Ontogeny and homology of cranial bones associated with lateral-line canals of the Senegal Bichir,Polypterus senegalus (Actinopterygii: Cladistii: Polypteriformes), with a discussion on the formation of lateral-line canal bones in fishes

The association between lateral-line canals and skull bones in fishes has been the subject of several studies and raised a series of controversies, particularly with regard to the hypothesized role of lateral-line organs (i.e. neuromasts) in osteogenesis and the consequences for hypotheses of homology of the bones associated with lateral-line canals. Polypteridae, a group of freshwater fishes that occupies a key phylogenetic position as the most basal extant lineage of ray-finned fishes (Actinopterygii), provides an interesting model for the study of the relationships between lateral-line canals and skull bones. We describe the development of bones associated with lateral-line canals in the Senegal Bichir, Polypterus senegalus, and use these data to re-address previous hypotheses of homology of skull bones of polypterids. We demonstrate that the lateral-line canals constitute a separate component of the dermatocranium that may interact with a membranodermal component, thereby forming compound bones in the adult. Differences in the interactions between these components determine the characteristics of the development of each independent bone in the skull of adult P. senegalus. Our results shed light on long-standing controversies about the identity of skull bones such as the rostral, preopercle, and sphenotic in Polypteridae, and suggest the presence of an ancestral two-component pattern of formation of bones associated with lateral-line canals in bony fishes. These findings reveal the need to re-address previous hypotheses of homology of bones associated with lateral-line canals in different groups of bony fishes, especially fossil taxa.     

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia.     

MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis

A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients’ data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.     

Elevated erythroferrone distinguishes erythrocytosis with inherited defects in oxygen-sensing pathway from primary familial and congenital polycythaemia

Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel–Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options.     

Early coronavirus disease 2019 restrictive measures and changes in maternal characteristics,use of assisted reproductive technology,and stillbirth

Background

The initial COVID-19 pandemic response−related effects on conceptions following the use of assisted reproductive technologies (ART), and on changes in the maternal characteristics of women who conceived during the early vs. pre-pandemic period, have been understudied.

Objectives

To examine the effects of ART clinic closures in the United States (US) in March 2020 on the frequency of ART-conceived live births, multiple births and stillbirths; and to describe changes in the characteristics of women who conceived in the early pandemic period.

Methods

Population-based cohort study including all births in the US from January 2015 to December 2020 (22,907,688 live births; 134,537 stillbirths). Interrupted time series (ITS) methodology was used to estimate rate ratios (RR) of expected versus observed rates in December 2020 (i.e., among births conceived mainly in March 2020). Demographic and clinical characteristics were compared between mothers who conceived in March 2020 versus March 2015–2019.

Results

Overall, 1.1% of live births and 1.7% of stillbirths were conceived by ART. ART-conceived live births decreased by 57.0% in December 2020 (observed vs. expected RR 0.43, 95% confidence interval [CI] 0.40, 0.45), and these declines occurred in all subgroups of women. Multiple births also declined in December 2020. Stillbirth rates increased in December 2020 in ART-conceived births (RR 2.55, 95% CI 1.63, 3.92) but remained unchanged in the non-ART group. Maternal characteristics of women who conceived in the early pandemic versus pre-pandemic period differed and included an increased prevalence of pre-pregnancy obesity class 3 and chronic hypertension.

Conclusions

The early pandemic closure of ART clinics resulted in a substantial decline in ART-conceived live births and multiple births in December 2020 and an increase in the proportion of stillbirths among ART-conceived births. Women who conceived in the early pandemic period also had an increased prevalence of obesity and chronic hypertension.