Complete or partial loss of the Y chromosome in an unselected cohort of 865 non-vasectomized, azoospermic men.

BACKGROUND: Structural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men. RESULTS: Eleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line. CONCLUSIONS: In men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.

RéSUMé: CONTEXTE: Des anomalies structurelles ainsi que des variations mineures du chromosome Y peuvent provoquer des troubles de la différenciation sexuelle ou, plus fréquemment, une azoospermie. Cette étude visait à déterminer la prévalence de la perte de matériel chromosomique Y dans le spectre allant de petites microdélétions dans la région du facteur d'azoospermie (AZF) à la perte complète du chromosome Y chez les hommes azoospermiques. RéSULTATS: Onze des 865 hommes azoospermiques (1,3 %), collectés entre 1997 et 2022, présentaient un caryotype comprenant une lignée cellulaire 45,X. Deux avaient un caryotype pur 45,X et neuf avaient un caryotype mosaïque 45,X/46,XY. La région AZF, ou une partie de celle-ci, était absente chez huit des neuf hommes présentant un chromosome Y anormal sur le plan structurel. Sept hommes présentaient un caryotype avec un chromosome Y structurellement anormal sous une forme non mosaïque. De plus, des microdélétions du chromosome Y ont été trouvées chez 34 hommes présentant un chromosome Y de structure normale. Aucune malformation congénitale n'a été détectée par échocardiographie et échographie des reins des 11 hommes porteurs d'une lignée cellulaire 45,X mosaïque ou non mosaïque. CONCLUSIONS: Chez les hommes qui ont une azoospermie, une perte du chromosome Y, allant de petites microdélétions à une perte complète du chromosome Y, a été observée chez 6,1 % (53/865). Les microdélétions partielles de la région AZFb peuvent donner un phénotype testiculaire plus doux que les microdélétions complètes de l'AZFb.

Prolonged baleen hormone cycles suggest atypical reproductive endocrinology of female bowhead whales.

Serial measurements of hormone concentrations along baleen plates allow for reconstructions of mysticete whale reproductive histories. We assessed gestation and calving interval in bowhead whales (Balaena mysticetus) by measuring progesterone, oestradiol, corticosterone and nitrogen stable isotope ratios (δ15N) along baleen of 10 females from the eastern Canada-west Greenland population. Three immature females (body size < 14.32 m) had uniformly low progesterone concentrations across their baleen, while seven mature females (body size ≥ 14.35 m) had repeated, sustained elevations of progesterone indicative of pregnancies. The mean duration of progesterone elevations (23.6 ± 1.50 months) was considerably longer than the approximately 14 month gestation previously estimated for this species. We consider several possible explanations for this observation, including delayed implantation or sequential ovulations prior to gestation, strategies that would allow females to maximize their fitness in variable Arctic conditions, as well as suggest modified criteria defining gestation as a shorter component of the entire progesterone peak. Calving intervals varied within and among individuals (mean = 3.7 years; range = range 2.8-5.7 years), providing population-specific reproductive estimates for growth models used in bowhead whale management and conservation.

Training support workers about the overmedication of people with intellectual disabilities: an Australian pre-post pilot study.

BACKGROUND: There is evidence that psychotropic medications are overprescribed and overused to manage behaviours of concern for people with intellectual disabilities. Disability support workers and support staff lack education and training on the administration and safety of psychotropic medication use. This study aimed to test the applicability and preliminary efficacy of SPECTROM, an education programme developed in the UK, in an Australian context. METHODS: The training comprises two parts: Module 1 encompasses psychotropic medications, their use and side effects. Module 2 focuses on non-pharmacological interventions for supporting people with behaviours of concern. Thirty-three participants attended the training course and completed pre-training and post-training surveys on the Psychotropic Knowledge Questionnaire and Management of Aggression and Violence Attitude Scale-Revised at four time points: pre-training, 2 weeks, 3 months and 5 months post-training. RESULTS: Psychotropic Knowledge Questionnaire scores showed statistically significant post-training improvement at all post-training time points (P < 0.05). Management of Aggression and Violence Attitude Scale-Revised scores were high at pre-training and did not change significantly at any of the post-training survey time points. A 2-week post-training feedback questionnaire reported 80% agreement that the training programme was appropriate, useful and valid. Only 36% of participants completed questionnaires at all time points. CONCLUSIONS: SPECTROM training increased staff knowledge of psychotropic medications, yet loss of participants was high. Further refinement of the applicability of the training for the Australian context and evaluation of the feasibility of implementation, clinical and cost-effectiveness of the programme are required.

Atypical teratoid rhabdoid tumours (ATRTs)-a 21-year institutional experience.

PURPOSE: Atypical teratoid/rhabdoid tumours (ATRTs) are malignant embryonal tumours of childhood that affect the central nervous system (CNS). We aim to determine which factors, including patient age, extent of resection (EOR), presence of distal metastasis and use of adjuvant therapies, affect overall survival in children with atypical teratoid/rhabdoid tumours (ATRTs) treated at this single centre. METHODS: Retrospective cohort review of patients with histological diagnosis of ATRT treated over 21 years (1999-2020) was conducted. Data on demographics, tumour location, presence of metastasis, use of adjuvant therapy, extent of resection (EOR), complications, neurological outcome post-surgery, and overall survival were collected. Kaplan-Meier survival analysis was performed. RESULTS: A total of 45 children (mean age 2 years) underwent 64 operations. 25 patients were <1 year of age. Gross-total resection (GTR) pre-adjuvant therapy was achieved in 15, near-total resection (NTR) in 15, subtotal resection (STR) in 9, and biopsy in 6 children. Most children had good neurological outcomes post-operatively (28/45 with GOS 5). Fourteen patients survived longer than 4 years. Survival analysis showed a significant difference in median survival in favour of GTR and localised disease. There was no significant difference in median survival between patients <1 year vs >1 year of age (p=0.84). CONCLUSION: We find that presence of metastasis was an important factor in poor survival in patients with ATRT. GTR, where possible, may confer significant survival benefit in ATRT. Children aged <1 year appear to have performed as well as those >1 year and therefore should still be considered for radical surgery.

Sex-specifics of ECT outcome.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for patients with severe major depressive disorder (MDD). Given the known sex differences in MDD, improved knowledge may provide more sex-specific recommendations in clinical guidelines and improve outcome. In the present study we examine sex differences in ECT outcome and its predictors. METHODS: Clinical data from 20 independent sites participating in the Global ECT-MRI Research Collaboration (GEMRIC) were obtained for analysis, totaling 500 patients with MDD (58.6 % women) with a mean age of 54.8 years. Severity of depression before and after ECT was assessed with validated depression scales. Remission was defined as a HAM-D score of 7 points or below after ECT. Variables associated with remission were selected based on literature (i.e. depression severity at baseline, age, duration of index episode, and presence of psychotic symptoms). RESULTS: Remission rates of ECT were independent of sex, 48.0 % in women and 45.7 % in men (X2(1) = 0.2, p = 0.70). In the logistic regression analyses, a shorter index duration was identified as a sex-specific predictor for ECT outcome in women (X2(1) = 7.05, p = 0.01). The corresponding predictive margins did show overlapping confidence intervals for men and women. CONCLUSION: The evidence provided by our study suggests that ECT as a biological treatment for MDD is equally effective in women and men. A shorter duration of index episode was an additional sex- specific predictor for remission in women. Future research should establish whether the confidence intervals for the corresponding predictive margins are overlapping, as we find, or not.

Visual outcomes and predictors in optic pathway glioma: a single centre study.

BACKGROUND/AIMS: Optic pathway gliomas (OPGs) may cause progressive visual loss despite chemotherapy. Newer, less toxic treatments might be given earlier, depending on visual prognosis. We aimed to investigate the prognostic value of visual evoked potentials (VEP) and optical coherence tomography (OCT). METHODS: A retrospective study of OPG patients (treated 2003-2017) was conducted. Primary outcome was PEDIG category visual acuity in better and worse eyes (good < = 0.2, moderate 0.3-0.6 and poor > = 0.7 logMAR). Binary logistic regression analysis was used to identify predictors of these outcomes. RESULTS: 60 patients (32 Neurofibromatosis type 1 [NF1] and 28 sporadic) had median presentation age 49 months (range 17-183) (NF1) and 27 months (range 4-92) (sporadic). Median follow up was 82 months (range 12-189 months). At follow up 24/32 (75%) of NF1 children and 14/28 (50%) of sporadic children had good better eye visual acuity and 11/32 (34%) of NF1 children and 15/28 (54%) of sporadics had poor worse eye acuity. Mean peripapillary retinal nerve fibre layer (RNFL) thickness predicted good better eye final acuity (OR 0.799, 95%CI 0.646-0.987, p = 0.038). Presenting with visual symptoms (OR 0.22 95% CI 0.001-0.508, p = 0.017) and poorer VEP scores (OR 2.35 95% CI 1.1-5.03, p = 0.027) predicted poor worse eye final acuity. 16 children had homonymous hemianopias at follow up, predicted by poor presenting binocular VEP score (OR 1.449 95%CI 1.052-1.995, p = 0.02). CONCLUSIONS: We found that both RNFL thickness on OCT and VEP were useful in predicting future visual acuity and vision and potentially in planning treatment. We had a high prevalence of homonymous hemianopia.

A Scoping Review of Adverse Incidents Research in Aged Care Homes: Learnings, Gaps, and Challenges.

Background: Adverse incidents are well studied within acute care settings, less so within aged care homes. The aim of this scoping review was to define the types of adverse incidents studied in aged care homes and highlight strengths, gaps, and challenges of this research. Methods: An expanded definition of adverse incidents including physical, social, and environmental impacts was used in a scoping review based on the PRISMA Extension for Scoping Reviews Checklist. MEDLINE, CINAHL, and EBSCOhost were searched for English language, peer-reviewed studies conducted in aged care home settings between 2000 and 2020. Forty six articles across 12 countries were identified, charted, and analyzed using descriptive statistics and narrative summary methods. Results: Quantitative studies (n = 42, 91%) dominated adverse incidents literature. The majority of studies focused on physical injuries (n = 29, 63%), with fewer examining personal/interpersonal (15%) and environmental factors (22%). Many studies did not describe the country's aged care system (n = 26, 56%). Only five studies (11%) included residents' voices. Discussion: This review highlights a need for greater focus on resident voices, qualitative research, and interpersonal/environmental perspectives in adverse event research in aged care homes. Addressing these gaps, future research may contribute to better understanding of adverse incidents within this setting.

Increased incidence of genital warts among women and men with type 1 diabetes compared with the general population-results from a nationwide registry-based, cohort study.

AIMS: To estimate the incidence rates of genital warts (GWs) in women and men with type 1 diabetes compared to persons without diabetes. METHODS: In this nationwide registry-based cohort study, we included the entire population aged 15 to 49 years living in Denmark between 1996 and 2016. From national registries, we retrieved individual level information on diabetes status, diagnoses and treatment of GWs, and potential confounding variables. We used Poisson regression to model sex- and age-specific incidence rates of GWs in persons with type 1 diabetes and persons without diabetes. Based on the models, we computed sex-specific incidence rate ratios (IRRs) of GWs in persons with type 1 diabetes compared to persons without diabetes, overall and according to age. RESULTS: The analysis included 3,514,824 persons without type 2 diabetes and no GW diagnoses before baseline. The incidence rate of GWs in persons with type 1 diabetes was higher than in those without diabetes, both among women (IRR = 1.59; 95% CI, 1.42-1.78) and men (IRR = 1.36; 95% CI, 1.25-1.48). The pattern of increased incidence rates of GWs in persons with type 1 diabetes was seen at all ages. CONCLUSIONS: Persons with type 1 diabetes have higher incidence rates of GWs than persons without diabetes. This supports the importance of HPV vaccination of young girls and boys with type 1 diabetes.

Assisted reproductive technology treatment and risk of breast cancer: a population-based cohort study.

STUDY QUESTION: Is there an increased risk of breast cancer among women after ART treatment including ovarian hormone stimulation? SUMMARY ANSWER: The risk of breast cancer was slightly increased among women after ART treatment compared to age-matched, untreated women in the background population, and the risk was further increased among women initiating ART treatment when aged 40+ years. WHAT IS KNOWN ALREADY: The majority of breast cancer cases are sensitive to oestrogen, and ovarian hormone stimulation has been suggested to increase the risk of breast cancer by influencing endogenous oestrogen levels. Previous studies on ART treatment and breast cancer have varied in their findings, but several studies have small sample sizes or lack follow-up time and/or confounder adjustment. Recent childbirth, nulliparity and higher socio-economic status are breast cancer risk factors and the latter two are also associated with initiating ART treatment. STUDY DESIGN, SIZE, DURATION: The Danish National ART-Couple II (DANAC II) cohort includes women treated with ART at public and private fertility clinics in 1994-2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with no cancer prior to ART treatment were included (n = 61 579). Women from the background population with similar age and no prior history of ART treatment were randomly selected as comparisons (n = 579 760). The baseline mean age was 33.1 years (range 18-46 years). Results are presented as hazard ratios (HRs) with corresponding CIs. MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up (median 9.69 years among ART-treated and 9.28 years among untreated), 5861 women were diagnosed with breast cancer, 695 among ART-treated and 5166 among untreated women (1.1% versus 0.9%, P < 0.0001). Using Cox regression analyses adjusted for nulliparity, educational level, partnership status, year, maternal breast cancer and age, the risk of breast cancer was slightly increased among women treated with ART (HR 1.14, 95% CI 1.12-1.16). All causes of infertility were slightly associated with breast cancer risk after ART treatment. The risk of breast cancer increased with higher age at ART treatment initiation and was highest among women initiating treatment at age 40+ years (HR 1.37, 95% CI 1.29-1.45). When comparing women with a first birth at age 40+ years with or without ART treatment, the increased risk among women treated with ART persisted (HR 1.51, 95% CI 1.09-2.08). LIMITATIONS, REASONS FOR CAUTION: Although this study is based on a large, national cohort of women, more research with sufficient power and confounder adjustment is needed, particularly in cohorts with a broad age representation. WIDER IMPLICATIONS OF THE FINDINGS: An increased risk of breast cancer associated with a higher age at ART treatment initiation has been shown. Ovarian stimulation may increase the risk of breast cancer among women initiating ART treatment when aged 40+ years. Age-related vulnerability to hormone exposure or higher hormone doses during ART treatment may explain the increased risk. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the DANAC II cohort was received from the Ebba Rosa Hansen Foundation. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

An accessory muscle of the posterior compartment of leg of clinical significance: a cadaveric case report / Un músculo accesorio del compartimento posterior de la pierna de importancia clínica: reporte de un caso cadavérico

SUMMARY: Accessory and anomalous muscles are common in humans, although their unique morphologic characteristics can make accurate identification difficult. In this case report, we attempt to identify an anomalous accessory muscle of the posterior compartment of the leg [Compartimentum posterius cruris] detected during cadaveric dissection and discuss its clinical significance. The muscle was found on the right lower limb of an 81-year-old female cadaver and extended from the distal femur to attach to the gastrocnemius muscle at the point where the medial and lateral heads fuse. At its origin, the muscle was found lateral to the popliteal vessels and crossed posterior to these vessels and tibial nerve. It displayed characteristics similar to both an accessory plantaris muscle and gastrocnemius tertius, thus making its ultimate identification difficult. Though the muscle displayed a morphologically similar appearance to the plantaris, we suggest that its common insertion with the gastrocnemius best identifies it as a gastrocnemius tertius. In addition, due to its relationship with the popliteal neurovasculature, it is possible that this muscle could have resulted in neurovascular entrapment although it is unknown whether or not this cadaver exhibited symptoms.

RESUMEN: Los músculos accesorios y anómalos son comunes en los seres humanos, aunque sus características morfológicas pueden dificultar la identificación precisa. En este reporte de caso, intentamos identificar un músculo accesorio anómalo del compartimento posterior de la pierna [Compartimentum posterius cruris] detectado durante la disección cadavérica y discutir su importancia clínica. El músculo fue encontrado en el miembro inferior derecho de una mujer de 81 años de edad y se extendía desde la parte distal del fémur para unirse al músculo gastrocnemio en la fusión de sus cabezas medial y lateral. En su origen, el músculo se encontraba lateral a los vasos poplíteos y cruzaba posteriormente a estos vasos y al nervio tibial, presentando características similares tanto al músculo plantar accesorio como al gastrocnemio tercero, lo que dificultaba su identificación final. Similar al músculo plantar, sugerimos que debido a su inserción común con el gastrocnemio lo identifica mejor como un músculo gastrocnemio tercero. Además, debido a su relación con la neurovasculatura poplítea, es posible que este músculo haya dado lugar a un síndrome de compresión neurovascular aunque se desconoce si este individuó presentó síntomas o no en vivo.

Can probiotic supplements prevent early childhood caries? A systematic review and meta-analysis.

The aim of this study was to explore the preventive effect of probiotic supplements on the development of early childhood caries (ECC). We searched the PubMed, Google Scholar and Cochrane databases up to January 15, 2021. The authors screened the hits independently for relevance, extracted outcome data and assessed the risk of bias. We performed a random effects meta-analysis to pool and compare the incidence of ECC in children assigned to test or placebo groups, respectively. The authors included nine randomised controlled trials published between 2001 and 2021, involving 2,363 preschool children. We assessed two publications with a moderate risk of bias and seven with high risk of bias. The median caries incidence in the probiotic test groups was 8.5% compared with 17.5% in the placebo groups and this difference was statistically significant (P<0.001). A pooled random effects meta-analysis on caries incidence on subject level showed a small but statistically significant risk difference in favour of the probiotic intervention (-0.05, 95% confidence interval (CI) -0.10, -0.00; P<0.05). The mean difference in caries increment on tooth/surface level was -0.57, (95% CI -0.91, -0.23; P<0.01). In conclusion, we demonstrated a small but statistically significant preventive effect of probiotic supplements on ECC. However, the certainty of this finding was low due to the risk of bias, heterogeneity and inconsistencies across the studies. Further long-term randomised controlled trials with low risk of bias are required in order to answer the research question with a higher certainty.

Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns.

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.

Hemoglobin A1c-levels and subsequent risk of depression in individuals with and without diabetes.

BACKGROUND: It has been suggested that long-term glycemic load as reflected in plasma levels of Glycosylated Hemoglobin, Type A1C (HbA1c) is associated with higher risk of depression, however results have been conflicting. We examined the potential association between HbA1c and risk of depression in a large population-based cohort without baseline diabetes (the Glostrup cohort) defined by either self-reported diabetes, registry diagnosis of diabetes or use of antidiabetic medication at baseline and in a national diabetes cohort (the Danish Adult Diabetes Database). METHODS: A total of 16,124 middle-aged individuals from the Glostrup cohort and 93,544 patients registered in the Danish Adult Diabetes Database were followed from the first registered HbA1c measurement (1999-2014) for subsequent diagnosis of depression or use of antidepressant medication in nation-wide Danish registers. The association was analyzed using a Cox proportional hazards regression model with HbA1c on both a continuous scale using restricted cubic splines and categorized based on the groups found in the spline model. We adjusted for relevant sociodemographic and clinical variables including previous depression and tested for interaction of both gender, insulin use and diabetes type. RESULTS: During follow-up, 2694 (17%) in the Glostrup cohort and 29,234 (31%) in the diabetes cohort developed depression. In the Glostrup cohort, we found an indication of a positive linear association between HbA1c and depression in women, while no clear association was found in men. In patients with diabetes, we found a U-shaped association between HbA1c and depression in both men and women with the lowest risk estimates for HbA1c levels of 58 mmol/mol (7.5%) in men and of 60 mmol/mol (7.6%) in women. When HbA1c was categorized, men with the highest HbA1c-levels had significantly elevated risk of depression (HRHbA1c>9.4 1.16 (95%CI 1.10-1.23)) after multifactorial adjustment compared to the reference group with HbA1c of 42.1-56.2 mmol/mol (6.0-7.3%). Women in the lowest and highest category of HbA1c had significantly higher risk of depression HRHbA1c<6.0 1.15 (95% CI 1.09-1.22) and HRHbA1c>9.3 1.10 (95% CI 1.04-1.16), respectively, compared to the reference group with HbA1c 42.1-55.0 mmol/mol (7.2-9.3%). There was a significant interaction with gender, but no interaction for insulin use or diabetes type. CONCLUSIONS: In a population without baseline diabetes, higher HbA1c levels seemed associated with higher depression risk in women, whereas a U-shaped association was found in patients with known diabetes.

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG).

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

Intrauterine testosterone exposure and depression risk in opposite-sex and same-sex twins, a Danish register study.

BACKGROUND: Males have a lower prevalence of depression than females and testosterone may be a contributing factor. A comparison of opposite-sex and same-sex twins can be used indirectly to establish the role of prenatal testosterone exposure and the risk of depression. We therefore aimed to explore differences in depression risk using opposite-sex and same-sex twins. METHODS: We included 126 087 opposite-sex and same-sex twins from the Danish Twin Registry followed in nationwide Danish registers. We compared sex-specific incidences of depression diagnosis and prescriptions of antidepressants between opposite-sex and same-sex twins using Cox proportional hazard regression. RESULTS: During follow-up, 2664 (2.1%) twins were diagnosed with depression and 19 514 (15.5%) twins had purchased at least one prescription of antidepressants. First, in male twins, we found that the opposite-sex male twins had the same risk of depression compared to the same-sex male twins {hazard ratio (HR) = 1.01 [95% confidence interval (CI) 0.88-1.17)]}. Revealing the risk of use of antidepressants, the opposite-sex male twins had a slightly higher risk of 4% (HR = 1.04 (95% CI 1.00-1.11)) compared with the same-sex male twins. Second, in the female opposite-sex twins, we revealed a slightly higher, however, not statistically significant risk of depression (HR = 1.08 (95% CI 0.97-1.29)) or purchase of antidepressants (HR = 1.01 (95% CI 0.96-1.05)) when compared to the same-sex female twins. CONCLUSIONS: We found limited support for the hypothesis that prenatal exposure to testosterone was associated with the risk of depression later in life.

Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group.

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study.

BACKGROUND: Cognitive disturbances are common and disabling features of major depressive disorder (MDD). Previous studies provide limited insight into the co-occurrence of hot (emotion-dependent) and cold (emotion-independent) cognitive disturbances in MDD. Therefore, we here map both hot and cold cognition in depressed patients compared to healthy individuals. METHODS: We collected neuropsychological data from 92 antidepressant-free MDD patients and 103 healthy controls. All participants completed a comprehensive neuropsychological test battery assessing hot cognition including emotion processing, affective verbal memory and social cognition as well as cold cognition including verbal and working memory and reaction time. RESULTS: The depressed patients showed small to moderate negative affective biases on emotion processing outcomes, moderate increases in ratings of guilt and shame and moderate deficits in verbal and working memory as well as moderately slowed reaction time compared to healthy controls. We observed no correlations between individual cognitive tasks and depression severity in the depressed patients. Lastly, an exploratory cluster analysis suggested the presence of three cognitive profiles in MDD: one characterised predominantly by disturbed hot cognitive functions, one characterised predominantly by disturbed cold cognitive functions and one characterised by global impairment across all cognitive domains. Notably, the three cognitive profiles differed in depression severity. CONCLUSION: We identified a pattern of small to moderate disturbances in both hot and cold cognition in MDD. While none of the individual cognitive outcomes mapped onto depression severity, cognitive profile clusters did. Overall cognition-based stratification tools may be useful in precision medicine approaches to MDD.

Familial risk and heritability of depression by age at first diagnosis in Danish twins.

OBJECTIVE: Familial and genetic factors seem to contribute to the development of depression but whether this varies with age at diagnosis remains unclear. We examined the influence of familial factors on the risk of depression by age at first diagnosis. METHODS: We included 23 498 monozygotic and 39 540 same-sex dizygotic twins from the population-based Danish Twin Registry, followed from 1977 through 2011 in nationwide registers. We used time-to-event analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of first depression by age using monozygotic and same-sex dizygotic twin pairs. RESULTS: During follow-up, a total of 1545 twins were diagnosed with depression. For twins at age 35 or younger at first depression, heritability was estimated to be 24.8% (95% confidence interval [CI], 4.6-43.1%), whereas at age 90 it was 14.7% (95% CI, 3.1-26.3%). The relative recurrence risk was higher at younger ages: At age 35, the risk was 27.7-fold (95% CI, 20.0-35.5) and 6.9-fold (95% CI, 3.9-9.8) higher than the population risk for monozygotic and same-sex dizygotic twins, respectively, while the corresponding numbers were 3.0 (95% CI, 2.3-3.6) and 1.8 (95% CI, 1.3-2.2) at age 90. Heritability seemed similar for male and female twins. CONCLUSION: Familial risk of depression, caused either by genes or shared environment, seemed to slightly decrease with age at diagnosis and an elevated concordance risk for monozygotic over same-sex dizygotic pairs suggested a genetic contribution to the development of depression.