Cohort profile: The Copenhagen Analgesic Study-The COPANA cohort.

BACKGROUND: Development of the gonads during fetal life is complex and vital for adult reproductive health. Cell and animal studies have shown an alarming effect of mild analgesics on germ cells in both males and females. More than 50% of pregnant women use mild analgesics during pregnancy, which potentially could compromise the reproductive health of the next generation. OBJECTIVES: We present a research protocol designed to evaluate the effect of prenatal exposure to mild analgesics and endocrine-disrupting chemicals on gonadal function in the offspring. POPULATION: Healthy, singleton pregnant women and their partners. DESIGN: The COPANA cohort is a prospective, observational pregnancy and birth cohort. METHODS: Participants were enrolled during the first trimester of pregnancy. Information on the use of mild analgesics was collected retrospectively 3 months prior to pregnancy and prospectively every 2 weeks throughout the study. We collected extensive data on lifestyle and reproductive health. Biospecimens were collected in the first trimester (maternal and paternal urine- and blood samples), in the third trimester in conjunction with a study-specific ultrasound scan (maternal urine sample), and approximately 3 months post-partum during the infant minipuberty period (maternal and infant urine- and blood samples). A comprehensive evaluation of reproductive function in the infants during the minipuberty phase was performed, including an ultrasound scan of the testis or ovaries and uterus. PRELIMINARY RESULTS: In total, 685 pregnant women and their partners were included between March 2020 and January 2022. A total of 589 infants (287 males) and their parents completed the follow-up during the minipuberty phase (December 2020-November 2022). CONCLUSIONS: The Copenhagen Analgesic Study holds the potential to provide novel and comprehensive insights into the impact of early and late prenatal exposure to mild analgesics and other endocrine-disrupting chemicals on future reproductive function in the offspring.

Paracetamol use prior to and in early pregnancy: Prevalence and patterns among women with and without chronic medical diseases.

AIMS: Paracetamol is commonly consumed by pregnant women, even though recent data have questioned its safety. Having chronic medical diseases (CMDs) may influence the prevalence of use during pregnancy. We aimed to assess the prevalence and patterns of use 3 months prior to pregnancy and in the first trimester among women with and without CMDs and the potential influence of CMDs on frequent use in the first trimester. METHODS: We used patient-reported data from the Copenhagen Pregnancy Cohort from 1 October 2013 to 23 May 2019 with information on CMDs and paracetamol use. Prevalence and patterns of use were assessed descriptively and by multivariable logistic regression models. RESULTS: We included 24 019 pregnancies. Use of paracetamol prior to and in early pregnancy was significantly higher among women with CMDs compared to women without (40.7% vs. 35.8% and 9.1% vs. 5.1%, respectively). Women with CMDs were 2.7 times more likely to have a frequent intake compared to women without [aOR 2.69 (95% CI 2.05-3.32)]. Migraine, rheumatoid arthritis and mental disease were associated with a higher use of paracetamol [aOR 4.39 (3.20-6.02), aOR 4.32 (2.41-7.72) and aOR 2.74 (1.67-4.49), respectively]. CONCLUSIONS: Women with CMDs had a higher paracetamol use before and during pregnancy than women without CMDs. Women with migraine, rheumatoid arthritis and mental disease showed the highest risk of frequent use. This study highlights the importance of discussing pain relief in pregnancy and evaluating the influence of maternal CMDs when assessing adverse effects of paracetamol use during pregnancy.

Accelerated loss of oogonia and impaired folliculogenesis in females with Turner syndrome start during early fetal development.

STUDY QUESTION: How are germ cell numbers and initiation of folliculogenesis affected in fetal Turner syndrome (TS) ovaries? SUMMARY ANSWER: Germ cell development was severely affected already in early second trimester pregnancies, including accelerated oogonia loss and impaired initiation of primordial follicle formation in TS ovaries, while the phenotype in TS mosaic ovaries was less severe. WHAT IS KNOWN ALREADY: Females with TS are characterized by premature ovarian insufficiency (POI). This phenotype is proposed to be a consequence of germ cell loss during development, but the timing and mechanisms behind this are not characterized in detail. Only few studies have evaluated germ cell development in fetal TS and TS mosaic ovaries, and with a sparse number of specimens included per study. STUDY DESIGN, SIZE, DURATION: This study included a total of 102 formalin-fixed and paraffin-embedded fetal ovarian tissue specimens. Specimens included were from fetuses with 45,X (N = 42 aged gestational week (GW) 12-20, except one GW 40 sample), 45,X/46,XX (N = 7, aged GW 12-20), and from controls (N = 53, aged GW 12-42) from a biobank (ethics approval # H-2-2014-103). PARTICIPANTS/MATERIALS, SETTING, METHODS: The number of OCT4 positive germ cells/mm2, follicles (primordial and primary)/mm2 and cPARP positive cells/mm2 were quantified in fetal ovarian tissue from TS, TS mosaic and controls following morphological and immunohistochemical analysis. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for gestational age, the number of OCT4+ oogonia was significantly higher in control ovaries (N = 53) versus 45,X ovaries (N = 40, P < 0.001), as well as in control ovaries versus 45,X/46,XX mosaic ovaries (N = 7, P < 0.043). Accordingly, the numbers of follicles were significantly higher in control ovaries versus 45,X and 45,X/46,XX ovaries from GW 16-20 with a median range of 154 (N = 11) versus 0 (N = 24) versus 3 (N = 5) (P < 0.001 and P < 0.015, respectively). The number of follicles was also significantly higher in 45,X/46,XX mosaic ovaries from GW 16-20 compared with 45,X ovaries (P < 0.005). Additionally, the numbers of apoptotic cells determined as cPARP+ cells/mm2 were significantly higher in ovaries 45,X (n = 39) versus controls (n = 15, P = 0.001) from GW 12-20 after adjusting for GW. LIMITATIONS, REASONS FOR CAUTION: The analysis of OCT4+ cells/mm2, cPARP+ cells/mm2 and follicles (primordial and primary)/mm2 should be considered semi-quantitative as it was not possible to use quantification by stereology. The heterogeneous distribution of follicles in the ovarian cortex warrants a cautious interpretation of the exact quantitative numbers reported. Moreover, only one 45,X specimen and no 45,X/46,XX specimens aged above GW 20 were available for this study, which unfortunately made it impossible to assess whether the ovarian folliculogenesis was delayed or absent in the TS and TS mosaic specimens. WIDER IMPLICATIONS OF THE FINDINGS: This human study provides insights about the timing of accelerated fetal germ cell loss in TS. Knowledge about the biological mechanism of POI in girls with TS is clinically useful when counseling patients about expected ovarian function and fertility preservation strategies. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC). TRIAL REGISTRATION NUMBER: N/A.

Cohort profile: The COPENHAGEN Minipuberty Study-A longitudinal prospective cohort of healthy full-term infants and their parents.

BACKGROUND: The hypothalamic-pituitary-gonadal (HPG) axis governs sexual maturation and reproductive function in humans. In early postnatal life, it is transiently active during which circulating sex steroids reach adult levels. While this so-called minipuberty represents a universal phenomenon in infants of both sexes, its role for early maturation and growth remains incompletely understood. OBJECTIVES: To provide normative data on auxology as well as serum and urinary hormone levels in healthy, full-term infants throughout the first year of life and to investigate associations of postnatal HPG axis dynamics as well as hormonal, genetic and environmental exposures with early genital development and growth. POPULATION: Healthy, Danish, full-term, singleton newborns including their parents. DESIGN: Single-centre, prospective, observational longitudinal pregnancy and birth cohort. METHODS: Newborns were followed with six repeated clinical examinations during a one-year follow-up period. An umbilical cord blood sample was drawn at birth. At each visit, infants underwent a clinical examination focusing on auxology and genital development. Further, blood (serum, plasma, DNA) and urine samples were collected at each visit. Mothers and fathers underwent a clinical examination and provided blood samples prior to and after birth. A subset of parents provided urine samples and breast milk samples. Pregnancy and obstetrical outcomes, and detailed parental questionnaires were compiled. PRELIMINARY RESULTS: Between August 2016 and August 2018, 2481 women with singleton pregnancies were invited to participate of which 298, including their partners, were enrolled (12.0%). A total of 268 healthy, full-term newborns born appropriate for gestational age (AGA) were included at birth, 233 newborns participated in the postnatal follow-up period and 186 completed the one-year follow-up period (9.4% and 7.5%, respectively). CONCLUSION: The COPENHAGEN Minipuberty Study provides detailed, longitudinal data on early genital development and growth including hormonal and genetic profiles and environmental exposure in healthy infants including additional data in their parents.

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).

Clinical oral dryness score: evaluation of a new screening method for oral dryness.

The purpose of this study was to explore the association of the clinical oral dryness score (CODS) with salivary flow rates, xerostomia inventory (XI), and bother index (BI). 147 patients were screened using CODS, which determined 10 features of oral dryness. Each feature contributed 1 point, and the total score varied from 0 to 10. Unstimulated (UWS), chewing-stimulated (CH-SWS) and acid-stimulated (A-SWS) whole salivary flows and the XI and BI were measured. Associations were explored with a bootstrapped Spearman rank correlation test (1000 × bootstrapping). Based on unstimulated salivary flow, 55 patients were classified as hyposalivators, 31 as low salivators, 48 as normosalivators and 13 as high salivators. Median CODS in the hyposalivation group was 5 (IQR 3-6) compared with 3 (IQR 2-5) in the low salivation group, 2 (IQR 1-4) in the normal salivation group and 2 (IQR 1-2.5) in the high salivation group. Significant associations between CODS and the other parameters were only found in the hyposalivation group between CODS and UWS (ρ(53) = - 0.513; p < 0.01), between CODS and CH-SWS (ρ(53) = - 0.453; p < 0.01), between CODS and A-SWS (ρ(53) = - 0.500; p < 0.01), CODS and XI (ρ(53) = 0.343; p < 0.001) and between CODS and BI (ρ(53) = 0.375; p = 0.01). In patients with hyposalivation, CODS is associated with unstimulated and stimulated salivary flow and XI and BI. CODS alone or a combination of CODS with a subjective measure, such as the XI or BI, could be recommended during routine clinical assessment to detect hyposalivation.

Anthropometry, DXA, and leptin reflect subcutaneous but not visceral abdominal adipose tissue on MRI in 197 healthy adolescents.

BackgroundAbdominal fat distribution is associated with the development of cardio-metabolic disease independently of body mass index (BMI). We assessed anthropometry, serum adipokines, and DXA as markers of abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) using magnetic resonance imaging (MRI).MethodsWe performed a cross-sectional study that included 197 healthy adolescents (114 boys) aged 10-15 years nested within a longitudinal population-based cohort. Clinical examination, blood sampling, DXA, and abdominal MRI were performed. SAT% and VAT% were adjusted to total abdominal volume.ResultsGirls had a higher SAT% than did boys in early and late puberty (16 vs. 13%, P<0.01 and 20 vs. 15%, P=0.001, respectively), whereas VAT% was comparable (7% in both genders, independently of puberty). DXA android fat% (standard deviation score (SDS)), suprailiac skinfold thickness (SDS), leptin, BMI (SDS), waist-to-height ratio (WHtR), and waist circumference (SDS) correlated strongly with SAT% (descending order: r=0.90-0.55, all P<0.001) but weakly with VAT% (r=0.49-0.06). Suprailiac skinfold was the best anthropometric marker of SAT% (girls: R2=48.6%, boys: R2=65%, P<0.001) and VAT% in boys (R2=16.4%, P<0.001). WHtR was the best marker of VAT% in girls (R2=7.6%, P=0.007).ConclusionsHealthy girls have a higher SAT% than do boys, whereas VAT% is comparable, independently of puberty. Anthropometry and circulating leptin are valid markers of SAT%, but not of VAT%.

Periodontitis and early mortality among adults treated with hemodialysis: a multinational propensity-matched cohort study.

BACKGROUND: Periodontitis is associated with cardiovascular mortality in the general population and adults with chronic diseases. However, it is unclear whether periodontitis predicts survival in the setting of kidney failure. METHODS: ORAL-D was a propensity matched analysis in 3338 dentate adults with end-stage kidney disease treated in a hemodialysis network in Europe and South America designed to examine the association between periodontitis and all-cause and cardiovascular-related mortality in people on long-term hemodialysis. Participants were matched 1:1 on their propensity score for moderate to severe periodontitis assessed using the World Health Organization Community Periodontal Index. A random-effects Cox proportional hazards model was fitted with shared frailty to account for clustering of mortality risk within countries. RESULTS: Among the 3338 dentate participants, 1355 (40.6%) had moderate to severe periodontitis at baseline. After using propensity score methods to generate a matched cohort of participants with periodontitis similar to those with none or mild periodontal disease, moderate to severe periodontitis was associated with a lower risk of all-cause (9.1 versus 13.0 per 100 person years, hazard ratio 0.74, 95% confidence interval 0.61 to 0.90) and cardiovascular (4.3 versus 6.9 per 100 person years, hazard ratio 0.67, 0.51 to 0.88) mortality. These associations were not changed substantially when participants were limited to those with 12 or more natural teeth and when accounting for competing causes of cardiovascular death. CONCLUSION: In contrast to the general population, periodontitis does not appear to be associated with an increased risk of early death in adults treated with hemodialysis.

Genetic variations altering FSH action affect circulating hormone levels as well as follicle growth in healthy peripubertal girls.

STUDY QUESTION: Do variants of the genes encoding follicle stimulating hormone (FSH) beta subunit (B) and FSH receptor (R) impact circulating reproductive hormone levels and ovarian follicle maturation in healthy peripubertal girls? SUMMARY ANSWER: FSHB and FSHR genetic variants exert, alone or their combination, distinct effects on reproductive hormone levels as well as ovarian follicle maturation in healthy peripubertal girls. WHAT IS KNOWN ALREADY: FSHB and FSHR genetic variants impact reproductive hormone levels as well as associated pathologies in women. While FSHR c. 2039A>G is known to alter gonadotrophin levels in women, FSHR c.-29G>A has not yet been shown to exert effect and there are conflicting results concerning FSHB c.-211G>T. STUDY DESIGN, SIZE, DURATION: This population-based study included 633 girls recruited as part of two cohorts, the COPENHAGEN Puberty Study (2006-2014, a cross-sectional and ongoing longitudinal study) and the Copenhagen Mother-Child Cohort (1997-2002, including transabdominal ultrasound (TAUS) of the ovaries in a subset of 91 peripubertal girls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical examinations, including pubertal breast stage (Tanner's classification B1-B5) were performed. Circulating levels of FSH, luteinizing hormone (LH), estradiol, anti-Mullerian hormone (AMH) and inhibin-B were assessed by immunoassays. In a subset of the girls (n = 91), ovarian volume and the number/size of antral follicles were assessed by TAUS. Genotypes were determined by competitive PCR. MAIN RESULTS AND THE ROLE OF CHANCE: FSHR c.2039A>G minor alleles were positively associated with serum FSH (ß = 0.08, P = 0.004), LH (ß = 0.06, P = 0.012) and estradiol (ß = 0.06, P = 0.017) (adjusted for Tanner stages). In a combined model, FSHR c.-29G>A and FSHR c.2039A>G alleles were positively associated with FSH levels in early-pubertal girls (B2 + B3, n = 327, r = 0.1, P = 0.02) and in young adolescents (B4 + B5, n = 149, r = 0.2, P = 0.01). Serum AMH and inhibin B levels were not significantly influenced by the single nucleotide polymorphisms (SNPs). Single SNPs were not associated with follicles counts, however, a cumulative minor allele count (FSHB c.-211 G>T and FSHR c.-29G>A) was negatively associated with the number of large follicles (≥5 mm) (n = 91, P = 0.04) (adjusted for Tanner stages). LIMITATIONS, REASONS FOR CAUTION: Since we studied girls and young adolescents during pubertal transition, our study may not be fully comparable with previous studies on FSHB and FSHR variants in adult women. The group of young adolescents (Tanner B4 + B5) reflects the endocrine situation in adult women best, however, the group is not large enough to contribute substantially to the conflicting results concerning the influence of FSHB c.-211G>T in adult women. Furthermore, we have no information about the exact day of the menstrual cycle in the subgroup of girls with menarche. WIDER IMPLICATIONS OF THE FINDINGS: The sex-specific interaction of FSHB and FSHR genetic variants and physiological as well as pathological conditions is being increasingly elucidated. The variant triplet set might serve as diagnostic and pharmacogenetic marker. For the first time, we show an additional effect of FSHR c.-29G>A on serum FSH levels in healthy girls. Moreover, morphological data suggest impaired FSH-induced maturation of ovarian follicles in minor allele carriers of FSHB c.-211G>T and FSHR c.-29G>A. This may explain previous findings of delayed pubertal onset in these girls. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Danish Agency for Science, Technology and Innovation (09-067180), Danish Ministry of the Environment, CeHoS (MST-621-00065), Capital Region of Denmark (December 2011), Ministry of Higher Education and Science (DFF-1331-00113) and EDMaRC (Danish Ministry of Health). A.S.B. was funded from December 2015 by ReproUnion (EU Interreg Öresund-Kattegat-Skagerrak). The authors declare no conflict of interest.

Glandular breast tissue volume by magnetic resonance imaging in 100 healthy peripubertal girls: evaluation of clinical Tanner staging.

BACKGROUND: Appearance of glandular breast tissue may be difficult to distinguish from fat tissue by palpation, especially in obese girls. To our knowledge, validation of the clinical assessment of pubertal breast stages by magnetic resonance imaging (MRI) has never been performed. Our objective was to report normative data of glandular breast tissue volume and validate the clinical evaluation of pubertal breast staging by MRI of breast tissue and to evaluate circulating reproductive hormone levels and estrogen-dependent transabdominal ultrasound (TAUS) parameters as markers of glandular breast tissue. METHODS: Glandular breast tissue volume quantified by MRI and breast stage evaluation was performed in 100 healthy peripubertal girls. Circulating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and estradiol were measured by immunoassays. Ovarian volume, uterine volume, and endometrial thickness were assessed by TAUS. RESULTS: Glandular breast tissue volume was positively associated with Tanner stages (r = 0.858, P < 0.001). The sensitivity and specificity of breast palpation to detect presence of glandular breast tissue using MRI as gold standard were 96 and 95%, respectively. The best parameters to distinguish prepubertal girls from girls with breast development were: LH (area under the curve (AUC) by receiver operating characteristic analysis = 0.871), inhibin B (AUC = 0.847) and estradiol (AUC = 0.830). CONCLUSION: Clinical palpation reliably detects the presence of glandular breast tissue.

Patterns of oral disease in adults with chronic kidney disease treated with hemodialysis.

BACKGROUND: Oral disease is a potentially treatable determinant of mortality and quality of life. No comprehensive multinational study to quantify oral disease burden and to identify candidate preventative strategies has been performed in the dialysis setting. METHODS: The ORAL disease in hemoDialysis (ORALD) study was a prospective study in adults treated with hemodialysis in Europe (France, Hungary, Italy, Poland, Portugal and Spain) and Argentina. Oral disease was assessed using standardized WHO methods. Participants self-reported oral health practices and symptoms. Sociodemographic and clinical factors associated with oral diseases were determined and assessed within nation states. RESULTS: Of 4726 eligible adults, 4205 (88.9%) participated. Overall, 20.6% were edentulous [95% confidence interval (CI), 19.4-21.8]. Participants had on average 22 (95% CI 21.7-22.2) decayed, missing or filled teeth, while moderate to severe periodontitis affected 40.6% (95% CI 38.9-42.3). Oral disease patterns varied markedly across countries, independent of participant demographics, comorbidity and health practices. Participants in Spain, Poland, Italy and Hungary had the highest mean adjusted odds of edentulousness (2.31, 1.90, 1.90 and 1.54, respectively), while those in Poland, Hungary, Spain and Argentina had the highest odds of ≥14 decayed, missing or filled teeth (23.2, 12.5, 8.14 and 5.23, respectively). Compared with Argentina, adjusted odds ratios for periodontitis were 58.8, 58.3, 27.7, 12.1 and 6.30 for Portugal, Italy, Hungary, France and Poland, respectively. National levels of tobacco consumption, diabetes and child poverty were associated with edentulousness within countries. CONCLUSIONS: Oral disease in adults on hemodialysis is very common, frequently severe and highly variable among countries, with much of the variability unexplained by participant characteristics or healthcare. Given the national variation and high burden of disease, strategies to improve oral health in hemodialysis patients will require implementation at a country level rather than at the level of individuals.

Intra-arterial versus intra venous contrast-enhanced computed tomography of the equine head.

BACKGROUND: The anatomical complexity of the horse's head limits the abilities of radiography. Computed tomography (CT) in combination with contrast enhanced CT is used more often for diagnosing various head pathology in horses. The objective of this study was to compare intravenous and intra-arterial contrast-enhancement techniques and describe normal and abnormal contrast enhancement in the horse's head. RESULTS: All 24 horses included in the study recovered without complication from the procedures. Compared to the pre-contrast studies, post-contrast studies showed significant contrast enhancement in the pituitary gland (IA: p < 0.0001; IV: p < 0.0001), IA nose septum (p = 0.002), nose mucosa (IA: p < 0.0001; IV: p = 0.02), parotid salivary gland (IA: p < 0.0001; IV p < 0.0001), cerebrum (IA: p < 0.0001; IV: p < 0.0001), rectus capitis muscle (IA: p < 0.0001; IV p = 0.001), IA temporal muscle (p < 0.0001), IA masseter muscle (p <0.0001) and IV brainstem (p = 0.01). No significant contrast enhancement was seen in the eye (IA: p = 0.23; IV p = 0.33), tongue (IA p = 0.2; IV p = 0.57), IA brainstem (p = 0.88), IV nose septum (p = 0.26), IV temporal muscle (p = 0.09) and IV masseter muscle (p = 0.46). Three different categories of abnormal enhancement were detected: a strong vascularised mass, an enhanced rim surrounding an unenhanced structure and an inflamed anatomical structure with abnormal contrast enhancement. CONCLUSION: Using the intra-arterial technique, similar contrast enhancement is achieved using less contrast medium compared to the intravenous technique. And a potential major advantage of the IA technique is the ability to evaluate lesions that are characterized by increased blood flow. Using the intravenous technique, a symmetrical and homogenous enhancement is achieved, however timing is more crucial and the contrast dosage is more of influence in the IV protocol. And a potential major advantage of the IV technique is the ability to evaluate lesions that are characterized by increased vascular permeability. Knowing the different normal contrast enhancement patterns will facilitate the recognition of abnormal contrast enhancements.

The efficacy of continuous-flow cryo and cyclic compression therapy after hip fracture surgery on postoperative pain: design of a prospective, open-label, parallel, multicenter, randomized controlled, clinical trial.

BACKGROUND: The number of hip fractures and resulting post-surgical outcome are a major public health concern and the incidence is expected to increase significantly. The acute recovery phase after hip fracture surgery in elder patients is often complicated by severe pain, high morphine consumption, perioperative blood loss with subsequent transfusion and delirium. Postoperative continuous-flow cryocompression therapy is suggested to minimize these complications and to attenuate the inflammatory reaction that the traumatic fracture and subsequent surgical trauma encompass. Based on a pilot study in patients undergoing total hip arthroplasty for osteoarthritis, it is anticipated that patients treated with continuous-flow cryocompression therapy will have less pain, less morphine consumption and lower decrease of postoperative hemoglobin levels. These factors are associated with a shorter hospital stay and better long-term (functional) outcome. METHODS/DESIGN: One hundred and sixty patients with an intra or extracapsular hip fracture scheduled for internal fixation (intramedullary hip nail, dynamic hip screw or cannulated screws) or prosthesis surgery (total hip or hemiarthroplasty) will be included in this prospective, open-label, parallel, multicenter, randomized controlled, clinical superiority trial. Patients will be allocated to two treatment arms: group 'A' will be treated with continuous-flow cryocompression therapy and compared to group 'B' that will receive standard care. Routine use of drains and/or compressive bandages is allowed in both groups. The primary objective of this study is to compare acute pain the first 72 h postoperative, measured with numeric rating scale for pain. Secondary objectives are: (non-) morphine analgesic use; adjusted postoperative hemoglobin level; transfusion incidence; incidence, duration and severity of delirium and use of psychotropic medication; length of stay; location and duration of rehabilitation; functional outcome; short-term patient-reported health outcome; general and cryotherapy related complications and feasibility. DISCUSSION: This is the first randomized controlled trial that will assess the analgesic efficiacy of continuous-flow cryocompression therapy in the acute recovery phase after hip fracture surgery. TRIAL REGISTRATION: www.trialregister.nl, NTR4152 (23(rd) of August 2013).

Opinions of dentists on the barriers in providing oral health care to community-dwelling frail older people: a questionnaire survey.

OBJECTIVE: The aim of this study was to investigate to what extent dentists in the Netherlands experience barriers in providing oral health care to community-dwelling older people. BACKGROUND: As most publications on the barriers in providing oral health care to older people consist of surveys on oral health care in care homes, it was decided to investigate the barriers dentists experience in their own dental practices while providing oral health care to community-dwelling frail older people. MATERIAL AND METHODS: A representative sample of 1592 of the approximately 8000 dentists in the Netherlands aged 64 or younger were invited to respond to a questionnaire online. The dentists were asked to respond to 15 opinions concerning oral healthcare provision to community-dwelling frail older people aged 75 years or more who experience problems in physical, psychological and social areas, as well as possible financial problems. RESULTS: The total response rate was 37% (n = 595; male=76%; average age 49). The majority of those who responded agreed that the reimbursement of oral health care to older people is poor. Two thirds of those who responded (66%) agreed that there are limited opportunities to refer the frail and elderly with complex oral healthcare problems to a colleague with specific knowledge and skills. CONCLUSION: Dentists experienced barriers in two domains; a lack of knowledge and practical circumstances. It was concluded that the dentist's gender, age, year of graduation and the number of patients aged 75 years or more treated weekly were in some respect, related to the barriers encountered.

Dental Health and Mortality in People With End-Stage Kidney Disease Treated With Hemodialysis: A Multinational Cohort Study.

BACKGROUND: Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. STUDY DESIGN: Prospective multinational cohort. SETTING & PARTICIPANTS: 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis [ORAL-D] Study). PREDICTORS: Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. OUTCOMES: All-cause and cardiovascular mortality at 12 months after dental assessment. MEASUREMENTS: Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. RESULTS: During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score ≥ 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 [95% CI, 0.32-0.85], 0.79 [95% CI, 0.64-0.97], 0.76 [95% CI, 0.58-0.99], 0.84 [95% CI, 0.71-0.99], 0.79 [95% CI, 0.65-0.95], and 0.79 [95% CI, 0.65-0.96], respectively) were associated with better survival. Results for cardiovascular mortality were similar. LIMITATIONS: Convenience sample of clinics. CONCLUSIONS: In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival.

Elevated serum IGF-I, but unaltered sex steroid levels, in healthy boys with pubertal gynaecomastia.

OBJECTIVE: Pubertal gynaecomastia is a very common condition. Although the underlying aetiology is poorly understood, it is generally accepted that excess of oestrogens and deficit of androgens are involved in the pathogenesis. Furthermore, adiposity as well as the GH/IGF-I axis may play a role. In this study, we elucidate the association of adiposity and levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), testosterone, oestrogen, IGF-I and IGFBP-3 with the presence of pubertal gynaecomastia in a large cohort of healthy boys. PATIENTS: A total of 501 healthy Danish school boys (aged 6·1-19·8 year) from the COPENHAGEN Puberty Study. MEASUREMENTS: Anthropometry and pubertal stages (PH1-6 and G1-5) were evaluated, and the presence of gynaecomastia was assessed. Body fat percentage was calculated by means of four skin folds and impedance. Nonfasting blood samples were analysed for FSH, LH, testosterone, SHBG, oestradiol, IGF-I, IGFBP-3 and prolactin. RESULTS: We found that 23% (31/133) of all pubertal boys had gynaecomastia. More specifically, 63% (10/16) of boys in genital stage 4 had gynaecomastia. Boys with gynaecomastia had significantly higher IGF-I levels compared with controls (IGF-I SD-score 0·72 vs -0·037, P < 0·001). This difference was maintained after adjusting for confounders (age and pubertal stage). Sex steroid levels, oestradiol/testosterone ratio or free testosterone were not associated with the presence of gynaecomastia with or without adjustment for confounders. CONCLUSIONS: IGF-I levels were elevated in healthy boys with pubertal gynaecomastia compared with boys without gynaecomastia, whereas sex steroid levels did not differ. We speculate that the GH-IGF-I axis may be involved in the pathogenesis of pubertal gynaecomastia.

Determination of adrenal volume by MRI in healthy children: associations with age, body size, pubertal stage and serum levels of adrenal androgens.

BACKGROUND: Adrenal disorders such as congenital adrenal hyperplasia result in abnormal adrenal size and morphology, but little is known about the clinical value of magnetic resonance imaging (MRI) in determining adrenal volume. OBJECTIVE: To evaluate the potential usefulness of MR methodology, to estimate adrenal size in healthy children and to evaluate determinants of adrenal volume such as age, gender, body size, pubic hair stage and serum levels of adrenal androgens. DESIGN: Two hundred and thirty-five healthy children (116 girls and 119 boys) (age range 10.0-14.8 years) were examined by MRI. Clinical examinations (anthropometry and pubertal staging) were performed, and five androgen metabolites were measured in blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: It was possible to determine adrenal volume in 115/235 children using MRI. The adrenals were not measurable in 51% of children due to breathing and moving artefacts. The median volume of the right adrenal gland was 0.46 ml in girls and 0.46 ml in boys. The median volume of the left adrenal gland was 0.34 ml in girls and 0.40 ml in boys. Adrenal size was positively associated with body surface area (estimate B = 0.34 ml/year, P = 0.03), age (estimate B = 0.05 ml/year, P = 0.021) and pubic hair stage (estimate B = 0.05 ml/stage, P = 0.075). No associations between adrenal size and serum levels of adrenal androgens were observed. CONCLUSION: It was possible to determine adrenal volume by MRI in only 50% of healthy children aged 10-15 years. Adrenal volume increased with age and Tanner stage of pubic hair. Future studies will unravel whether adrenal MRI is useful when evaluating children with adrenal diseases.

Serum levels of insulin-like factor 3, anti-Mullerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study.

Insulin-like factor 3 (INSL3) is a promising marker of Leydig cell function with potentially high clinical relevance. Limited data of INSL3 levels in relation to other reproductive hormones in healthy pubertal boys exist. In this study, we aimed to evaluate longitudinal serum changes in INSL3 compared with LH, FSH, testosterone, inhibin B, and anti-Müllerian hormone (AMH) during puberty in healthy boys. Ten boys were included from the longitudinal part of the COPENHAGEN Puberty Study. Pubertal evaluation, including testicular volume, was performed and blood samples were drawn every 6 months for 5 years. Serum concentrations of testosterone were determined by a newly developed LC-MS/MS method, and serum concentrations of INSL3, AMH, inhibin B, FSH, and LH respectively were determined by validated immunoassays. The results showed that serum INSL3 levels increased progressively with increasing age, pubertal onset, and testicular volume. In six of the ten boys, LH increased before the first observed increase in INSL3. In the remaining four boys, the increase in LH and INSL3 was observed at the same examination. The increases in serum concentrations of LH, testosterone, and INSL3 were not parallel or in ordered succession and varied interindividually. We demonstrated that INSL3 concentrations were tightly associated with pubertal onset and increasing testicular volume. However, the pubertal increases in LH, INSL3, and testosterone concentrations were not entirely parallel, suggesting that INSL3 and testosterone may be regulated differently. Thus, we speculate that INSL3 provides additional information on Leydig cell differentiation and function during puberty compared with traditional markers of testicular function.

The 2014 Danish references from birth to 20 years for height, weight and body mass index.

AIM: To construct new Danish growth charts for 0- to 20-year-olds and to compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0-5 years from 2006, by applying similar inclusion and exclusion criteria. METHODS: Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12,671 height measurements (8055 in boys and 4616 in girls) were included. Reference charts were developed using the generalised additive models for location, scale and shape. RESULTS: From prepubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty, and final heights were increased by 1.4 cm in boys and 2.9 cm in girls compared to 1982 references. In boys, but not girls an upward shift in body mass index (BMI) above median levels was found. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards. CONCLUSION: We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements.

Parsonage-Turner syndrome following post-exposure prophylaxis.

BACKGROUND: The 'Parsonage-Turner syndrome' (PTS) is a rare but distinct disorder with an abrupt onset of shoulder pain, followed by weakness and atrophy of the upper extremity musculature, and a slow recovery requiring months to years. To our best knowledge, this is the first case describing symptoms and signs of PTS following the administration of a post-exposure prophylaxis (PEP) regimen against possible human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. CASE PRESENTATION: A 25-year-old Caucasian man presented with pain and unilateral scapular winging following PEP against possible HIV and HBV infection. Although atrophy and weakness were observed for the right supraspinatus muscle, a full range of motion was achievable. Neurological examination, plain radiography of the right shoulder and electromyography showed no additional abnormalities. The patient was diagnosed with post-vaccination PTS and treated non-operatively. During the following 15 months the scapular winging receded and full muscle strength was regained. CONCLUSION: Parsonage-Turner syndrome is a rare clinical diagnosis. The precise pathophysiological mechanism of PTS remains unclear, but it seems to involve an interaction between genetic predisposition, mechanical vulnerability and an autoimmune trigger. An immunological event, such as - in this case - a vaccination as part of PEP treatment, can trigger the onset of PTS. The clinical presentation is distinctive with acute severe pain followed by patchy paresis, atrophy and sensory symptoms that persist for months to years. No currently available tests can provide a definite confirmation or exclusion of PTS. Routine blood examination, electromyography (EMG), and computed tomography (CT) or magnetic resonance imaging (MRI) serve mainly to exclude other disorders. The recovery can be quite lengthy, non-operative treatment is the accepted practice. Supplementary administration of oral prednisolone could shorten the duration of pain. Although the outcome is typically preferable, a substantial amount of patients are left with some residual paresis and functional impairment.