment of blood pressure in 60 girls with Turner syndrome compared to 1888 healthy Danish girls.

OBJECTIVE: Hypertension contributes to increased risk of cardiovascular disease in patients with Turner syndrome (TS). Our objective was to evaluate blood pressure (BP) in girls with TS followed longitudinally through childhood and adolescence compared to a newly established BP reference material. DESIGN: Cohort study with data collected from 1991 to 2019 consisting of a population-based reference cohort and a group of girls with TS followed at a single tertiary centre. PATIENTS/PARTICIPANTS: Reference population of 1888 healthy girls with 4890 BP recordings and 60 girls with TS with 365 BP recordings. MEASUREMENTS: Difference in diastolic BP (DBP) and systolic BP (SBP), expressed in standard deviation scores (SDS), between girls with TS and the reference population, unadjusted and adjusted for BMI. Difference in BP (SDS) between TS subgroups (karyotype, oestrogen treatment, cardiac diagnosis). RESULTS: The girls with TS had significantly higher DBP (mean ± SD, 0.72 SDS ± 0.95; p < .001) and SBP (0.53 SDS ± 1.11; p = .001) than the reference population. Adjusted for BMI, girls with TS had significantly higher DBP (mean ± SE, 0.71 SDS ± 0.12; p < .001) but not SBP (0.17 SDS ± 0.16; p = .29). There was no significant difference in DBP (median, IQR: 0.97 SDS, 0.30-1.58 vs. 0.76 SDS, 0.10-1.20; p = .31) or SBP (0.51 SDS, 0.15-1.30 vs. 0.57 SDS, -0.30 to 1.05; p = .67) between individuals with or without a cardiac diagnosis. In the TS population, 55% (31/56) had at least one BP recording above the hypertension threshold. CONCLUSIONS: Our findings indicate that standardised longitudinal routine monitoring of BP in girls with TS already in childhood is of utmost importance.

Pathogen distribution and antimicrobial resistance in infections in migrants and nonmigrants in Denmark, a cross-sectional study.

OBJECTIVE: To investigate differences in bacterial distribution and resistance patterns of relevant pathogens in skin and tissue infections among migrants compared to nonmigrants. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Optimized detection of germ cell neoplasia in situ in contralateral biopsy reduces the risk of second testis cancer.

OBJECTIVE: 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%. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A phase I/II study of acute and late physician assessed and patient-reported morbidity following whole pelvic radiation in high-risk prostate cancer patients.

BACKGROUND: The aim of this study was to assess acute and late morbidity measured by the physician and patient-reported outcomes (PROs) in high-risk prostate cancer (PC) patients receiving whole pelvic intensity-modulated radiotherapy (IMRT) in the setting of a national clinical trial. MATERIAL AND METHODS: A total of 88 patients with adenocarcinoma of the prostate and high-risk parameters were enrolled from 2011 to 2013. All patients received 78 Gy in 39 fractions of IMRT delivering simultaneous 78 Gy to the prostate and 56 Gy to the seminal vesicles and lymph nodes. Physician-reported morbidity was assessed by CTCAE v.4.0. PROs were registered for gastro-intestinal (GI) by the RT-ARD score, genito-urinary (GU) by DAN-PSS, sexual and hormonal by EPIC-26, and quality of life (QoL) by EORTC QLQ-C30. RESULTS: Median follow-up (FU) time was 4.6 years. No persistent late CTCAE grade 3+ morbidity was observed. Prevalence of CTCAE grade 2+ GI morbidities varied from 0 to 6% at baseline throughout FU time, except for diarrhea, which was reported in 19% of the patients post-RT. PROs revealed increased GI morbidity (≥1 monthly episode) for "rectal urgency", "use of pads", "incomplete evacuation", "mucus in stool" and "bowel function impact on QoL" all remained significantly different (p < .05) at 60 months compared to baseline. CTCAE grade 2+ GU and sexual morbidity were unchanged. GU PROs on obstructive and irritative GU items (≥daily episode) increased during RT and normalized at 24 months. No clinically significant differences were found in sexual, hormonal, and QoL scores compared to baseline. CONCLUSIONS: Whole pelvic RT resulted in a mild to the moderate burden of late GI morbidities demonstrated by a relatively high prevalence of PROs. Whereas, physician-assessed morbidity revealed a low prevalence of late GI morbidity scores. This emphasizes the importance of using both PROs and physician-reported scoring scales when reporting late morbidity in clinical trials.

Socioeconomic and demographic risk factors in COVID-19 hospitalization among immigrants and ethnic minorities.

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.

Waiting for family reunification and the risk of mental disorders among refugee fathers: a 24-year longitudinal cohort study from Denmark.

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 < 9 months, the HR of any mental disorder was 1.43 (95% CI 1.08-1.89) for 9-11 months' separation, increasing to 2.02 (95% CI 1.52-2.68) for 18-23 months' separation. Results were driven by post-traumatic stress disorder. 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.

Familial resemblance in markers of testicular function in fathers and their young sons: a cross-sectional study.

STUDY QUESTION: Is testicular function associated within father-son pairs? SUMMARY ANSWER: Familial resemblance in testis volume and serum markers of spermatogenesis was observed in father-son pairs. WHAT IS KNOWN ALREADY: Studies suggest familial clustering of male subfertility and impaired spermatogenesis, but in men from the general population little is known about concordance in testicular function between fathers and sons. STUDY DESIGN, SIZE, DURATION: This cross-sectional study with simultaneous collection of data in fathers and sons included 72 pairs (144 fathers and sons), unselected regarding testicular function were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: A subgroup of men from the background population and participating in a study on testicular function were asked permission to invite their fathers to participate in a similar setup. Fathers (median age of 53 years) and sons (median age of 19 years) participated in the same study setup including assessment of testis size, having a blood sample taken and analysed for serum levels of reproductive hormones (FSH, inhibin B, LH, testosterone, oestradiol, sex hormone-binding globulin (SHBG) and calculated free testosterone) and delivering a semen sample for assessment of traditional semen parameters. Mixed-effects models were fitted to estimate the familial resemblance as the proportion of variance in markers of testicular function due to shared factors for fathers and sons accounted for using random-effects. Variance components were calculated from both unadjusted and adjusted models. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustments, variance component analyses showed that familial resemblance between fathers and sons accounted for 48% (P < 0.001) of the variation in testicular volume, 32% (P = 0.009) of the variation in FSH, 31% (P = 0.009) of the variation in the inhibin B/FSH ratio, 33% (P = 0.007) and 45% (P < 0.001) of the variation in testosterone and free testosterone, respectively, and 31% (P = 0.009) of the variation in SHBG. None of the semen parameters were associated within father-son pairs. LIMITATIONS, REASONS FOR CAUTION: The present study may have lacked power to detect associations for semen quality, as large intra- and inter-individual variation occur in semen parameters. WIDER IMPLICATIONS OF THE FINDINGS: In this study, testis volume, serum testosterone and serum markers of spermatogenesis including FSH were associated in fathers and sons, suggesting an impact of paternal genetics for testicular function in the son. However, the estimated familial resemblance for spermatogenesis markers highlights that other factors, such as maternal genetics and prenatal as well as adult exposures, are also of major importance for testicular function. STUDY FUNDING/COMPETING INTEREST(S): The study has received funding from Danish Health Authority, Research Fund of the Capital Region of Denmark and Independent Research Fund Denmark (8020-00218B). None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper of publication decisions. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Does height and IGF-I determine pubertal timing in girls?

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 < 0.01, respectively). Girls with higher IGF-I levels experienced thelarche and menarche earlier compared with the rest of the cohort (p < 0.01). Genotypes were not associated with age at thelarche nor menarche, but the PAPPA2 minor allele carriers were shorter compared with major allele carriers, p = 0.03. CONCLUSIONS: Height and IGF-I, but not PAPP-A, PAPP-A2, and STC2 genotypes, were negatively associated with age at thelarche and menarche. IMPACT: Girls with tall and short stature enter puberty earlier and later compared with girls with normal height. Girls with higher insulin-growth factor-I in childhood enter puberty earlier. Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood. Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing.

First perinatal psychiatric episode among refugee and family-reunified immigrant women compared to Danish-born women: a register-based study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Identification of Binding Sites on Human Serum Albumin for Somapacitan, a Long-Acting Growth Hormone Derivative.

Somapacitan, a human growth hormone derivative that binds reversibly to albumin, was investigated for human serum albumin (HSA) and HSA domain binding. Isothermal titration calorimetry (ITC) binding profiles showed high-affinity binding (∼100-1000 nM) of one somapacitan molecule and low-affinity binding (∼1000-10000 nM) of one to two somapacitan molecules to HSA. The high-affinity site was identified in HSA domain III using size exclusion chromatography (SEC) and ITC. SEC studies showed that the neonatal Fc receptor shields one binding site for somapacitan, indicating its position in domain III. A crystal structure of somapacitan in complex with HSA optimized for neonatal Fc receptor binding, having four amino acid residue replacements, identified a low-affinity site in fatty acid-binding site 6 (domain II). Surface plasmon resonance (SPR) showed these replacements affect the kinetics of the high-affinity binding site. Furthermore, small-angle X-ray scattering and SPR brace two somapacitan-binding sites on HSA.

A history of cryptorchidism is associated with impaired testicular function in early adulthood: a cross-sectional study of 6376 men from the general population.

STUDY QUESTION: Is there a difference in testicular function in early adulthood between men born with cryptorchidism and men born with normally descended testes? SUMMARY ANSWER: In men from the general population, a history of cryptorchidism was associated with lower total testis volume and impaired semen quality as well as altered serum levels of reproductive hormones. WHAT IS KNOWN ALREADY: The association between cryptorchidism and testicular function is well documented in studies based on sub-fertile or infertile men recruited from a clinical setting. However, the association has not previously been investigated in men from the general population, who were unselected regarding fertility status. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional population-based study of 6376 young Danish men examined from 1996 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study is based on young men from the greater Copenhagen area, Denmark (median age of 19 years) who were unselected regarding fertility status and semen quality. The young men delivered a semen sample, had a blood sample drawn and underwent a physical examination including assessment of testis volume. Participants completed a questionnaire regarding cryptorchidism at birth, current lifestyle and their mother's pregnancy, after consulting their mother. The differences in markers of testicular function, including testis volume, semen parameters and reproductive hormones between men with and without a history of cryptorchidism were investigated with multiple linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The participation rate was 24% for the entire study period. Overall, a history of cryptorchidism was associated with reduced testicular function. In the adjusted models, a history of cryptorchidism was associated with a 3.5 ml lower total testis volume, determined by orchidometer (P < 0.001), 28% lower sperm concentration (95% CI: -37 to -20) and 26% lower inhibin B/FSH ratio (95% CI: -50 to -22) compared to men without a history of cryptorchidism, suggesting a reduced spermatogenetic capacity. Men with a history of cryptorchidism also had a slightly reduced Leydig cell function expressed as a 6% lower testosterone/LH ratio (95% CI: -12 to -0.7). The significant effect sizes and different markers of testicular function pointing in the same direction across the different models based on a large sample size support that the results are not chance findings. LIMITATIONS, REASONS FOR CAUTION: Information on cryptorchidism at birth and treatment modus was obtained by retrospective self-report, and each participant only delivered one semen sample. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that men with a history of cryptorchidism could be at increased risk of experiencing fertility problems. However, among these men there is a wide variation in semen quality and further research is needed in order to identify the subgroup of boys born with cryptorchidism who are at the greatest risk of impaired semen quality when reaching adulthood. STUDY FUNDING/COMPETING INTEREST(S): The study received financial support from the Research fund of Rigshospitalet, Copenhagen University Hospital; the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT-2002-00603. FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Møller and wife Chastine McKinney Møllers Foundation; and Svend Andersens Foundation. None of the founders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

The LH/FSH ratio is not a sex-dimorphic marker after infancy: data from 6417 healthy individuals and 125 patients with Differences of Sex Development.

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).

Age-related renal function decline in Fabry disease patients on enzyme replacement therapy: a longitudinal cohort study.

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.

Towards proton arc therapy: physical and biologically equivalent doses with increasing number of beams in pediatric brain irradiation.

Background: Proton arc therapy may improve physical dose conformity and reduce concerns of elevated linear energy transfer (LET) and relative biological effectiveness (RBE) at the end of the proton range, while offering more degrees of freedom for normal tissue sparing. To explore the potential of proton arc therapy, we studied the effect of increasing the number of beams on physical and biologically equivalent dose conformity in the setting of pediatric brain tumors. Material and methods: A cylindrical phantom (Ø = 150 mm) with central cylindrical targets (Ø = 25 and 30 mm) was planned with increasing number of equiangular coplanar proton beams (from 3 to 36). For four anonymized pediatric brain tumor patients, two 'surrogate' proton arc plans (18 equiangular coplanar or sagittal beams) and a reference plan with 3 non-coplanar beams were constructed. Biologically equivalent doses were calculated using two RBE scenarios: RBE1.1; and RBELET, the physical dose weighted by the LET. For both RBE scenarios, dose gradients were assessed, and doses to cognitive brain structures were reported. Results: Increasing the number of beams resulted in an improved dose gradient and reduced volume exposed to intermediate LET levels, at the expense of increased low-dose and low-LET volumes. Most of the differences between the two RBE scenarios were seen around the prescription dose level, where the isodose volumes increased with the RBELET plans, e.g. up to 63% in the 3-beam plan for the smallest phantom target. Overall, the temporal lobes were better spared with the sagittal proton arc surrogate plans, e.g. a mean dose of 3.9 Gy compared to 6 Gy in the reference 3-beam plan (median value, RBE1.1). Conclusion: Proton arc therapy has the potential to improve dose gradients to better spare cognitive brain structures. However, this is at the expense of increased low-dose/low-LET volumes, with possible implications for secondary cancer risks.