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STUDY QUESTION What is the impact of variants in the genes INSL3 (Insulin Like 3) and RXFP2 (Relaxin Family Peptide Receptor 2), respectively, on cryptorchidism and male infertility? SUMMARY ANSWER Bi-allelic loss-of-function (LoF) variants in INSL3 and RXFP2 result in bilateral cryptorchidism and male infertility, whereas heterozygous variant carriers are phenotypically unaffected. WHAT IS KNOWN ALREADY The small heterodimeric peptide INSL3 and its G protein-coupled receptor RXFP2 play a major role in the first step of the biphasic descent of the testes, and variants in the INSL3 and RXFP2 genes have long been implicated in inherited cryptorchidism. However, only one single homozygous missense variant in RXFP2 has clearly been linked to familial bilateral cryptorchidism, so the effects of bi-allelic variants in INSL3 and heterozygous variants in both genes on cryptorchidism and male infertility remain unclear. STUDY DESIGN, SIZE, DURATION Exome data of 2412 men from the MERGE (Male Reproductive Genomics) study cohort including 1902 infertile men with crypto-/azoospermia, of whom 450 men had a history of cryptorchidism, were screened for high-impact variants in INSL3 and RXFP2. PARTICIPANTS/MATERIALS, SETTING, METHODS For patients with rare, high-impact variants in INSL3 and RXFP2, detailed clinical data were collected and the testicular phenotype was determined. Genotyping of family members was performed to analyse the co-segregation of candidate variants with the condition. Immunohistochemical staining for INSL3 in patient testicular tissue and measuring serum INSL3 concentration was performed to analyse the functional impact of a homozygous loss-of-function variant in INSL3. For a homozygous missense variant in RXFP2, its impact on the protein’s cell surface expression and ability to respond to INSL3 in CRE reporter gene assay was determined. MAIN RESULTS AND THE ROLE OF CHANCE This study presents homozygous high-impact variants in INSL3 and RXFP2 and clearly correlates these to bilateral cryptorchidism. Functional impact of the identified INSL3 variant was demonstrated by absence of INSL3-specific staining in patients’ testicular Leydig cells as well as undetectable blood serum levels. The identified missense variant in RXFP2 was demonstrated to lead to reduced RXFP2 surface expression and INSL3 mediated receptor activation. LIMITATIONS, REASONS FOR CAUTION Further investigations are needed to explore a potential direct impact of bi-allelic INSL3 and RXFP2 variants on spermatogenesis. With our data, we cannot determine whether the infertility observed in our patients is a direct consequence of the disruption of a possible function of these genes on spermatogenesis or whether it occurs secondarily due to cryptorchidism. WIDER IMPLICATIONS OF THE FINDINGS In contrast to previous assumptions, this study supports an autosomal recessive inheritance of INSL3- and RXFP2-related bilateral cryptorchidism while heterozygous LoF variants in either gene can at most be regarded as a risk factor for developing cryptorchidism. Our findings have diagnostic value for patients with familial/bilateral cryptorchidism and additionally shed light on the importance of INSL3 and RXFP2 in testicular descent and fertility. STUDY FUNDING/COMPETING INTEREST(S) This study was carried out within the frame of the German Research Foundation (DFG) funded by Clinical Research Unit ‘Male Germ Cells: from Genes to Function’ (DFG, CRU326). Research at the Florey was supported by an NHMRC grant (2001027) and the Victorian Government Operational Infrastructure Support Program. A.S.B. is funded by the DFG (‘Emmy Noether Programme’ project number 464240267). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Context Minipuberty, a period of a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in both sexes, enables evaluation of gonadal function in infants suspected of hypogonadism. However, female minipuberty remains poorly elucidated. Objective We aimed to establish continuous reference ranges for the most commonly used reproductive hormones and to evaluate the dynamics of the HPG axis in females aged 0 to 1 year. Design The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), a longitudinal, prospective cohort study. Setting Healthy infants from Copenhagen. Patients or Other Participants A total of 98 healthy, term female infants followed with 6 examinations including venipuncture during the first year of life. Intervention(s) None. Main Outcome Measure(s) Serum concentrations of LH, FSH, inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and SHBG were quantified using highly sensitive methods in 266 serum samples. Results Reference ranges were established for LH, FSH, inhibin B, AMH, E1, E2, and SHBG. Two peaks were observed in normalized mean curves for all hormones. The first peaks were timed around postnatal days 15 to 27 followed by a general nadir for all hormones around days 58 to 92. The second peaks occurred around days 107 to 125 for inhibin B, AMH, E1, E2, and SHBG and days 164 to 165 for LH and FSH. Conclusions We present age-related, continuous reference ranges of the most commonly used reproductive hormones and present novel data revealing a biphasic and prolonged female minipuberty. ClinicalTrials.gov ID NCT02784184

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

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Background At the University Medical Center Hamburg-Eppendorf (UKE), health care research has been established as one of five research priorities recommended by the Research Council with the founding of the Center for Health Care Research (CHCR) in 2006. The CHCR was involved in numerous research projects with the focus on strengthening regional networking. Despite the numerous initiatives, there is still potential for improvement with regard to a systematic and sustainable exchange in the region of Hamburg, Germany. Methods These requirements led to the initiation of the ‘Hamburg Network Health Services Research (HAM-NET)'. The mission of HAM-NET is to build an open forum for all relevant institutions, to concentrate their interests and needs in health services research and to promote and conduct innovative, efficient, needs-based and patient-centred health services research projects in the metropolitan area of Hamburg. Three main tasks were appointed: 1) linking health care research to relevant regional institutions, 2) promoting research activities and new fields of research and 3) using methodological expertise to promote young scientists. Results By today 40 institutions from all sectors of health care joined HAM-NET. The regularly general meetings offer exchange and advice. Internal communication is promoted by mailing lists and newsletters. Also, HAM-NET presents itself with a website, logo and by organizing recurring events and participating in international and national congresses and networks. Within two funding phases a total of four overarching research projects were developed and implemented. Furthermore, a person with lived experience committee was established. Conclusions For the further development of health care research as one the core disciplines of public health a regional network with an efficient infrastructure is needed. HAM-NET promotes this with the implementation of an innovative, efficient and patient-oriented network. Key messages • Regional networks help to integrate multiple public health initiatives and community stakeholders. • Public health networks can be established on multidisciplinary cooperations in different out- and inpatient sector levels.

Background Limited evidence exists regarding the impact of atrial fibrillation (AF) on outcomes after percutaneous mitral valve repair (PMVR). The aim of the present study was to compare 1-year clinical outcomes following PMVR in patients with and without AF. Methods 426 patients with PMVR for severe MR were included in the COburg MItraclip (COMI) registry between 2016 and 2021. Patients were divided into an AF group (group A, n=284) and a non-AF group (group B, n=142). Clinical profiles, PMVR procedure characteristics and the clinical follow-up were compared between the two groups. Results Patients with AF were older (79.3±6.3 [AF] vs. 77.8±8 years [non-AF], p=0.03), had higher N-terminal B-type natriuretic peptide levels (NT-pro BNP: 5675±5544.2 vs 8516±11184.5, p=0.004), more often a coronary artery disease (62% vs 38%, p=0.03) and had a lower stroke risk (CHA2DS2-VASc score: 4.6±1.2 vs 4.9±1.3, p=0.01). There were no significant differences between groups with regard to the gender, logistic Euroscore or prevalence of chronic heart failure, hypertension, diabetes mellitus or severe mitral regurgitation. Acute procedural success (post-procedural 2. MR, 95.1% vs. 94.4%; p=0.76) and procedure-related major complications were similar. There were no significant differences in 1-year MACCE (death, MI, stroke, bleeding), health-related quality of life or clinical improvement. Conclusion In patients with mitral regurgitation who underwent PMVR, AF is common and appears not to have a relevant negative impact on the clinical outcome at 1 year compared to patients with sinus rhythm. Funding Acknowledgement Type of funding sources: None.

Im Rahmen der COVID-19-Pandemie wird die Frage nach einer gerechten Gesundheitsversorgung anhand verschiedener Interventionsebenen diskutiert. Menschen mit niedrigem sozioökonomischem Status weisen aufgrund ihrer höheren Exposition zum Virus ein höheres Infektionsrisiko auf. Intergenerationale Gerechtigkeit, beispielsweise im Kontext der Impfpriorisierung, ist ebenfalls in der Diskussion. Menschen, die nicht an COVID-19 erkrankt sind, nehmen Gesundheitsleistungen seltener in Anspruch. Um eine gerechtere Gesundheitsversorgung zu gewährleisten wird vorgeschlagen, dass eine sozial gerechte Grundstruktur nicht die gleichmäßige Verteilung von Ressourcen bedeutet, sondern dass eine gleiche Ausgangslage für alle den Ausschlag für mehr Gerechtigkeit in der Krise gibt. Abstract: Is the Virus a Respecter of Persons? Fair Provision of Health-Services in the Current Crisis. In the context of the COVID-19 pandemic the issue of a fair provision of health-services is being raised on different layers of intervention. People with a low socio-economic status face a higher risk of infection because of increased exposure to the virus. Intergenerational fairness is under discussion, for instance in the context of the prioritization of inoculation. People that suffer from other diseases than COVID-19 take less advantage of the health-care system. For ensuring a more suitable distribution of resources it is being suggested that not equality in the distribution of resources but equity in initial positions will ensure more justness in a crisis.

Background: Anti-Müllerian hormone (AMH) is produced by granulosa cells in small growing ovarian follicles. In adult women, serum concentrations of AMH reflect the ovarian reserve of resting primordial follicles, and low AMH is associated with risk of early menopause. In contrast, patients with polycystic ovary syndrome (PCOS) have elevated AMH. The primary aim of this study was to evaluate the individual tracking of serum AMH concentrations, as well as whether AMH in early childhood reflects ovarian activity in adolescence. Methods: In this large longitudinal study of healthy girls were examined from infancy to adolescence (1997–2019) including physical examination, assessment of serum concentrations of reproductive hormones (in infancy, median age 0.3 yrs; mid-childhood, 7.2 yrs; puberty, 11.3 yrs; and adolescence, 15.9 yrs), transabdominal ultrasound (TAUS, puberty and adolescence) and magnetic resonance imaging (MRI, puberty) of the ovaries. Findings: Each girl maintained her relative AMH concentration (expressed as standard deviation (SD) scores) over time; mean variation of individual age adjusted AMH concentrations was 0.56 ± 0.31 SD. Serum concentrations of AMH in adolescence correlated with AMH in infancy and childhood; infancy: r = 0.347; mid-childhood: r = 0.637; puberty: r = 0.675, all p < 0.001. AMH correlated negatively with FSH concentrations in all age groups (infancy: r = −0.645, p < 0.001; mid-childhood: r = −0.222, p < 0.001; puberty: r = −0.354, p < 0.001; adolescence: n = 275, r = −0.175, p = 0.004). Serum AMH concentrations in mid-childhood correlated with the number of follicles in puberty (TAUS and MRI) as well as in adolescence (TAUS); e.g. total number of follicles: TAUS puberty (r = 0.607), MRI puberty (r = 0.379), TAUS adolescence (r = 0.414), all p < 0.001. AMH concentration in infancy as well as in mid-childhood predicted low AMH (30.0 pmol/L vs. other girls) had higher adolescent LH (median 4.53 vs. 3.29 U/L p = 0.041), LH/FSH ratio (1.00 vs 0.67, p = 0.019), testosterone (1.05 vs 0.81 nmol/L, p = 0.005), total number of follicles (23 vs. 19, p = 0.004), and higher prevalence of irregular cycles (10/15 = 67% vs. 28/113 = 25%, p = 0.002). Interpretation: The present findings suggest remarkably stable ovarian activity from small growing follicles in healthy girls, supporting AMH in early life as a useful clinical tool to predict future ovarian activity. Funding: 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), the EU ( QLK4-CT1999-01422; QLK4-2001-00269), the Novo Nordisk Foundation and The Danish Ministry of Science Technology and Innovation ( 2107-05-0006). A.S.B. is funded by the Deutsche Forschungsgemeinschaft ( DFG, German Research Foundation) – 464240267. KM receives honoraria from Novo Nordisk A/S for teaching at the Danish annual postgraduate course of pituitary diseases.

Diese Stellungnahme der Deutschen Gesellschaft fur Kardiologie fasst Informationen und Empfehlungen zum Umgang mit nicht-aktiven (auch genannt „passiven“) kardiovaskularen Implantaten (z. B. Koronarstents) bei der Magnetresonanztomographie (MRT) zusammen. Es wird empfohlen, bei jedem Patienten vor einer MRT-Untersuchung das Vorhandensein von nicht-aktiven kardiovaskularen Implantaten zu erfragen, gegebenenfalls detaillierte Implantat-Informationen einzuholen und schlieslich unter individueller Nutzen-Risiko-Abwagung die Entscheidung fur oder gegen die MRT-Untersuchung zu treffen. Bei der MRT-Untersuchung sind gegebenenfalls Anpassungen der technischen MRT-Parameter oder des Untersuchungsablaufs zu berucksichtigen. Diese Aufgaben obliegen dem die MRT-Untersuchung durchfuhrenden Arzt. Er wird unterstutzt, indem der Patient selbst sowie der uberweisende Arzt die notwendigen Informationen rechtzeitig zur Verfugung stellen. Dabei ist die Verwendung von Implantatpassen und Implantatdatenbanken hilfreich. Werden diese Vorsichtsmasnahmen berucksichtigt, sind nach derzeitigem Kenntnisstand MRT-Untersuchungen bei Patienten mit nicht-aktiven kardiovaskularen Implantaten im Allgemeinen ohne gravierende Sicherheitsbedenken durchfuhrbar.

Context A close link between body mass index (BMI) and female pubertal onset is well established. However, observations in boys remain inconclusive. Objective We aim to determine whether BMI as well as total and central adiposity in prepubertal Chilean boys is associated with pubertal timing. Methods We performed a longitudinal study in which 494 boys from the Growth and Obesity Chilean Cohort Study were followed starting from birth and throughout puberty, including 5 prepubertal visits. The main outcome measures included anthropometric data and semi-annual clinical pubertal staging. The association between BMI, obesity (BMI standard deviation score [SDS] ≥ 2) and central adiposity (waist circumference ≥ 90th centile) with precocious puberty and age at gonadarche was analyzed using survival- and logistic regression models. Results BMI, prevalence of total obesity, and central obesity increased throughout childhood. Among the study population, 45 boys entered puberty before the age of 9 years (9.1%). Obesity at 4 to 7 years and childhood mean BMI SDS were significantly associated with precocious gonadarche. Mean age at testicular enlargement (≥4 mL), was 11.0 years (95% CI, 10.9-11.1) and was inversely associated with BMI SDS, waist circumference, and percentage fat mass in almost all prepubertal visits. Age at testicular enlargement in normal weight, overweight, and obese boys was 11.2 (11.0-11.3), 10.9 (10.6-11.1) and 10.7 (10.4-11.1) years, respectively. Conclusion Our observation supports the association of BMI SDS and obesity with pubertal timing and precocious gonadarche in boys, respectively. Early intervention controlling the obesity epidemic could be useful in decreasing detrimental impact on later health.

One of the most prominent methodologies gaining recognition in recent years is the Agile-Stage-Gate approach. The relatively new hybrid model is a combination of the Stage-Gate and the Agile-Scrum models. Several companies already using the Stage-Gate process have recently adopted the Agile-Stage-Gate approach to improve product development and project management. However, each of these companies has added their adjustments and modifications to the new approach in order to accommodate their specialized needs and to achieve the goals that are unique to their company. Therefore, no fixed structure or standardized features have been explicitly assigned to this hybrid approach. Instead, each company has added on different features and manipulated the new approach to fit whatever needs arise from moment to moment. This ambiguity leads to the question of whether the structure, roles, and responsibilities of this new approach can be defined and if so, how these clear and consistent definitions can improve productivity, efficiency, communication and market response time. The purpose of this study is to explore the structure, roles, and responsibilities within this new approach and to identify patterns that emerge during the product development and project management processes. The research questions presented were administered and examined through a qualitative survey. Fifty-two complete responses were collected from experienced individuals who have varying degrees of experience with the Agile-Stage-Gate approach. These findings revealed many similarities and differences between the structure, roles, and responsibilities of this approach, which were also dependent on the product and project type being considered. The most apparent similarities between roles and responsibilities were found in the case of software products and new product development projects. The Agile-Stage-Gate approach has also had a significant and undeniable impact on team communication and performance and was shown to improve overall quality and productivity. Keywords: agile, stage-gate, customer, scrum, sprint, hybrid, ideation, combination products, backlog, retrospective

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

Zusammenfassung Hintergrund Studierende als junge Erwachsene mit Pflegeverantwortung für eine nahestehende Person finden in der deutschsprachigen Forschungslandschaft bisher kaum Berücksichtigung, obwohl davon auszugehen ist, dass sie mit einer Mehrfachbelastung konfrontiert sind, die langfristig einen negativen Einfluss nicht nur auf den Studienverlauf haben kann. Vor dem Hintergrund gesundheitsförderlicher und präventiver Aspekte sind Erkenntnisse zur Zielgruppe daher insbesondere für Hochschulen von großer Relevanz. Ziel der Arbeit Zielsetzung der vorliegenden Studie ist die Erfassung der Pflege- und Unterstützungssituation von betroffenen Studierenden, die Darstellung der Nutzung von Unterstützungsangeboten und die Identifizierung von Ansätzen zur zielgruppengerechten Entlastung. Material und Methoden Zur Erreichung der Ziele wurde im Januar 2017 ein standardisierter Onlinesurvey an immatrikulierte Studierende (N = 16.964) der Hochschule für Angewandte Wissenschaften Hamburg versandt. Die Datenauswertung fand mithilfe deskriptiver Methoden und ausgewählter inferenzstatistischer Testverfahren statt. Ergebnisse und Diskussion Die Ergebnisse verdeutlichen, dass ca. 15 % (n = 126) der Befragten regelmäßig in Pflege oder Unterstützung einer angehörigen Person eingebunden sind, wobei Art und Umfang der Unterstützung variieren. Studierende mit Pflegeverantwortung kümmern sich nicht nur um eine nahestehende Person, sie arbeiten zur Finanzierung des Studiums, bereiten sich auf Prüfungsleistungen vor und besuchen Seminare. Trotz z. T. hoher (Mehrfach‑)Belastung nutzen Studierende das Unterstützungsangebot der Hochschule nicht. Flexiblere (curriculare) Rahmenbedingungen werden als ein Ansatz identifiziert, um Studierenden die Vereinbarkeit von Studium, Privatleben und Pflege zu erleichtern.

Aims To compare the safety and efficacy of insulin glargine 300 U/mL (Gla-300) versus first-generation standard-of-care basal insulin analogues (SOC-BI; insulin glargine 100 U/mL or insulin detemir) at 6 months. Methods In the 12-month, open-label, multicentre, randomized, pragmatic ACHIEVE Control trial, insulin-naive adults with type 2 diabetes (T2D) and glycated haemoglobin A1c (HbA1c) 64-97 mmol/mol (8.0%-11.0%) after ≥1 year of treatment with ≥2 diabetes medications were randomized to Gla-300 or SOC-BI. The composite primary endpoint, evaluated at 6 months, was the proportion of participants achieving individualized HbA1c targets per HEDIS criteria without documented symptomatic (blood glucose ≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia at any time of the day at 6 months. Results Of 1651 and 1653 participants randomized to Gla-300 and SOC-BI, respectively, 31.3% and 27.9% achieved the composite primary endpoint at 6 months (odds ratio [OR] 1.19; 95% CI 1.01-1.39; P = 0.03 for superiority); 78.4% and 75.3% had no documented symptomatic or severe hypoglycaemia (OR 1.19; 95% CI 1.01-1.41). Changes from baseline to month 6 in HbA1c, fasting plasma glucose, weight, and BI analogue dose were similar between groups. Conclusions Among insulin-naive adults with poorly controlled T2D, Gla-300 was associated with a statistically significant higher proportion of participants achieving individualized HEDIS HbA1c targets without documented symptomatic or severe hypoglycaemia (versus SOC-BI) in a real-life population managed in a usual-care setting. The ACHIEVE Control study results add value to treatment decisions and options for patients, healthcare providers, payers, and decision makers. ClinicalTrials.gov identifier: NCT02451137 This article is protected by copyright. All rights reserved.

Context Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. Objective The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. Design An observational, 20-year national registry study was conducted. Setting This population-based study used nationwide registry data. Participants Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. Main Outcome Measures All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. Results Overall, a total 17 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10 000 men (age 0-80 years). The average annual incidence was 6.5/10 000 in postpubertal males age 16 to 20 years and 4.6/10 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. Conclusions The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.

Transient thelarche (TT), that is, the appearance, regression and subsequent reappearance of breast buds, is a frequent phenomenon, but little is known about pubertal transition in these girls.To describe pubertal progression, growth, genotypes, reproductive hormones and growth factors in girls with TT compared to those who do not present TT (non-TT).Retrospective analysis of a longitudinal population-based study.Girls (n = 508) of the Chilean Growth and Obesity cohort.Pubertal progression, reproductive hormones, follicle stimulating hormone (FSH) beta subunit/FSH receptor gene single nucleotide polymorphisms and growth.Thirty-seven girls (7.3%) were presented TT. These girls entered puberty by pubarche more frequently (51%) than girls with normal progression (non-TT; n = 471; 23%, P = .005). Girls with TT who were under 8 years old had lower androgens, anti-Müllerian hormone (AMH), luteinizing hormone (LH) and oestradiol (all P .05) than older girls with TT. At the time of Tanner breast stage 2 (B2), girls with TT had higher androgens, LH, FSH, IGF1, LH, insulin and oestradiol (P .01) than at the time of TT. TT girls were older at B2 (10.3 ± 1.1 vs. 9.2 ± 1.2 years, P .001) and menarche (12.3 ± 0.8 vs. 12.0 ± 1.0 years, P = .040) than their counterparts (non-TT). No differences in anthropometric variables or FSHB/FSHR genotypes were detected.Transient thelarche is a frequent phenomenon that does not appear to be mediated by hypothalamic-pituitary-gonadal axis activation or by adiposity. Hormonal differences between earlier TT and later TT suggest that their mechanisms are different.

Context Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. Objective To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. Experimental Design Longitudinal study. Subjects and Methods 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). Main Outcome Measures Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. Results The PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). Conclusions Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.

Traffic light control falls into two main categories: Agnostic systems that do not exploit knowledge of the current traffic state, e.g., the positions and velocities of vehicles approaching intersections, and holistic systems that exploit knowledge of the current traffic state. Emerging fifth generation (5G) wireless networks enable Vehicle-to-Infrastructure (V2I) communication to reliably and quickly collect the current traffic state. However, to the best of our knowledge, the optimized traffic light management without and with current traffic state information has not been compared in detail. This study fills this gap in the literature by designing representative Deep Reinforcement Learning (DRL) agents that learn the control of multiple traffic lights without and with current traffic state information. Our agnostic agent considers mainly the current phase of all traffic lights and the expired times since the last change. In addition, our holistic agent considers the positions and velocities of the vehicles approaching the intersections. We compare the agnostic and holistic agents for simulated traffic scenarios, including a road network from Barcelona, Spain. We find that the holistic system substantially increases average vehicle velocities and flow rates, while reducing CO2 emissions, average wait and trip times, as well as a driver stress metric.

Sponges have co-evolved with microbes for over 400 myr. Previous studies have demonstrated that sponges can be classified according to the abundance of microbes in their tissues as Low Microbial Abundance (LMA) and High Microbial Abundance (HMA). While LMA sponges rely mainly on water column microbes, HMA appear to rely much more on symbiotic fermentative and autotrophic microbes maintained in their tissues. However, it is unclear if this pattern holds when comparing different species of tropical sponges under extreme nutrient conditions and sediment loads in the water column, such as the Great Amazon Reef System (GARS), which covers an area of ~56,000 km

Objective Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants. Design A prospective, longitudinal cohort study of healthy infants aged 0–1.2 years. Methods In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants. Results In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging from 93 to 100% with correspondingly narrow 95% CIs. Conclusions Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remain to be elucidated.

Background: Atherosclerotic cardiovascular disease is a significant cause of morbidity and mortality worldwide. While use of statin therapy has improved management of lipids, an unmet need in reducing residual atherosclerotic cardiovascular disease risk and ischemic events persists. We provide an overview of the pharmacology of omega-3 fatty acids, omega-3 fatty acid cardiovascular outcomes trials, landmark clinical data and pharmacology of icosapent ethyl (a stable and highly purified ethyl ester of eicosapentaenoic acid), and the critical differences between fish oil supplements and prescription omega-3 fatty acids. Method: A PubMed literature review was conducted in April 2020 to identify articles discussing omega-3 fatty acid cardiovascular outcomes trials, pharmacology of icosapent ethyl, and the evaluation of fish oil dietary supplements and prescription omega-3 fatty acids. Results: Both eicosapentaenoic acid and docosahexaenoic acid have been widely associated with positive health benefits; however, data are inconsistent regarding the benefit of combination eicosapentaenoic acid and docosahexaenoic acid in patients with cardiovascular disease. Eicosapentaenoic acid, and specifically icosapent ethyl, has demonstrated atherosclerotic cardiovascular disease risk reduction among statin-treated patients. Important clinical differences exist between dietary supplement and prescription omega-3 fatty acid products. Conclusions: As research regarding the optimal management of dyslipidemia continues, additional therapy beyond statins is necessary to reduce atherosclerotic cardiovascular disease risk. In large cardiovascular outcomes trials, eicosapentaenoic acid has demonstrated cardiovascular benefit. Icosapent ethyl possesses a favorable efficacy and safety profile and should be considered as an adjunct to statin therapy to reduce ischemic event risk.

Context Pubertal timing in boys is associated with body mass index (BMI). Studies consistently report an inverse correlation of BMI and pubertal timing within the normal BMI range. However, observations in obese boys are conflicting with different studies reporting either early or delayed pubertal onset in obese boys. Objective We aimed to assess the association of male pubertal timing with age-specific BMI (zBMI) in obese boys. Design, Setting, and Participants A total of 218 obese boys (zBMI > +2SD, with a median age at baseline of 10.8 years (range 4.2–17.0), were recruited as part of a prospective outpatient childhood obesity intervention program at Nordsjællands Hospital, Hillerød, Denmark, between 2009 and 2017. Serving as controls, we included 660 healthy boys participating in the population-based COPENHAGEN Puberty Study (-2SD < zBMI ≤ +2SD, 2006–2014). Subanalyses were performed on overweight controls (+1SD < zBMI ≤ +2SD). The clinical assessment of pubertal development by Tanner staging, including testis volume using a Prader’s orchidometer, was performed by trained physicians. The timing of pubertal milestones was estimated by probit analyses. Main Outcome Measures Timing of testicular volume ≥ 4 mL, genital stage ≥ 2, and pubarche. Results The mean (95% confidence interval [CI]) age of onset of pubertal event in obese boys was as follows: testicular volume ≥ 4 mL, 11.3 years (11.0–11.6); genital stage ≥ 2, 11.6 yrs (11.3–11.9); and pubarche, 11.9 years (11.5–12.3). Testicular volume ≥ 4 mL occurred significantly earlier in obese boys compared to controls (-2SD < zBMI ≤ +2SD) (P = 0.01). We did not observe significant differences for either the timing of pubarche nor the genital stage ≥ 2 (P = 0.06 and P = 0.94, respectively) Conclusions We demonstrate that testicular enlargement in obese boys occurs significantly earlier compared to a population-based normal-weight reference cohort.

STUDY QUESTION How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION The study included a population-based mixed cross-sectional and longitudinal cohort (2006–2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE Voice break occurred at mean age 13.6 (95% CI: 13.5–13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0–11.7) nmol/L, 2.4 (2.2–2.5) IU/L and 24 (23–25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43–0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (−0.35 years/approximate SD, P LIMITATIONS, REASONS FOR CAUTION Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER NCT01411527

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.