Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)¹, which influences offspring development and adult phenotypes^1–7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood⁸. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Anthropometric quantities are widely used in epidemiologic research as possible confounders, risk factors, or outcomes. 3D laser-based body scans (BS) allow evaluation of dozens of quantities in short time with minimal physical contact between observers and probands. The aim of this study was to compare BS with classical manual anthropometric (CA) assessments with respect to feasibility, reliability, and validity. We performed a study on 108 individuals with multiple measurements of BS and CA to estimate intra- and inter-rater reliabilities for both. We suggested BS equivalents of CA measurements and determined validity of BS considering CA the gold standard. Throughout the study, the overall concordance correlation coefficient (OCCC) was chosen as indicator of agreement. BS was slightly more time consuming but better accepted than CA. For CA, OCCCs for intra- and inter-rater reliability were greater than 0.8 for all nine quantities studied. For BS, 9 of 154 quantities showed reliabilities below 0.7. BS proxies for CA measurements showed good agreement (minimum OCCC > 0.77) after offset correction. Thigh length showed higher reliability in BS while upper arm length showed higher reliability in CA. Except for these issues, reliabilities of CA measurements and their BS equivalents were comparable.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N= 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

To date, gross total resection (GTR) of the contrast-enhancing area of glioblastoma (GB) is the benchmark treatment regarding surgical therapy. However, GB infiltrates beyond those margins, and most tumors recur in close proximity to the initial resection margin. It is unclear whether a supramarginal resection (SMR) enhances progression-free survival (PFS) time without increasing the incidence of postoperative surgical complications. The aim of the present meta-analysis was to investigate SMR with regard to PFS and postoperative surgical complications. We searched for eligible studies comparing SMR techniques with conventional GTR in PubMed, Cochrane Library, Web of Science, and Medline databases. From 3158 initially identified records, 11 articles met the criteria and were included in our meta-analysis. Our results illustrate significantly prolonged PFS time in SMR compared with GTR (HR: 11.16; 95% CI: 3.07–40.52, p = 0.0002). The median PFS of the SMR arm was 8.44 months (95% CI: 5.18–11.70, p < 0.00001) longer than the GTR arm. The rate of postoperative surgical complications (meningitis, intracranial hemorrhage, and CSF leaks) did not differ between the SMR group and the GTR group. SMR resulted in longer median progression-free survival without a negative postoperative surgical risk profile. Multicentric prospective randomized trials with a standardized definition of SMR and analysis of neurologic functioning and health-related quality of life are justified and needed to improve the level of evidence.

Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.

Obesity can affect linear growth of children but there is uncertainty regarding the dynamics and potential causes. In the population-based LIFE Child and the obesity-enriched Leipzig Obesity Childhood cohorts (8,629 children, 37,493 measurements), recruited from 1999 to 2018 in Germany, we compared height, growth, and endocrine parameters between normal-weight and children with obesity (0–20 years). Derived from the independent German CrescNet registry (12,703 children) we generated height reference values specific for children with obesity (data collected from 1999 to 2020). Children with obesity were significantly taller than normal-weight peers, differing at maximum by 7·6 cm (1·4 height, standard deviation scores or SDS) at age 6–8 years. Already at birth, children with obesity were slightly taller and thereafter had increased growth velocities by up to 1·2 cm/year. This growth acceleration was unrelated to parental height, but was accompanied by increased levels of insulin-like growth factor-1 (IGF-1), insulin and leptin. During puberty, children with obesity showed a catch-down in height SDS. The reduction in pubertal growth velocity by up to 25% coincided with a decrease in levels of IGF-1 (by 17%) and testosterone (by 62%) in boys and estradiol (by 37%) in girls. We confirmed these alterations in growth in the independent CrescNet cohort and furthermore provide height reference values for children with obesity for open access. Dynamics of linear growth are altered distinctively in different developmental phases in children with obesity. Early emergence before other profound comorbidities implies predisposition, environmental, and/or endocrine factors affecting growth in early life. Height reference values for children with obesity may enhance the precision of clinical health surveillance. German Research Foundation, German Diabetes Association, EU, ESF, ERDF, State of Saxony, ESPE, Hexal, Novo Nordisk, Pfizer Pharma.