GP consultations for menstrual disorders after COVID-19 vaccination - A self-controlled cohort study based on routine healthcare data from the Netherlands.

INTRODUCTION: Several studies described that COVID-19 vaccinations can cause menstrual disorders. Our study aimed to describe whether this also resulted in more general practitioner (GP) consultations for menstrual disorders after COVID-19 vaccination, based on a large cohort study. METHODS: A retrospective self-controlled cohort study was performed including vaccinated women in 2021 aged 12-49 years from two large, representative GP databases in the Netherlands. Incidence rates and incidence rate ratio's (IRR) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection as time-varying confounder. The exposed period was set at maximum six months after each COVID-19 vaccination and the non-exposed period was defined as all-time outside the exposed period. RESULTS: The cohort included 631,802 women, of which 18,986 (3 %) consulted the GP for a menstrual disorder during 2021. Increased GP consultations were observed among 12-14 year olds for amenorrhea/hypomenorrhea/oligomenorrhea (IRR: 1.85, 95 % CI: 1.30-2.65) and irregular/frequent menstruation (IRR: 1.33, 95 % CI: 1.06-1.69) after COVID-19 vaccination in general, and after Pfizer/BioNTech vaccination (IRR: 1.87, 95 % CI: 1.31-2.67 for amenorrhea/hypomenorrhea/oligomenorrhea and IRR: 1.35, 95 % CI: 1.06-1.70 for irregular/frequent menstruation). Persons from this age group were in general also vaccinated with Pfizer/BioNTech. No increase in the frequency of GP consultations were observed for older age groups, other vaccine brands, and potential risk groups. CONCLUSION: For the majority of women, no increased GP consultations for menstrual disorders was found. Solely for the youngest age group (12-14 year olds) increased GP consultations for specific types of menstrual disorders was found after Pfizer/BioNTech vaccination.

The role of co-morbidities in the development of an AEFI after COVID-19 vaccination in a large prospective cohort with patient-reported outcomes in the Netherlands.

BACKGROUND: The effect of a preexisting comorbidity on the occurrence of adverse events after immunization (AEFIs) has been studied poorly. In this longitudinal cohort study, we assess the association between co-morbidities and the occurrence of AEFIs after COVID-19 vaccination. Also, we described the occurrence of flare-ups and their manifestation after COVID-19 vaccination in people with rheumatic diseases. RESEARCH DESIGN AND METHODS: We performed multivariable logistic regression to investigate the association between the occurrence of AEFIs and 10 common comorbidities using patient-reported data from people vaccinated with the AstraZeneca, Johnson&Johnson, Moderna, or Pfizer vaccine. RESULTS: Occurrence of any AEFI, injection site reactions, headache, fatigue, and/or malaise was significantly associated with presence of comorbidities, including psychological disorders, musculoskeletal disorders, and endocrine disorders after the first and second doses (OR ranges 1.23-1.77). One participant with rheumatoid arthritis experienced a flare-up after receiving the first dose of the AstraZeneca vaccine. DISCUSSION/CONCLUSION: The results showed that the odds of reporting an AEFI after COVID-19 vaccination is significantly higher in the presence of some comorbidities whilst flare-ups are uncommon after receiving COVID-19 vaccination in people with rheumatic disease. In-depth research is needed to validate our results and unravel the observed associations from a mechanistic perspective.

The Effect of Sex on the Incidence, Latency, Duration and Perceived Burden of Adverse Events Following Seasonal Influenza Vaccination in the Netherlands.

INTRODUCTION: The annual reformulation of the seasonal influenza vaccine results in fluctuating frequencies and severity of adverse effects following immunization (AEFIs), which stresses the importance of pharmacovigilance. Also, sex-related factors are known to influence the development of AEFIs. This study aims to describe the difference in incidence and course (i.e., time-to-onset, time-to-recovery, and perceived burden) of AEFIs between males and females after seasonal influenza vaccination. METHODS: We assessed data from cohort event monitoring studies, which were performed over nine consecutive years (2013-2021), each covering several months during the seasonal influenza campaign in the Netherlands. Participants reported information about AEFIs over a 30-day period in three questionnaires. The effect of sex, age, body mass index, study year, and comorbidities on the incidence of any AEFI, local reactions, fever and the five most reported AEFIs was analyzed using logistic regression. The difference in time-to-onset, time-to-recovery, and perceived burden between males and females was analyzed by the Kruskal-Wallis test. RESULTS: The cohort included 7789 participants (53.0% females). Females had around 2.5-fold (p < 0.001) higher odds of developing any AEFI compared with males. Some study years and comorbidities were positively associated with AEFI incidence, whereas age was negatively associated. An AEFI had a significant shorter time-to-onset, a longer time-to-recovery, and a higher perceived burden in females compared to males. CONCLUSION: Overall, the results confirm that females experience AEFIs more often than males. Additionally, this study shows that the course of AEFIs only partially differs between the sexes.

The abruptex mutations of notch disrupt the establishment of proneural clusters in Drosophila.

The receptor encoded by the Notch gene plays a central role in preventing cells from making decisions about their fates until appropriate signals are present. This function of Notch requires the product of the Suppressor of Hairless gene. Loss of either Notch or Suppressor of Hairless function results in cells making premature and incorrect cell fate decisions, whilst increases in Notch signalling prevent cells from making these decisions. Here we find that the proneural clusters are not established correctly in certain Abruptex mutations of Notch and this failure to establish proneural clusters correctly is not due to increased Notch signalling during lateral inhibition. In addition we show that the overexpression of certain dominant negative Notch molecules can disrupt the initiation of proneural cluster development in a manner similar to the Abruptex mutants.

Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos.

Notch, a transmembrane protein found in a wide range of organisms, is a component of a pathway that mediates cell-fate decisions that involve intercellular communication. In this paper, we show that in Drosophila melanogaster, Notch (N) is processed in a ligand-dependent fashion to generate phosphorylated, soluble intracellular derivatives. Suppressor of Hairless [Su(H)] is predominantly associated with soluble intracellular N. It has been demonstrated by others that N has access to the nucleus, and we show that when tethered directly to DNA, the cytoplasmic domain of N can activate transcription. Conversely, a viral activator fused to Su(H) can substitute for at least some N functions during embryogenesis. We suggest that one function of soluble forms of N is to bind to Su(H), and in the nucleus, to act directly as a transcriptional transactivator of the latter protein. Although N has functional nuclear localization signals, the N/Su(H) complex accumulates in the cytoplasm and on membranes suggesting that its nuclear entry is regulated. Localization studies in cultured cells and embryos suggest that Su(H) plays a role in this regulation, with the relative levels of Delta, N and Su(H) determining whether a N/Su(H) complex enters the nucleus.

Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei.

Loss of any one of several neurogenic genes of Drosophila results in overproduction of embryonic neuroblasts at the expense of epidermoblasts. In this paper a variety of altered Notch proteins are expressed in transgenic flies. Dominant lethal, antineurogenic phenotypes were produced by expression of three classes of mutant proteins: (1) a protein comprised of the cytoplasmic domain of Notch and devoid of sequences permitting membrane association; (2) a transmembrane protein lacking the extracellular, lin12/Notch repeats; and (3) transmembrane proteins carrying amino acid substitutions replacing one or both extracellular cysteines thought to be involved in Notch dimerization. These Notch proteins not only suppress the neural hypertrophy observed in Notch- embryos, but also generate a phenotype in which elements of the embryonic nervous system are underproduced. Action of the intracellular cdc10 repeats appears to be essential for wild-type Notch function or for the antineurogenic activity of these proteins. The activities of the dominant, gain-of-function proteins indicate that Notch functions as a signal transducing receptor during ectoderm development. Production of antineurogenic Notch proteins in embryos deficient for the other neurogenic genes allowed functional dependencies to be established. Delta, mastermind, bigbrain, and neuralized appear to function in elaboration of a signal upstream of Notch. Genes of the Enhancer of split complex act after Notch. The cytoplasmic domain of Notch contains nuclear localization sequences that function in cultured cells, and one of the Notch antineurogenic proteins, the cytoplasmic domain, accumulates in nuclei in vivo.

Single amino acid substitutions in EGF-like elements of Notch and Delta modify Drosophila development and affect cell adhesion in vitro.

Notch locus EGF-like element mutations spl, altering eye development, and AxE2, affecting wing and sensilla development, are modified by mutations at Delta. It is shown that two allele-specific suppressors of spl involve single amino acid substitutions in the 4th (Dlsup5) and 9th (Dlsup4) EGF-like elements of the Delta protein. Cultured cells producing spl or AxE2 aggregate with cells producing wild-type Delta or Dlsup5 protein, and Dlsup5-producing cells adhere to cells producing wild-type Notch protein. However, spl,AxE2, and Dlsup5 are each defective in promoting these cell affinities, as none of the mutant proteins can compete with the corresponding wild-type proteins for formation of cell aggregates. Thus, widely separated EGF-like elements of Notch and Delta appear to participate in functional molecular interactions between the proteins. Dlsup5 does not improve adhesiveness of spl in vitro, so suppression in vivo may involve altered developmental signaling by spl-Dlsup5 complexes, rather than modified cell adhesion.

Embryonal rhabdomyosarcoma of the common bile duct.

A 2 4/12-year-old boy with obstructive jaundice caused by a tumor of the portal area that proved to be an embryonal rhabdomyosarcoma of the common bile duct is reported. The diagnosis was made clinically, radiographically, ultrasonographically, and histologically. Surgery was elected as the primary therapy; there were no intra- or postoperative complications. The prognosis and its improvement by means of aggressive chemotherapy and local irradiation are discussed.

Histone gene expression during sea urchin spermatogenesis: an in situ hybridization study.

The expression of testis-specific and adult somatic histone genes in sea urchin testis was investigated by in situ hybridization. The testis-specific histone genes (Sp H2B-1 of Strongylocentrotus purpuratus and Sp H2B-2 of Lytechinus pictus) were expressed exclusively in a subset of male germ line cells. These cells are morphologically identical to replicating cells pulse-labelled with 3H-thymidine. Genes coding for histones expressed in adult somatic and late embryo cells (H2A-beta for S. purpuratus and H3-1 for L. pictus) were expressed in the same germ line cells, as well as in the supportive cells (nutritive phagocytes) of the gonad. All histone mRNAs detected in the male germ lineage declined precipitously by the early spermatid stage, before cytoplasmic reduction. The data suggest that both testis-specific and adult somatic histone genes are expressed in proliferating male germ line cells. Testis-specific gene expression is restricted to spermatogonia and premeiotic spermatids, but somatic histone expression is not. The decline of histone mRNA in nondividing spermatids is not merely a consequence of cytoplasmic shedding, but probably reflects mRNA turnover.

A histone H1 protein in sea urchins is encoded by a poly(A)+ mRNA.

Typical histone genes lack intervening sequences and encode small mRNAs (400-800 nucleotides) with short leader and trailer regions. Most histone mRNAs are not polyadenylylated but rather terminate in a highly conserved stem and loop structure. The early, late, and testis-specific histone genes of sea urchins, described to date, have this typical histone gene structure. We have identified an unusual H1 gene, H1-delta, in sea urchins that encodes a poly(A)+ mRNA. This mRNA is one of a group of polyadenylylated transcripts homologous with H1 gene probes. The sequence of H1-delta had been determined. H1-delta encodes a different H1 protein. Although the temporal expression of H1-delta mRNA is similar to that of other late H1 (beta and gamma) mRNAs, its spatial distribution at the time of maximal accumulation is distinct and confirms that H1-delta is regulated differently than other H1 genes.

Analysis of histone gene expression in adult tissues of the sea urchins Strongylocentrotus purpuratus and Lytechinus pictus: tissue-specific expression of sperm histone genes.

We analyzed the histone mRNA population found in several adult tissues of the sea urchin Strongylocentrotus purpuratus and in testis of Lytechinus pictus. Unique species of H1 and H2b mRNAs encoding the sperm-specific histone subtypes can be found exclusively in testis RNA. S. purpuratus contains two distinct testis-specific H1 transcripts, while L. pictus contains one such transcript. Each of these mRNAs is larger than either early or late embryonic H1 mRNAs. Other somatic adult tissues contain transcripts derived from members of the late embryonic H1 histone gene family. S. purpuratus contains one H2b transcript found exclusively in testis, while L. pictus contains two such H2b mRNAs. Similarly, in tissues other than testis, late H2b transcripts were found. While there is no sperm-specific H2a protein, a limited set of late histone H2a genes encoding primarily the H2a-beta subtype is expressed in testis. The majority of the H2a protein found in diploid adult tissues is also the H2a-beta subtype; however, the size of the H2a transcripts differs between testis and other tissues. We conclude that different members of the late H2a gene family are differentially expressed in embryos and adult tissues. We prepared and characterized cDNA clones encoding the sperm-specific H2b protein as well as the H2a-beta protein found in testis.

Sea urchin (lytechinus pictus) late-stage histone H3 and H4 genes: characterization and mapping of a clustered but nontandemly linked multigene family.

We have cloned and characterized members of a small multigene family that encodes late-stage histone H3 and H4 mRNAs from the sea urchin Lytechinus pictus. Unlike their highly repetitive histone gene counterparts, which are expressed at an earlier developmental stage, late H3 and H4 histone genes are not present in tandem repeats. In addition, the late stage H3 and H4 genes are not always tightly clustered together with the H1, H2A and H2B genes as they are in early histone genes. The spacer DNA that separates adjoining H3 and H4 coding regions is not conserved between nonallelic members of the late histone gene family. We have determined the nucleotide sequence of a continuous 2100 bp segment of DNA including both H3 and H4 coding sequences, the entire spacer DNA separating the genes and surrounding nonhistone DNA. The late histone H3 and H4 genes encode proteins identical to their early gene counterparts; however, the 5' leader sequence is shorter in late genes and the codon usage is different.