Risk of endometrial cancer among women with benign ovarian tumors - A Danish nationwide cohort study.

OBJECTIVE: The few studies on the association between benign ovarian tumors and endometrial cancer have been inconclusive. Using data from a large Danish register-based cohort study, we assessed the overall and type-specific risk of endometrial cancer among women with a benign ovarian tumor. METHODS: We identified all Danish women diagnosed with a benign ovarian tumor during 1978-2016 in the Danish National Patient Register (n = 149,807). The study population was followed for subsequent development of endometrial cancer by linkage to the Danish Cancer Register and standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) were calculated after correction for hysterectomy. RESULTS: After a one-year delayed study entry, women with benign ovarian tumors had a decreased incidence of endometrial cancer (SIR = 0.74, 95% CI: 0.68-0.81) compared with women in the general Danish population. Both solid benign ovarian tumors (SIR = 0.79, 95% CI 0.70-0.88) and cystic benign ovarian tumors (SIR = 0.68, 95% CI 0.58-0.78) were associated with decreased incidences of endometrial cancer. Likewise, women with benign ovarian tumors had decreased incidences of both type I and type II endometrial cancer. The incidence of endometrial cancer was decreased to virtually the same magnitude irrespective of the age at diagnosis of a benign ovarian tumor and the reduction persisted throughout the follow-up period. CONCLUSIONS: The risk of endometrial cancer was decreased beyond the first year after a benign ovarian tumor and the decrease persisted for 20 or more years. The possible underlying mechanisms are not known and should be investigated further.

Risk of head-and-neck cancer following a diagnosis of severe cervical intraepithelial neoplasia: a nationwide population-based cohort study in Denmark.

OBJECTIVE: Women with a history of cervical intraepithelial neoplasia grade 3 including adenocarcinoma in situ (CIN3/AIS) may be more prone to develop cancers of the ano-genital region and head-and-neck cancers. The current literature is, however, limited. METHODS: We established a nationwide cohort of approximately 2,500,000 Danish women born in 1918-1990. By linking the cohort to population-based health registries, we obtained information on CIN3/AIS, cancer, migration, death, education, and smoking. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the association between CIN3/AIS and risk of head-and-neck squamous cell carcinoma (HNSCC). HRs were presented for any HNSCC and for four subgroups categorized by their anticipated degree of association with human papillomavirus (HPV). RESULTS: A history of CIN3/AIS was significantly associated with an increased overall relative risk of HNSCC after adjustment for year of birth, attained age, and length of education. The risk was especially high for sites anticipated to be strongly associated with HPV (e.g. base of tongue, tonsils) (HR, 2.49; 95% CI, 1.84-3.36). Lower risks were found for sites anticipated to be not or weakly associated with HPV (e.g. nasal cavity, middle ear, sinuses) (HR, 1.29; 95% CI, 0.61-2.76). CONCLUSION: Women with a history of CIN3/AIS have a significantly higher risk of HNSCC than women without such a history. The increased relative risk persisted for at least 20years after the CIN3/AIS diagnosis. Women with CIN3/AIS may be more susceptible to the consequences of HPV and/or may have higher risk behavior, such as smoking.

Full genome ultra-deep pyrosequencing associates G-to-A hypermutation of the hepatitis B virus genome with the natural progression of hepatitis B.

Human APOBEC3 (A3) cytosine deaminases are antiviral restriction factors capable of editing the genome the hepatitis B virus (HBV). Despite the importance of the human A3 protein family for the innate immune response little is known about the clinical relevance for hepatitis B. The aim of this study was to utilize ultra-deep pyrosequencing (UDPS) data to analyse the phenomenon of G-to-A hypermutation of the complete HBV genome and to relate it to fundamental characteristics of patients with chronic hepatitis B. By analysing the viral population of 80 treatment naïve patients (47 HBeAg-positive and 33 HBeAg-negative), we identified an unequal distribution of G-to-A hypermutations across the genome. Our data indicate that G-to-A hypermutation occurs predominantly in a region between nucleotide positions 600 and 1800 a region which is usually single stranded in matured HBV particles. This implies that A3 likely edits HBV in the virion. Hypermutation rates for HBeAg-negative patients were more than 10-fold higher than those of HBeAg-positive patients. For HBeAg-negative patients higher hypermutation rates were significantly associated with the degree of fibrosis. Additionally, we found that for HBeAg-positive chronic hepatitis G-to-A hypermutation rates were significantly associated with the relative prevalence of the G1764A mutation, which is related to HBeAg seroconversion. In total, our data imply an important association of hypermutation mediated by A3 deaminases with the natural progression of chronic hepatitis B infections both in terms of HBeAg seroconversion and disease progression towards cirrhosis.

HPV16 is associated with younger age in women with cervical intraepithelial neoplasia grade 2 and 3.

OBJECTIVE: To evaluate if women with HPV16 positive CIN2 and CIN3 are diagnosed at a younger age. METHODS: We conducted a population-based cohort study including more than 40,000 women having a liquid based cervical cytology sample taken as part of routine screening. HPV analysis was performed using Hybrid Capture 2 and LiPAv2. The study population was linked to the Danish Pathology Data Bank to retrieve information on subsequent cervical histology. We included HR HPV positive CIN2/3 samples, comprising 173 CIN2 and 467 CIN3 lesions. Due to a high number of multiple concurrent HPV infections, the causative HPV type was assigned to a hierarchically group. RESULTS: In CIN3, the estimated proportion of lesions positive for HPV16 was 68.1% among women aged 20 years and decreased to 38.9% among women aged 50 years. A decrease in HPV16 positivity with increasing age was also observed in CIN2. In a multinomial logistic regression analysis, young age was strongly associated with HPV16 positivity in CIN3 lesions (OR=0.46 per 10 year increase in age, 95% CI: 0.32-0.65). The proportion of HPV16 and/or 18 positive lesions among women diagnosed with CIN2 and CIN3 below 30 years of age was 44% and 75%, respectively. CONCLUSIONS: HPV16 positivity was significantly associated with younger age at diagnosis of CIN3. In a population vaccinated against HPV16 and 18, we will experience a shift to older ages in cervical precancerous lesions. These findings may imply that cervical cancer screening programs could start at an older age in HPV vaccinated populations.

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.

In situ and invasive squamous cell carcinoma of the vulva in Denmark 1978-2007-a nationwide population-based study.

OBJECTIVE: To determine the incidence of vulvar carcinoma in situ (CIS) and cancer of squamous cell (SC) origin in Denmark in the period 1978-2007. METHODS: Using the nationwide Danish Cancer Registry, we identified 980 women diagnosed with vulvar CIS 1978-2003 (67.8% were SC) and 2455 women diagnosed with vulvar cancer 1978-2007 (76.0% were SC). Analysis was restricted to vulvar CIS and cancer of SC origin. We assessed age-specific incidence rates, age-standardized incidence rates, and distribution of stage at diagnosis. Poisson regression analysis was used to estimate the average annual percentage change. RESULTS: During the study period the age-standardized incidence rate of vulvar SC CIS increased by 1.97% per year (95% CI: 0.99% to 2.96%) with a tendency toward a steeper increase among women younger than 50 years. The age-standardized incidence rate of vulvar SC cancer showed a stable or slightly increasing pattern. However, among women below 60 years of age a significantly increasing trend was observed (1.60% per year; 95% CI: 0.50% to 2.71%). The distribution in the extent of vulvar SC cancer at diagnosis showed a tendency toward a higher proportion being diagnosed with localized disease in the more recent calendar years. CONCLUSIONS: The incidence rates of vulvar SC CIS and vulvar SC cancer among women below the age of 60 years have increased since 1978. Human papillomavirus (HPV) could explain the increase and thus, the recent introduction of HPV vaccination may in the future result in a notable reduction of vulvar malignancies.

Analysis of ten Brucella genomes reveals evidence for horizontal gene transfer despite a preferred intracellular lifestyle.

The facultative intracellular bacterial pathogen Brucella infects a wide range of warm-blooded land and marine vertebrates and causes brucellosis. Currently, there are nine recognized Brucella species based on host preferences and phenotypic differences. The availability of 10 different genomes consisting of two chromosomes and representing six of the species allowed for a detailed comparison among themselves and relatives in the order Rhizobiales. Phylogenomic analysis of ortholog families shows limited divergence but distinct radiations, producing four clades as follows: Brucella abortus-Brucella melitensis, Brucella suis-Brucella canis, Brucella ovis, and Brucella ceti. In addition, Brucella phylogeny does not appear to reflect the phylogeny of Brucella species' preferred hosts. About 4.6% of protein-coding genes seem to be pseudogenes, which is a relatively large fraction. Only B. suis 1330 appears to have an intact beta-ketoadipate pathway, responsible for utilization of plant-derived compounds. In contrast, this pathway in the other species is highly pseudogenized and consistent with the "domino theory" of gene death. There are distinct shared anomalous regions (SARs) found in both chromosomes as the result of horizontal gene transfer unique to Brucella and not shared with its closest relative Ochrobactrum, a soil bacterium, suggesting their acquisition occurred in spite of a predominantly intracellular lifestyle. In particular, SAR 2-5 appears to have been acquired by Brucella after it became intracellular. The SARs contain many genes, including those involved in O-polysaccharide synthesis and type IV secretion, which if mutated or absent significantly affect the ability of Brucella to survive intracellularly in the infected host.

Alcohol consumption and the risk of self-reported perennial and seasonal allergic rhinitis in young adult women in a population-based cohort study.

BACKGROUND: Alcohol consumption has been suggested to be associated with the development of allergic rhinitis (AR), but there is limited data on the topic. OBJECTIVES: The objective of this study was to investigate the association between alcohol consumption and the risk of developing AR among young women. METHODS: Five thousand eight hundred and seventy Danish women aged 20-29 years participated in a prospective cohort study, and were free of seasonal and perennial AR at baseline (1991-1993). Alcohol consumption was assessed by a food frequency questionnaire. The main outcome measures were self-reported information on seasonal and perennial AR debuting during a mean follow-up period of 7.8 years. RESULTS: During follow-up, 831 women developed seasonal AR and 523 women developed perennial AR, corresponding to 14% and 9%. Alcohol consumption was positively associated with the risk of developing perennial AR. The adjusted odds ratio (OR) for perennial AR was 1.78 (95% CI, 1.13-2.80) among women drinking more than 14 drinks/week compared with women drinking <1 drink/week. There was no association between alcohol consumption and seasonal AR. Having one or two parents with asthma was, after adjustment, significantly associated with the risk of developing seasonal (OR, 2.01; 95% CI, 1.65-2.45) and perennial AR (OR, 2.28; 95% CI, 1.70-2.74). Smoking was not associated with an increased risk of developing AR. CONCLUSION: In this population of young adult women, alcohol consumption was associated with an increased risk of developing perennial AR.

APOBEC3 proteins and porcine endogenous retroviruses.

Xenotransplantation of porcine cells, tissues, and organs offers a solution to overcome the shortage of human donor materials. In addition to the immunological and physiological barriers, the existence of numerous porcine microorganisms including viruses poses a risk for xenozoonosis. Three classes of functional gamma-type porcine endogenous retroviruses (PERV) have been identified, whereby functional polytropic PERV-A and PERV-B infect human embryonic kidney (HEK 293) and other cell lines in vitro. In the course of risk assessment for xenotransplantation the capacity of human cells to counteract PERV infections should be analyzed. Primates and other mammals display different means of protection against viral infections. APOBEC3 proteins which are cytidine deaminases and a part of the intrinsic immunity mediate potent activity against a wide range of retroviruses including murine leukemia viruses (MLV). As PERV and MLV belong to the same genus, we raised the question as to whether PERV is affected by APOBEC3 proteins. Initial data indicate that human and porcine cytidine deaminases inhibit PERV replication, thereby possibly reducing the risk for infection of human cells by PERV as a consequence of pig-to-human xenotransplantation.

GPCRdb: the G protein-coupled receptor database - an introduction.

GPCRs make up the largest family of human membrane proteins and of drug targets. Recent advances in GPCR pharmacology and crystallography have shed new light on signal transduction, allosteric modulation and biased signalling, translating into new mechanisms and principles for drug design. The GPCR database, GPCRdb, has served the community for over 20 years and has recently been extended to include a more multidisciplinary audience. This review is intended to introduce new users to the services in GPCRdb, which meets three overall purposes: firstly, to provide reference data in an integrated, annotated and structured fashion, with a focus on sequences, structures, single-point mutations and ligand interactions. Secondly, to equip the community with a suite of web tools for swift analysis of structures, sequence similarities, receptor relationships, and ligand target profiles. Thirdly, to facilitate dissemination through interactive diagrams of, for example, receptor residue topologies, phylogenetic relationships and crystal structure statistics. Herein, these services are described for the first time; visitors and guides are provided with good practices for their utilization. Finally, we describe complementary databases cross-referenced by GPCRdb and web servers with corresponding functionality.

Draft Genomes for Eight Burkholderia mallei Isolates from Turkey.

Burkholderia mallei, the etiologic agent of glanders, is a Gram-negative, nonmotile, facultative intracellular pathogen. Although glanders has been eradicated from many parts of the world, the threat of B. mallei being used as a weapon is very real. Here we present draft genome assemblies of 8 Burkholderia mallei strains that were isolated in Turkey.

Neurophysiologic correlates of organic acidemias: a survey of 107 patients.

The files of 107 patients with 19 different types of organic acidemia were reviewed retrospectively. Approximately 50% of the patients had abnormal electroencephalogram (EEG) at the time of initial study. In patients who had serial studies, the EEG deteriorated in 38% and improved in 15%. The predominant EEG abnormality encountered was slowing of the background activity in various degrees. Focal or generalized paroxysmal activity occurring in conjunction with slow background activity indicated a poor prognosis. Brainstem auditory evoked potentials (BAEP), visual evoked potentials (VEP), and somatosensory evoked potentials (SEP) were analyzed. The VEP was abnormal in 44%, BAEP in 39%, and SEP in 29% of the patients. Given the magnitude and frequency by which neurophysiological abnormalities occur in organic acidemias, neurophysiology testing provides complementary functional information and has an important place in the clinical work-up of these diseases.

Whole-Genome Yersinia sp. Assemblies from 10 Diverse Strains.

Yersinia spp. are animal pathogens, some of which cause human disease. We sequenced 10 Yersinia isolates (from six species: Yersinia enterocolitica, Y. fredericksenii, Y. kristensenii, Y. pestis, Y. pseudotuberculosis, and Y. ruckeri) to high-quality draft or complete status. The genomes range in size from 3.77 to 4.94 Mbp.

Twenty Whole-Genome Bacillus sp. Assemblies.

Bacilli are genetically and physiologically diverse, ranging from innocuous to highly pathogenic. Here, we present annotated genome assemblies for 20 strains belonging to Bacillus anthracis, B. atrophaeus, B. cereus, B. licheniformis, B. macerans, B. megaterium, B. mycoides, and B. subtilis.

Draft Genome Assembly of Bordetella bronchiseptica ATCC 10580, a Historical Canine Clinical Isolate.

We present the scaffolded genome of Bordetella bronchiseptica ATCC 10580, assembled into 98 contigs. This 5.1-Mb assembly (68.2% G+C content) contains 4,870 coding regions. The strain was originally isolated from canine lung tissue and is used in quality control testing.

Complete Genome Assembly of a Quality Control Reference Isolate, Moraxella catarrhalis Strain ATCC 25240.

Generally an opportunistic pathogen in the United States, Moraxella catarrhalis has acquired resistance to multiple antibacterial/antimicrobial agents. Here, we present the complete 1.9-Mb genome of M. catarrhalis strain ATCC 25240, as deposited in NCBI under the accession number CP008804.

Whole-genome assemblies of 56 burkholderia species.

Burkholderia is a genus of betaproteobacteria that includes three notable human pathogens: B. cepacia, B. pseudomallei, and B. mallei. While B. pseudomallei and B. mallei are considered potential biowarfare agents, B. cepacia infections are largely limited to cystic fibrosis patients. Here, we present 56 Burkholderia genomes from 8 distinct species.

Multiple-type human papillomavirus infection in younger uncircumcised men.

A cohort of 388 young men enrolled for military service in the Danish army was established and the participants underwent a clinical examination with human papillomavirus (HPV) testing. In addition, a questionnaire containing questions regarding sociodemographic variables, sexual habits and lifestyle factors was completed. The prevalence of HPV was 33.4% in this cohort of uncircumcised men aged 18-29 years. Multiple HPV types were prevalent with one-third of the HPV-positive men being positive for more than one HPV type. Number of recent sexual partners and infrequent condom use were strong risk factors, particularly in men having multiple HPV types. Our findings re-emphasize the importance of sexual transmission and also point to a role of factors that may be related to individual susceptibility as genital warts, alcohol intake and, to a lesser extent, smoking were strongly associated with having multiple HPV types.

Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants.

OBJECTIVE: To assess the occurrence of spontaneous abortion, comparing two different data sources. To estimate the rate of spontaneous abortion over a 2-year period, and examine potential predictors of the risk for incident spontaneous abortion. METHODS: We used interview data from a population-based prospective cohort study comprising 11,088 women and data from a linkage of the cohort with the Hospital Discharge Register to compare spontaneous abortions as reported in the interview with those identified in the register. Based on interview data, we estimated the rate of spontaneous abortion during the two-year follow-up. Finally, risk determinants for incident spontaneous abortion were analyzed by means of logistic regression. RESULTS: A total of 654 spontaneous abortions before enrolment in the study were reported by the women compared to 531 abortions found in the register. More than 80% of the spontaneous abortions identified from both sources were recorded in the same year. During follow-up a total of 20.9% of pregnancies intended to be carried to term ended as a spontaneous abortion. In the risk factor analysis, we found that previous spontaneous abortion, being single, never having used oral contraceptives, and use of intrauterine device were associated with increased risk of subsequent spontaneous abortion. In addition, it was indicated that a short interpregnancy interval following a spontaneous abortion may confer an increased risk of abortion in the subsequent pregnancy. CONCLUSION: We found a high rate of spontaneous abortion in the present study and an acceptable agreement between information obtained by interview and register information. More than 25% of the spontaneous abortions were only reported by the women, and this could not be explained by erroneously reported induced abortions, and may be early, nonhospitalized abortions. We confirm that number of previous spontaneous abortions is a strong determinant, and our data may also indicate a role of previous contraceptive habits. A role of the length of interpregnancy interval in the risk of spontaneous abortion cannot be ruled out.

Murine leukemia virus recombinants that use phosphate transporters for cell entry induce similar spongiform encephalomyelopathies in newborn mice.

Amphotropic Moloney-murine leukemia virus recombinants (Mo-AmphoV) induce a severe spongiform encephalomyelopathy in newborn mice. We show here that a coisogenic recombinant with a 10A1-MuLV host range (Mo-10A1V) also induces a neurodegenerative disease, clinically characterized by mild tremor and ataxia. Spongiform lesions are most severe in the metencephalon and mesencephalon but extend into the prosencephalon and spinal cord. Significantly, the quality of histopathology was indistinguishable between Mo-AmphoV and Mo-10A1V, probably reflecting a final common pathogenic pathway. Common receptor use thus may be an important determinant in the pathogenicity of these viruses. These results have implications for the clinical use of retroviral pseudotypes that use phosphate transporters for cell entry.