Introns, as important vectors of biological functions, can influence many stages of mRNA metabolism. However, in recent research, post-spliced introns are rarely considered. In this study, the optimal matched regions between introns and their mRNAs in nine model organism genomes were investigated with improved Smith–Waterman local alignment software. Our results showed that the distributions of mRNA optimal matched frequencies were highly consistent or universal. There are optimal matched frequency peaks in the UTR regions, which are obvious, especially in the 3′-UTR. The matched frequencies are relatively low in the CDS regions of the mRNA. The distributions of the optimal matched frequencies around the functional sites are also remarkably changed. The centers of the GC content distributions for different sequences are different. The matched rate distributions are highly consistent and are located mainly between 60% and 80%. The most probable value of the optimal matched segments is about 20 bp for lower eukaryotes and 30 bp for higher eukaryotes. These results show that there are abundant functional units in the introns, and these functional units are correlated structurally with all kinds of sequences of mRNA. The interaction between the post-spliced introns and their corresponding mRNAs may play a key role in gene expression. In this dataset, the genes that contain more than one mRNA were excluded first. Next, the genes that contain ncRNAs and/or repetitive elements were excluded. Last, introns with lengths shorter than 40 bp were also excluded. The results of the dataset are shown in Genes from nine model organism genomes were selected as our dataset. They are http://mobyle.pasteur.fr/cgi-bin/). In the alignment process, the EDNAFULL matrix was used for calculating the optimal matched segments with the following parameters: 50.0 for the gap penalty and 5.0 for extend penalty. In this way, the most credible optimal matched segment of the tested sequence and its aligned sequence were obtained. The local alignment sketch map is shown in The interaction between introns and their mRNAs was represented by optimal matched segments. The interaction probability was determined by the quality of the optimal matched segments. The mRNAs were renamed as tested sequences, while their corresponding introns were aligned sequences. To obtain the matched alignment segments, introns were transformed into their complementary sequences, and similar alignments were performed using improved Smith–Waterman local alignment software , L means the length of the tested sequence, and Ns and Ne mean the start base site and the end base site of the optimal matched segment in the tested sequence, respectively. The effective value 1 is assigned to each base site within the optimal matched segment, while the ineffective value 0 is assigned to the base sites outside the optimal matched segment. The matched score values are assigned to each base site in the tested sequences.For the tested sequence, the matched score function F is defined by Eq. m means the number of the tested sequences, i means the ith tested sequence , j means the jth base site of the ith tested sequence , Li means the length of the ith tested sequence, and fij means the matched score function of the jth base site of the ith tested sequence. F is a relative matched value at the jth base site in m tested sequences. It reflects the interacting probability or the interaction intensity between the tested and aligned sequences in the jth base site.For the tested sequences, matched frequency F> for each base site is also defined by Eq. i means the ith tested sequence , li is the length of the optimal matched segment for the ith tested sequence, and Li is the length of the ith tested sequence. The <F> indicates the average matched frequency of the m tested sequences.The average matched frequency <RF of the jth base site in the tested sequence is defined by Eq. RF reflects the relative bias of each base site in the tested sequences. If RF > 1, it indicates that the interaction in the jth base site is positive in the tested sequence, and the regions with RF > 1 were optimal matched regions. RF = 1 represents an average matched frequency of the base sites for the tested sequences.The relative matched frequency RF or F distributions are obtained in the same way. When the RF values in the optimal matched regions of the mRNA all are higher than the CC-random sequences and average matched frequency <F>, we call these cases positive tests.To test the significance of our results, we constructed corresponding component constraint random sequences for comparison with real sequences. Component constraint random sequences mean the length and contents of A, C, G, and U are the same as the analyzed sequence, but the order of each base is random. We call them CC-random sequences. The sample of the corresponding component constraint random sequences is 10 times as many as the analyzed sequences, and then the corresponding RF or F by the following method.Due to the different lengths of the tested sequences, they are normalized to 100 to obtain the relative site distributions of nij is the jth relative site of the ith normalized tested sequence; the nij is obtained by the following formulation:Nij means the jth base site of the ith tested sequence, and Li is the length of ith tested sequence . The square brackets are Gaussian integer functions which are meant to take the integer part of a real number. Then, the m tested sequences with different lengths are normalized to 100. In addition, nis, nie, nie- nis+1, nij and 100 are used to replace Nis, Nie, li, Nij and Li in the formulation (1), (2), (3) and (4) respectively, the normalized relative matching frequency function RF or matching frequency function F distribution can be obtained.We hypothesized that D2 is a suitable parameter to describe the sequence characters; its definition is shown in Eq. Information entropy conception was used to analyze the characters of sequence composition. Second-order informational redundancy D2 is defined aspi or pj is the probability of the base i or j , and pij is the joint probability of the base pair ij. D2 reflects the adjacent base correlation of sequences  of D2 is D2(f.b.) = 15.65/N , the junction sites between the last exon with the penultimate exon (the last exon junction site), and the junctions in the middle exon (the middle exon junction site). The results are shown in Analytically, the distribution of optimal matched frequency of translation initiation sites of the nine model organisms is revealed to be of high consistency, that is, these model species show good universality for the distributions. The matched frequencies bounded by the translation initiation sites on the sequences near the translation initiation site are significantly altered, it is specifically manifested in the relative matched frequencies of the UTR on the left side of the translation initiation site, and the corresponding intron is generally higher. There is an excellent agreement between their distribution of optimal matched regions and the 5′-end of the mRNA. When comparing short introns, the distribution of their optimal matched region is consistent with that of long introns. Large differences in the distribution of optimal matched regions are observed in the short introns, but some distributions are very peculiar in that they may be significant and deserve to be studied in depth.C. elegans, the optimal matched regions between the flanks of the translation initiation site of mRNA and its corresponding introns are mainly located in the range of about −30 to 10 bp, and the peak value is about 1.4. The optimal matched regions of D. melanogaster are mainly located in the range of about −30 to 5 bp, and the peak value is about 2.0. The optimal matched regions of A. thaliana are mainly located in the range of about −30 to 10 bp, and the peak value is about 1.5. The optimal matched regions of A. mellifera are mainly located at about −10 bp, and the peak value is about 2.0. The optimal matched regions of A. gambiae are mainly located in the left range of about −30 to 5 bp, and the peak value is about 1.9. The optimal matched regions of O. sativa are mainly located at about −20 bp, and the peak value is about 1.2. The optimal matched regions of D. rerio are mainly located in the left range of about −30 bp, and the peak value is about 1.0. There is no distinctly optimal matched region for M. musculus. The optimal matched regions of H. sapiens are mainly located in the range of about −45 to −10 bp, and the peak value is about 1.3. These facts demonstrate that introns do interact with the translation initiation sites flanking their corresponding mRNAs.The distribution of the peak regions and peak value are slightly different despite having very similar distributions of optimal matched regions on the flanks of the translation initiation sites of the nine model organisms see . For C. Analytically, the distribution of optimal matched frequency of translation termination sites of the nine model organisms is revealed to be alike, that is, these model species show good universality for this distribution. The matched frequencies bounded by the translation termination sites are significantly altered; it is specifically manifested in the relative matched frequencies of the UTR on the right side of the translation termination sites, where it is generally higher. There is an excellent agreement between their distribution of optimal matched regions and the 3′-end of the mRNA. When comparing short introns, the distribution of their optimal matched region is consistent with that of long introns. Large differences in the distribution of optimal matched regions are observed in the short introns, but some distributions are very peculiar in that they may be significant and deserve to be studied in depth.C. elegans mRNA and their corresponding introns are mainly located in the right range of about −20 bp, and the peak value is about 4.5. The optimal matched regions of D. melanogaster are mainly located in the right range of about −10 bp, and the peak value is about 3.3. The optimal matched regions of A. thaliana are mainly located in the right range of about −20 bp, and the peak value is about 1.8. The optimal matched regions of A. mellifera are mainly located in the right range of about −20 bp, and the peak value is about 4.6. The optimal matched regions of A. gambiae are mainly located in the right range of about −15 bp, and the peak value is about 1.8. The optimal matched regions of O. sativa are mainly located in the range of about −30–60 bp, and the peak value is about 1.6. The optimal matched regions of D. rerio are mainly located in the right range of about −18 bp, and the peak value is about 2.6. The optimal matched regions of M. musculus are mainly located in the right range of about −10 bp, and the peak value is about 1.5. The optimal matched regions of H. sapiens are mainly located in the right range of about 16 bp, and the peak value is about 1.8. These facts demonstrate that introns do interact with the translation termination sites flanked by their corresponding mRNAs.The distribution of the peak regions and peak value are slightly different despite being very similar for the distribution of optimal matched regions on the flanks of the translation termination sites of the nine model organisms . The optThe distribution of the optimal matched regions around the first exon junction sites, the last exon junction sites, and the middle junction sites of the nine model organisms is detected to be alike after analysis, that is, these model species show good universality for this distribution. It is specifically manifested in the generally low relative matched frequencies of the junction flanked by the first exon with the corresponding introns , the lasD2 of the optimal matched segment, CDS, 3′-UTR, and 5′-UTR are analyzed, and the correlation between these sequences is discussed. The results are shown in The UTR regions of the mRNA preferentially interact with the introns, while the CDS regions of the mRNA are poorly matched to the introns. This is probably why the sequence features of the optimal matched segments are similar to the UTR features. GC content and second-order information redundancy The distributions in C. elegans, D. melanogaster, A. thaliana, A. gambiae, A. mellifera, D. rerio, and H. sapiens increased gradually. The average GC content of the optimal matched segments, 3′-UTR, CDS, and 5′-UTR in O. sativa and M. musculus increased gradually. It is an interesting case that there are two clear peaks in the average GC content distributions of the optimal matched segments for A. gambiae, M. musculus, and H. sapiens, and these results show that there are abundant functional units in the introns. Based on the GC content analysis results of the above sequences, similar GC content values may lead to the mRNA UTR preference for intron interaction, except for O. sativa and M. musculus.There are significant differences in the distribution center of the GC content in different sequences; however, the GC content of the optimal matched segments shows a special distribution pattern. In addition to having the lowest distribution center when compared to the other three types, the GC content distribution also has a very broad distribution range that almost completely encloses the distribution of the other sequences. It is shown that interactions between introns and mRNAare primarily based on weak bond binding, i.e., AT matching, but that high GC matching canalso occur. The average GC content of the optimal matched segments of introns in the nine model organisms is the closest to that of the 3′-UTR. The average GC content of the optimal matched segments, 3′-UTR, 5′-UTR, and CDS of D2 are shown in The intron of each gene is connected with the optimal matched segments of the mRNA, CDS, 3′-UTR (which includes 50 bp downstream of the translation initiation site), and 5′-UTR (which includes 50 bp upstream of the translation termination site) in a new line in sequence and are denoted as the optimal matched segments of the intron, CDS, 3′-UTR, and 5′-UTR. The results of the second-order information redundancy 2 values in 2 values are the closest to those of the optimal matched intron segments in the nine model species. This agrees with the GC content of the optimal matched intron segments. This is one of the reasons why there are optimal matched frequent peaks in the regions of UTR, which is obvious, especially in the 3′-UTR.By comparing the DH. sapiens) were analyzed. It was observed that the distribution of optimal matched frequencies in the mRNA sequence showed high consistency or universality among the nine model organisms. A peak distribution appeared in the untranslated regions (UTRs) of the mRNA, especially in the 3′-UTR, and the matched frequency in the coding sequence (CDS) was relatively low. It was discovered that introns, particularly the 3′-UTR, have a high preference for interacting with the UTR region of the mRNA. The function of the introns after splicing could be related to NMD. The matched frequencies bounded by functional sites in the sequences near the translation initiation site and translation termination site were different significantly, and the matched frequency of the junction region of the exon was relatively low. The distribution centers of the GC content in different sequences were different, but the GC content in the optimal matched segments showed a special distribution pattern. In addition to having a lower distribution center than the other three types, the GC content also had a very broad distribution range that almost completely enclosed the distribution of the other sequences. The results showed that the interactions between the introns and mRNAs were mainly dominated by weak bond binding, that is, not only AT matching but also in juggling high GC matching. In all nine species, a high degree of concordance of the distribution of the matched rate of the optimal matched segments was observed, primarily falling between 60% and 80%. In lower eukaryotes and higher eukaryotes, the most probable value of the optimal matched segment length distribution is around 20 bp and around 30 bp, respectively. These conclusions are in line with the results obtained in the ribonucleoprotein genes. Some peaks of the distribution of matched frequency are conserved for all organisms, and the results reveal the inherent mechanisms of the optimal matched segment composition.At the genome-wide level, the optimal matched regions of the introns and their corresponding mRNAs for protein-coding genes in nine model organisms (such as


The oncogenic potential of human papillomavirus (HPV) may be used to determine the tissue tropism of each HPV type. Cervical cancer develops in the squamo-columar junction of the cervices, and most lesions are induced by high-risk (HR) HPV types. This suggests that HR types preferentially infect the cervix, whereas the preferential infection site for low-risk (LR) types is not well defined. The determination of HPV tropism when using cytology samples can be uncertain since it is difficult to avoid contamination of cell samples between the cervix and the vagina. Herein, cell samples were carefully collected by independently scraping the cervix and vagina, after which the HPV types were determined. HPV tissue tropism was determined by considering what HPV types were positive at only one of the sites (the cervix or the vagina) as the viruses that preferentially infected that site. This method revealed that all LR types were only identified in vaginal samples, whereas 87% of HR types were identified in cervical sites. Thus, LR types may preferentially infect the vagina, whereas HR types infect the cervix. These findings suggest that preferential tissue tropism of certain HPV types is a probable factor for malignant progression. Approximately 50 human papillomavirus (HPV) types have so far been identified in the mucosal epithelium of the uterine cervix, vagina, and vulva . Of thesAnother mechanism for these differences in carcinogenicity may be tissue tropism ,12. MostTherefore, this study sought to define the HPV types that preferentially infect cervical or vaginal tissues by eliminating cross-contamination between sites from HPV genotyping results of cytology samples from the cervix, upper vaginal, and lower vaginal tissues. Our results support the hypothesis that LR types preferentially infect vaginal tissue and that HR types preferentially infect cervical tissue, while pHR types do not display a tissue preference.The prevalence and exact 95% CIs of HPV types in the cervical and vaginal (upper or lower) samples from the 264 HPV-positive cases are shown in 2(2) = 52.612, p < 0.01). HR types were significantly more common in the cervix than in the vagina, with 87% preferentially infecting the cervix (p < 0.01). HR types were 6.7-fold more common in the cervix than in the vagina. All LR types preferentially infected the vagina (p < 0.01). The prevalence of pHR types was comparable between the cervix and the vagina. A strong and significant association with the α phylogenetic group was also found (χ2(4) = 47.375, p < 0.01). The α-5 and α-9 phylogenetic groups preferentially infected the cervix over the vagina, 91.7% (p < 0.05) and 86.8% (p < 0.01), respectively. The α-5 and α-9 phylogenetic groups were 11.0- and 6.6-fold more frequent in the cervix than in the vagina, respectively. The α-11/α-1/α-8/α-10/α-13/α-3/α-15 phylogenetic groups all preferentially infected the vagina (p < 0.01).All HPV types detected in the 86 patients with inconsistent HPV type results between cervical and vaginal samples are shown in Because a cervical abrasion sample used for cervical cancer screening is often assumed to contain only cervical cells, assuming that LR types preferentially infect the vagina and HR types preferentially infect the cervix, the colocalization rates (including possible contamination) of different HPV risk groups in 178 cervical and vaginal samples with HPV-type concordance in each sample are shown in Herein, we used a highly sensitive HPV polymerase chain reaction (PCR) method to study HPV tissue tropism in cell samples from the cervix and vagina. Our results suggest that the LR and HR types have a significant preference for vaginal and cervical epithelium, respectively, while the pHR type displays no tissue preference. This study strongly supports the hypothesis that mucosal HPVs have tropism for specific sites within the lower genital tract.Prior studies of HPV tropism compared women with hysterectomies to those without ,16 and wWe consider that our results differ in part from those of previous studies because we eliminated contamination by vaginal cells in the cervical samples and by cervical cells in the vaginal samples to the extent possible. Thus, the HPV detection results at the three sites showed that the identified HPV types were almost identical. The only way to reveal HPV preference in this situation is to identify HPV types that are uncommon in each sample. We believe that this method of tropism analysis is why we can clarify the tissue susceptibility of each risk group.Tropism is accepted as a preference for a particular anatomical site and is not considered to be directly related to the development of cancer at that site ,12. ThisBecause the genotypes of pHR HPVs have a low prevalence in patients with cervical cancer, consensus has not emerged to classify these HPVs as HR types . The lowA cervical abrasion sample used for cervical cancer screening is often assumed to contain only cervical cells. However, assuming that LR types preferentially infect the vagina, our colocalization analysis revealed that approximately 30% of cervical specimens contained a mixture of LR type-infected cells of vaginal origin. In cervical cancer screening, a preclinical cervical infection is often determined when the Hybrid Capture II (HC) assay is positive and the biopsy is negative . AlthougThis study had some limitations. First, our statistics and inferences were restricted by the limited number of samples included in this study. Furthermore, this study only speculated on the tropism of HPV for the cervix and vagina based on HPV genotyping using cell samples obtained from a small population of women. In addition, our selection criteria for this study may have biased our findings. Unfortunately, this study did not have accurate HPV type data for the biopsied tissues, and we could not assess whether each HPV risk group truly exhibited tropism for each tissue. Nonetheless, given that similar results were obtained in studies using paired scraped cervical and vaginal samples, further research is warranted because additional data could further clarify HPV tropism and the development of cervical and vaginal lesions.A total of 324 randomly selected patients who had been referred for colposcopy because of abnormalities identified during cervical cytologic screening at Tokyo Genki Plaza Health Medical Center from 2020 to 2021 were enrolled in the study. Three types of SurePath™  liquid-based cytology (LBC) were used to collect samples from the cervix and the upper and lower vaginal tissues of the patients.Immediately before colposcopic assessment, a vaginal speculum was used to expose the cervix of each patient, and then the endocervix and portio vaginalis were scraped using an IM sampler instrument  consisting of a spatula and brush and eluted into a collection vial, which was used as the cervical sample. Then, while holding the vaginal speculum open, the bilateral portions from the vaginal vestibule to the upper half of the vaginal canal were scraped with a spatula and collected as the upper vaginal sample, and cells from the lower half of the vaginal canal were collected in the same manner as the lower vaginal sample. Samples were collected after obtaining written informed consent from the patients. The Ethics Committee on Human Research of Kyorin University approved the study protocol, which was implemented in accordance with the approved guidelines. Patients who were negative for HPV in three different samples were excluded, and consequently, 264 patients who were positive for any HPV type in any of the samples were evaluated . The patDNA was isolated from the cell pellet of each LBC sample using the hot sodium hydroxide method . Cell pePrevalence estimates and exact 95% CIs were calculated for each individual HPV type, HPV risk group, and α phylogenetic group detected in cervical, upper vaginal, and lower vaginal samples from 264 patients, and HPV types that preferred the cervix or vagina were then evaluated from the individual HPV types detected in the 86 patients with inconsistent HPV types in the vaginal (upper and lower) samples versus the cervical samples. HPV types detected in only one of the samples were identified as the HPV types that preferentially infected that site. For example, if HPV56 and HPV62 were positive in the cervical sample and only HPV62 was positive in the vaginal upper or lower samples, HPV62 was considered to be a virus that had migrated from one site and contaminated the other; HPV56 was identified as the only virus that preferentially infected the cervix. Differences in the prevalence of each HPV type were compared by using a z test for the difference between two proportions with Bonferroni adjustment for multiple comparisons using Statistical Package for the Social Sciences version 25.0 . Furthermore, we investigated the colocalization rate, including possible contamination of HPV types with vaginal tropism in the cervical samples and with cervical tropism in the vaginal samples based on the results of tropism analysis.This study evaluated HPV tissue tropism and eliminated cross-contamination of HPV genotyping results using cervical and vaginal cytology samples. The results emphasize that LR types preferentially infect vaginal tissue, while HR types preferentially infect cervical tissue. Thus, preferential tissue tropism of certain HPV types is a probable factor for malignant progression.


Objective To reveal the changes in the quality of life reported by women with Human papillomavirus (HPV)-induced lesions.Methods This is a cross-sectional, descriptive-exploratory study of a qualitative approach performed from June to August 2016. Semi-structured face-to-face interviews based on five questions on the concept of quality of life were used. The data were submitted to thematic analysis. All ethical aspects have been contemplated.Results A total of 20 women aged between 25 and 59 years old were interviewed. From the analysis of the data, the following thematic units emerged: physical and emotional changes, especially complaints of pruritus, discharge and pain, worry, fear, shame and sadness; changes in sexual and affective relationships with decreased libido, dyspareunia and interruption of sexual activity; changes in social relationships resulting in absenteeism at work.Conclusion Human papillomavirus infection impairs the quality of life of women as it significantly affects sexual, affective, physical, emotional, and everyday habits. Therefore, HPV infection can lead to exponential changes in the quality of life of women, which can be mitigated by the availability of sources of support such as family, friends and the multi-professional team, helping to improve knowledge and cope with HPV. Human papillomavirus (HPV) is a group of 226 viruses cataloged by the International Human Papillomavirus (HPV) Reference Center, in which each type of this large group receives a number. Only 13 types are evaluated as oncogenic because they present a greater probability or risk of generating persistent infections and precursor lesions. They usually do not have symptoms and are spontaneously eliminated by the organism.The Information Center on HPV and Cervical Cancer (ICO) estimated that there were ∼ 5,880,000 HPV-infected people in the world in 2017 and 2,784,000 women > 15 years old.Although HPV has the ability to infect the epithelium of both genders, the damage done to women is greater and more frequent. According to the Centers for Disease Control and Prevention (CDC), HPV-related cancers are not commonly found in men, with HPV infection being the most common sexually transmitted infection (STI).The social and economic inequalities experienced by women with HPV infection have several consequences related to stigma and prejudice, impacting their family, social, affective and sexual relationships.“the individual's perception of their position in life in the culture and value system context in which they live and in relation to their goals, expectations, standards, and concerns.”The World Health Organization (WHO) Quality of Life Group defines quality of life as Therefore, evaluating the quality of life of women with HPV infection is an important tool for the development of interventions regarding their physical, psychosocial and economic impact.In addition, the broad concept of quality of life proposed by Fayers et alThis is a cross-sectional, descriptive-exploratory, qualitative study performed from June to August 2016 in an outpatient clinic of a public hospital in the interior of the state of São Paulo, Brazil, specializing in infectious diseases in gynecology.To obtain a heterogeneous sample, the participants in the study were women aged ≥ 18 years old with a proven diagnosis of HPV infection with clinical lesions (condylomatosis) and subclinical lesions. The diagnosis was made through clinical examination and biopsies with histopathological examination. In the cases of subclinical lesions of cervical intraepithelial neoplasia II and III, the diagnosis was made through pap smears (cytopathology), colposcopy and biopsies. For subclinical lesions, vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia, the diagnosis was made through clinical examination and biopsies with a histopathological examination.The determination of the presence of the viral DNA HPV in the samples of biopsies collected was performed through the molecular diagnostic technique with the polymerase chain reaction (PCR) method. Polymerase chain reaction is one of the most sensitive and commonly used techniques for detecting HPV.Those with coinfection by the human immunodeficiency virus, considered a confounding factor, were excluded. The selection of the women was a matter of convenience, selecting those who came to the clinic on the day of the scheduled medical appointment.To evaluate the quality of life, the data were collected through a semistructured face-to-face interview, based on five questions proposed by Fayers et alThe questions were: 1: Do you know why HPV infection happens? 2: Has there been any change in your sex life after the diagnosis of HPV?; 3: Has there been any change in your daily life  after the diagnosis of HPV?; 4: How do you feel about the diagnosis of HPV?; 5: Do you feel any physical discomfort related to HPV?The interviews lasted from 30 to 40 minutes. Nobody refused to participate, and none of the participants dropped out during data collection or after. The interviews were conducted in a private setting in the outpatient clinic, where only the researcher and the interviewee were present, to preserve the privacy of the participants.The number of participants was based on the precepts of theoretical data saturation, as the interviews revealed the recurrence of ideas and practices related to the object of study.For the analysis of the data, the fully transcribed interviews generated a textual corpus that was submitted to thematic analysis after an exhaustive reading of the reports.An alphanumeric code made up of the letter “E” and the arabic numeral corresponding to the sequence of the interviews was used for the identification of the participants interviewed, thereby ensuring their anonymity.All of the recommendations of Resolution 466/12 of the National Health Council were respected; therefore, the interviews were only conducted after approval of the study by the Research Ethics Committee , and all of the participants read and signed the Informed Consent Term.A total of women aged between 25 and 59 years old were interviewed. Their cultural, social and educational characteristics are described in Their diagnosis was varied, 4 women with condylomatosis (20.0%), 5 women with grade II cervical intraepithelial neoplasia (CIN) (25.0%), 7 with grade III CIN (35.0%), 2 with vulvar intraepithelial neoplasia (10.0%), and 2 with intraepithelial vaginal neoplasia (10.0%). From the data analysis, three thematic units emerged: physical and emotional changes; changes in sexual and affective relationships; changes in social relationships.The women, as participants in the study, reported physical and emotional changes in their lives related to HPV infection. In the physical changes, abdominal pain (cramps) and genitalia pain were evidenced.[…] I feel pain when I clean the house. Sometimes, when I make some effort at home I feel cramps (E2).I have pain in my “lower stomach”and when I pee (E3).[…] I feel pain in my belly […] (E15).I feel pain when I wash it  in the shower (E19).Pain is perceived while carrying out everyday activities such as housekeeping and showering. Also, the presence of pruritus (itching) was also found in the speeches of the participants.I feel itchy a lot […] (E8)[…] sometimes I feel itchy (E15).I feel itchy a lot […] it bothers me when I sit down […] (E19).Regarding the emotional changes, the testimonies of the women showed the feelings of worry, sadness, and despair regarding the diagnosis of HPV, especially when it has been discovered.[…] it seems that just thinking about “this thing” makes me worried, sad […] (E7).The day I found out, I only cried, I became very sad and worried […] (E8).I was very sad when I found out, but nowadays, I don't keep thinking about it in order not to suffer […] (E9).[…] when I discovered it, I was desperate […] (E13).[…] I was very worried and a little desperate, I feel very ashamed […] (E15).There is also a feeling of shame in relation to other people in their social life, such as their children, as they have an STI.[…] I am very ashamed […] (E3).[…] I got really bad when I found out. I kept thinking about what people would think of me (E16).After I discovered it, I didn't even leave the house anymore because I thought people knew what I had […] (E19).When I found out, I was “stuck.” I thought of my children. I was ashamed […] (E20).With emotional changes, fear became present in the life of these women with HPV, through the knowledge of the association of the virus with the risk of cancer and, consequently, the fear of death.When I discovered it, I was very scared of cancer and I was thinking that my hair would fall out and I would get thin […] (E2).[…] I thought it was very serious, I thought it was cancer and I was afraid of dying (E10).[…] I'm very scared of dying because of this… I can't die because I have two daughters to raise (E1).Changes in the sexual and affective relationships of the women related to HPV were reported. The speeches show the loss of desire of the women and feeling of embarrassment of having sex after the HPV diagnosis.[…] I have less desire to have sex […] (E1).[…] I have almost no intercourse with my husband because I no longer have any desire (E8).[…] now I have less desire […] (E15).At the beginning of the treatment, I had no desire to have intercourse […] (E16).At first, I felt very ashamed and didn't feel like doing anything, and it continued and we finished […] (E19).The sensation and fear of pain, discomfort, and bleeding during sexual intercourse was reported several times, also negatively influencing having sex.[…] I'm afraid of it hurting. Because sometimes, depending on the position, it hurts. I feel a lot of pain during sex […] (E2).[…] In the beginning, it hurt a lot to have intercourse. […] I feel pain during intercourse, and it bothers me (E3).[…] I only feel pain when I have sex […] (E7).[…] I was afraid of it hurting […] (E10).[…] sometimes, it bleeds during sex […] (E11).[…] sometimes, when I have intercourse, it bleeds […] (E15).Interruption of sexual activities correlating with HPV infection was also evidenced.[…] Since I discovered that I had this, 4 years ago, I have not had sex again (E6).[…] After the doctor discovered it here, I did not have sex until the day I had the laser (E12).Also, as a consequence of the changes in sexual life, conjugal problems emerged. Dyspareunia and decreased libido are corroborating conditions for this situation.[…] My husband always complains because I feel a lot of pain […] (E1).I almost have no intercourse with my husband anymore because I don't want to, and he always gets angry about it […] (E8).The risk of infidelity and the mistrust of the partner were also highlighted by several women as a conflictive situation, causing wear and tear in the affective relationship.[…] I get angry, you know? Because my husband always had other women, and he never caught anything! “It” never appeared in him […] (E1).[…] I don't trust my partner, and I have already quarreled a lot with him […] (E5).[…] I was very suspicious of my boyfriend, but he said it was not him because he had nothing […] (E11).[…] at first, I mistrusted him […] (E17).It is also possible to verify that condom use encouraged by the partner and the fear of infertility also affected the affective relationships.[…] I never used condoms because my husband never let me (E2).[…] When I told my husband, he didn't like it because he was afraid that I couldn't have any more children (E3).On the other hand, there were three partners (15%) who faced the situation in a positive way, offering support and strengthening the affective relationship.[…] in the beginning, my husband thought that I didn't want to have intercourse, but now he understands the situation […] (E10).[…] I told my husband and he faced it very well […] (E13).The relationship between me and my husband remains the same […] (E15).The changes in social relationships included two antagonistic situations. Most of the interviewees affirmed that they maintained normal social activities, even with HPV infection.[…] I don't stop going out because of this disease […] (E2).[…] no, nothing has changed in my daily life […] (E4).However, some women reported lack of motivation to enjoy social activities after the diagnosis of HPV.[…] after I found out (HPV), I didn't even leave the house because I thought people knew what I had […] (E19).Also, HPV infection and its treatment had an impact on women's professional lives, mainly in terms of work-related absenteeism, leading in some cases to them losing their job.[…] I always miss work so I came here […] (E3).[…] I have had to miss my work on many occasions to come here (E6).[…] I lost my job because I always needed to be absent so I came here (E20).To face this difficulty, participant E10 reported the strategy used to not have a change in professional life.[…] There was no change in what I do because I work (I'm a cleaner), but I come here the day I can be absent from my work […] (E10).When women face the fact that they have HPV infection, they go through different situations that change their daily life by having to face the peculiarities of the diagnosis and to adapt to this new reality.In the present study, it was possible to verify physical changes such as pain and pruritus caused by HPV infection. However, most HPV infections are asymptomatic or not apparent and are transient, and may spontaneously disappear. It is estimated that in only 5% of infected people will there be some form of manifestation. However, as the disease progresses, precursor lesions or early-stage cancer may result in vaginal bleeding, discharge, and pain.The emotional aspect was also affected as a result of the infection caused by HPV. The positive diagnosis of an STI brings about feelings such as sadness, confusion, fear, fear of being judged, malaise, family contempt, partner anger, and bargaining behavior.Corroborating the results found in the present study, an investigation performed to assess the psychosocial burden and impact on the quality of life of HPV-related diseases observed a significant psychosocial impact in women.In a study designed to assess the prevalence of shame in women diagnosed with HPV/CIN, these women had a substantially higher state of shame than women diagnosed with another STI.Concerning feelings of fear of cancer and death, similar findings have been reported in studies involving women with HPV.In terms of sexual and affective aspects, the study by Dominiak-Felden et alCorroborating with the findings, a study conducted in Fortaleza, state of Ceará, Brazil, with 100 women diagnosed with HPV infection showed that 55.5% of the women stated there was a decrease in libido; also, 60.0% reported a decrease in the frequency of intercourse, and 37.8% reported sexual abstinence.Regarding the complaints of dyspareunia and leucorrhea, an investigation performed in Ecuador found an association between exposure to HPV infection and the presence of whitish vaginal secretion and dyspareunia.Thus, one of the most significant characteristics found in women diagnosed with HPV is the genital change, which may not only cause pain and bleeding in sexual intercourse but also shame and embarrassment, which could lead to marital problems.Thus, legitimating the findings of the present study, the distrust and the risk of infidelity were also pointed out by Jeng et alIn terms of the non-use of condoms, a similar result was found in a Brazilian study involving 977 women diagnosed with HPV infection in which it was possible to verify that the non-use of protection methods in stable relationships suggests an excessive confidence in the affective partner.However, the risk of cervical cancer and the fear of infertility are real concerns, especially in the lives of women with HPV infection, as described in a multicenter study in China.Despite the strengthening of affective-sexual relationships being a threat to the use of protection methods, these relationships are an important source of emotional support when there are fears of infection, and they also give practical support, helping in domestic activities or accompanying the patient to medical consultations.Regarding the social relationships changes, although most of the participants in the present study have normal social activities, and the lack of motivation to enjoy social activities and absenteeism at work with risk of layoffs are reported, corroborating with other studies.The HPV-related stigma added to misinformation leads to isolation through fear of disclosure of the diagnosis and negative self-image compared with other people.Regarding the social changes, similar aspects were revealed in a study developed in Ethiopia, in which the number of days of being absent from work for outpatient follow-up or hospitalization were quantified, with frequent absenteeism threatening the maintenance of employment.In this sense, considering the changes related to living with HPV infection, the importance of support networks can be seen. A study performed in Mexico pointed out that informal networks such as family and friends, and formal networks such as churches, support groups, and medical professionals and their guidelines help people to cope with HPV infection.The present study allows changes in the quality of life of women with HPV infection to be seen and, therefore, enables the management of and intervention in situations that can significantly affect treatment.The results show that, in general, women with HPV infection face a variety of physical, emotional, affective-sexual, and social changes, modifying their quality of life. Complaints of pain, pruritus and the presence of warts, discharge and bleeding can decrease libido and negatively impact self-image, influencing affective-sexual relationships. Human papillomavirus-related stigma and shame at the diagnosis lead to the loss of motivation of social activities, and absences from work for outpatient follow-up increase the fear of disclosure, as well as being a risk for future dismissals. Therefore, HPV infection can lead to exponential changes in the quality of life of women and can be mitigated by the availability of sources of support such as family, friends and the multi-professional team, helping to improve knowledge and cope with HPV.


Background: Military environmental exposures and care for subsequent health concerns have been associated with institutional betrayal, or a perception on the part of veterans that the US government has failed to adequately prevent, acknowledge, and treat these conditions and in doing so has betrayed its promise to veterans. Institutional courage is a term developed to describe organizations that proactively protect and care for their members. While institutional courage may be useful in mitigating institutional betrayal, there is a lack of definitions of institutional courage in healthcare from the patient perspective. Methods: Using qualitative methods, we sought to explore the notions of institutional betrayal and institutional courage among veterans exposed to airborne hazards  to inform and improve clinical practice. We performed initial interviews and follow-up interviews with veterans. Results: Veterans’ depictions of courageous institutions contained key themes of being accountable, proactive, and mindful of unique experiences, supporting advocacy, addressing stigma related to public benefits, and offering safety. Veterans described institutional courage as including both individual-level traits and systems or organizational-level characteristics. Conclusions: Several existing VA initiatives already address many themes identified in describing courageous institutions . Other themes, especially views of public benefits and being proactive, hold particular value for building trauma-informed healthcare. Institutional betrayal, or the failure of institutions to protect or care for its members , has beeEnvironmental exposures have been known to occur in spaces where military service members live and work and have been associated with perceptions of institutional betrayal . For exaWhile deployed to the Persian Gulf region in both 1991–1992 and in the decades after September 2001, many US and allied military members experienced exposure to airborne hazards, including pollution , fine particulate matter , and fumes . AirbornPrevious work on institutional betrayal among veterans have focused on two military stressors, GWI and military sexual trauma (MST). Research documents veterans’ belief that the Department of Defense (DoD) and VA have systematically denied the existence of GWI and its connection with environmental exposures ,20. ThisDescriptions of institutional courage can direct improvements in care for veterans who have environmental exposure concerns as well as other military-based experiences of institutional betrayal  ,21,22,23The Veterans Health Administration (VHA) provides healthcare to eligible veterans of the US military. Eligibility for VA healthcare is dependent upon a variety of factors, including financial means, disability, and era of service . The hean = 8) and women (n = 5). All veterans were deployed to the Persian Gulf Region. Participants were approached by a non-clinical team member, who was previously not known to the veteran. Participants were seen clinically at the WRIISC for a comprehensive evaluation of their post-deployment health concerns, including airborne hazard exposures in the previous three years. If a project team member participated in the veteran’s clinical evaluation, they did not interview the veteran. We approached 22 veterans for interviews, expecting half to decline given the length and depth of the interviews. While no veterans explicitly declined to be interviewed, 9 did not respond to invitations to participate. Participants included veterans who identified as men  Guidelines . We first briefly summarized themes related to the veterans’ experiences with institutional betrayal, both in the military and in healthcare, to provide perspective and context for the veterans’ discussion of institutional courage. We then looked to the veteran interviews for themes related to a definition of institutional courage and characteristics of courageous institutions. In this sample of veterans living with complex health conditions related to airborne hazards and other environmental exposures, the veterans described instances of institutional betrayal both within and outside of military service. In terms of environmental exposures while in the military, the veterans described feeling that they were either not warned about exposures or given proper protective equipment. Veterans also described retaliation when reporting wrongdoing or dangerous situations. This was the experience of a veteran who reported safety concerns in their workplace:Absolutely nothing was done and after I filed a…complaint, retaliation ensued and the commander…told me that if I didn’t stop turning in safety violations that I would lose my job. And so I ended up losing my job.Participant 2.Veterans often felt as though they were lied to by the military about other exposures. For example, the government denied that they were exposed to substances they believe they were in contact with or that the government downplayed its severity. Veterans also described other experiences related to their overall military service and when seeking healthcare. For instance, one veteran described being discharged from the military under Don’t Ask Don’t Tell (DADT), the policy that did not allow open service for sexual minority service members . Another veteran was able to describe a lack of institutional courage when the military allowed unsafe conditions to continue, “they could have pulled the plug on things in some of those situations a lot sooner than they did” (Participant 12). One challenge in developing a definition of institutional courage from the data was separating out and drawing on individual acts of courage that occurred while veterans were in the military. These acts were committed by the veterans themselves and those they served with and were shaped by the critical nature of their missions. For example, one veteran described serving as a medical provider who triaged and treated hundreds of combat casualties. Other veterans described incidents in which they placed themselves in danger to protect the lives of others in their unit. Veterans’ view of institutional and/or individual courage in civilian life seems to be informed in relation to their experiences of courage in wartime.What emerged readily from the data were characteristics of courageous institutions. Veterans spoke about VA, VHA, and VBA as institutions and spoke to institutional courage in healthcare generally. Veterans described six characteristics of courageous institutions: being accountable, proactive, and mindful of unique experiences, valuing advocacy, supporting a cultural shift around social welfare, and offering safety. Veterans discussed the notion that courageous institutions have active and strong accountability for members. This was described in three ways. First, as a means of operation—having systems to hold individuals in the institution accountable. For one veteran, accountability involved consequences to actions, or “teeth in it,” for example, “you have X amount of days to respond” (Participant 3) to a patient request. Another veteran states that the organization should have “ethical intelligence” or “if someone wants to actually provide value to society—that’s the goal—they have to actively create something that has a process for checks and balances” (Participant 2). Second, accountability also seemed linked to the idea that VA should hold the government accountable for the sacrifices made by the veteran. Failure to uphold this obligation was discussed by veterans. Participant 13 felt that the VA “has ignored or denied my injuries…what I was exposed to by my own government is going to kill me, and yet the same—my own government doesn’t want to help me, either.” As Participant 8 stated, “I believe in doing what you’re told and giving your all, I did what I was expected to do. And it ended up causing me to be injured.” Veterans raised the idea that VA was a space for reparations from the past, particularly betrayal that occurred within the military. As this veteran states, the VA was the only means of recourse or repair from conditions that originated during their time in the military: I think because we’re never going to get the justice that we were looking for from our branch of service. Matter of fact, you know, anything but it. You know as soon as you get your discharge, you’re done, goodbye…it’s like they don’t want to hear from you. So all we have left is the VA.Participant 1.Another veteran described holding VA accountable for their role in repairing injuries from the military, stating that they had hoped the VA “would assist me more, would’ve actually fought for me more” (Participant 12). Similarly, participants described feeling that if the VA does not help veterans there is little help outside VA. Third, veterans saw themselves as part of this process of accountability, perhaps stepping in to fill gaps in VA and American society. Veterans saw themselves as accountable to each other and thus were an intricate part of supporting VA as an institution. This meant helping veterans navigate the system, “I do believe that all this has happened to me for a reason. So I actually see what I go through as a gift… And maybe I was meant to go through this so some other veterans won’t… So I don’t see it as a curse, I see it as a blessing” (Participant 13). This also meant reaching out to other veterans to “get my story heard, two, get other veterans to hear it and want to sign up for the burn pit registry” (Participant 17). Veterans shared a desire for VHA to be more proactive and “preventative” (Participant 7 and Participant 13) in their efforts to treat veterans for military exposure concerns. This was especially important to veterans who felt that their condition was “progressive” (Participant 9) or that their prognosis was poor. Another veteran described the feeling that had their care been more proactive when their symptoms first started, “I wouldn’t be in the pain that I’m in now” (Participant 11). One veteran noted that they wanted their provider to be “really investigating…taking the time and…[asking] what might have caused this?” in reference to their medical conditions (Participant 1). Another veteran stated, “…if you don’t do the courageous thing of standing up and being preventative…they give you monetary compensation once you’re so sick that you’re in bed all the time” (Participant 7). Similarly, “I think it would behoove the VA to be…a little bit more proactive and do workups on people instead of waiting until… people are unable to do things” (Participant 7). This included assigning veterans to primary care providers based on the “health needs of the vet” and not on the doctor’s availability (Participant 13) and specific outreach to newer cohorts of veterans:…if there was a survey that asks you, do you have this symptom, this symptom, this symptom, this symptom?…if you scored over a certain point on that system I think you should automatically be sent for certain testing.Participant 20.One Veteran stated, “I didn’t know that I was even eligible to get medical care…after I exited the service” (Participant 11) suggesting it was the VA’s responsibility to reach out and inform them of the benefits they had earned. Another veteran described a desire for VA to note lapses in care and “zero contact” from VA (Participant 1). This participant described that they had been seeing a provider who left the VA; the veteran went on to receive care outside VA but was never contacted to ask about their welfare or need for a new provider. This veteran similarly defined being proactive as “they would put more time into checking the guys” who had been exposed to combat trauma (Participant 6). Another veteran offered a concrete solution:I think every single one of us should have a caseworker, or a social worker who is calling us every 90 days. Whether you’re a healthy vet or not…somebody should be calling me every 90 days going, are you making it to your doctor’s appointments? Are you getting the doctor’s appointments you need? Do you have a safe place to live? Do you have food on your table?—Participant 12.Many veterans described the feeling that a one-size-fits-all approach to their care was a form of betrayal. For these veterans, they wanted a system that adapted to their unique needs and “accept people where they’re at and assist them to thrive where they’re at” (Participant 7). As this veteran states:Because they don’t fit into their system, they’re not willing to work with them individually to be able to learn how to fit into the system…it’s the same way with the VA, it’s the same way with schools, it’s the same way with other places…I don’t think that a lot of places want to take the, have the courage to expand and help people to thrive in that environment.Participant 17.Another veteran went on to describe a positive experience with their care, where they were treated as an individual: I’m not just rushed in and rushed back out. I know I’m one of those trouble cases, you know, a difficult case they call me. I get that. And so sometimes doctors are like, yeah, we’ve heard it all, duh, duh, duh, duh, here’s what you need to do, bye. And the ones that are like, okay, tell me all of it, what more can I do? I think those are the ones that do have that institutional courage.Participant 12.Valuing the unique experiences of patients included a concrete recommendation from Participant 3, who noted that they wanted healthcare providers to read the entirety of their patient record or medical record and perform thorough history and physicals. This veteran stated that providers are not afforded enough time to adequately read records and effectively assess patients. The veteran then expanded on the idea that institutional betrayal often occurs in healthcare because of inadequate resources noting that providers are “overwhelmed by the numbers.” Veterans also discussed the value of advocacy for veterans in general and in healthcare. First, veterans expected the VA to be an advocate, “if the VA can’t be our advocate then why does the VA exist?” (Participant 1). This also applied to individual members of the institution, “I just wish more people would be willing to go outside themselves and advocate, there you go, advocate, and I mean really advocate for what needs to be done” (Participant 7). One veteran defined advocacy for oneself and others, “You have to be able to stand your ground…forcing the government to accept responsibility for what you’ve gone through” (Participant 4). Veterans also described employee advocacy as, “passion for helping us” (Participant 10) and not doing things for “recognition” (Participant 10). Here, veterans also reflected on the idea that leaders needed to advocate for their employees. This could, in some ways, offset the perils of a large bureaucracy. This veteran recalled asking their subordinates, “what do I need to do as your Commander, to get you promoted? What help do you need?” (Participant 13). For this veteran, this also meant attending to their personal lives, “if a person doesn’t have to worry about his home life, his work life is much better” (Participant 13).As with the theme of accountability, veterans reflected on their role in VA as members of the institution. This took the form of self-advocacy. Veterans spoke of their need to engage in self-advocacy after the system let them down. As this veteran described:I needed to take charge of my destiny and self-advocate. And that I was not in a situation I thought I was in. I thought I was in a meritocracy, where everyone’s treated equally and fairly and that people cared about me, loved me and valued me. And none of that turned out to be true.Participant 8.In one narrative, the idea of being seen as problematic or difficult can result from advocating, including when engaging in self-advocacy. Similar to leadership’s advocacy, for this veteran, individual advocacy on the part of employees could also compensate for difficulties inherent to large bureaucratic institutions: I’ll never say anything that’s universally bad or universally good…There are pockets of hope, and that makes things a little easier to deal with. You know, I get it’s a big bureaucracy, gets in its own way, but there are those who work in, within the confines of the bureaucracy that really do try to work for the benefit of the veteran.Participant 11.These descriptions also included the notion of tenacity related to advocacy; that often veterans and employees had to repeatedly return to situations where they were initially turned down, discounted, or invalidated. One example was in repeatedly applying for service-connected benefits despite initial denial for compensation from VBA. Several veterans expressed a feeling of validation or relief after being approved for service-connected conditions.Veterans discussed the notion that their receipt of both medical and monetary benefits from VA at times solicited a response from providers that they were “getting a free ride” or spoken about in the following regard: “look at them getting that free money” (Participant 5). This same veteran stated, “If I could give these injuries back, and give back the money because of that, we’d do it in a heartbeat.” Another veteran described their experience:It is better in some parts of the country—they think they’re doing you a favor and don’t believe in entitlement—systemic prejudice in helping veterans when it comes to money—don’t even think that its conscious.Participant 3.Participant 9 described feeling that they needed to prove their level of disability to their provider, perceiving the provider as saying, “we do not see anything wrong with you.” Similarly, Participant 1 said that the system should “give us the benefit of the doubt” instead of “denying” that something did or did not happen. Veterans also described the idea that benefits were more than merely financial compensation. As one veteran stated, “I don’t care about money” (Participant 9). This same veteran went on to say, “I’ve accomplished quite a bit in my life, and so to be labeled as disabled or anything like that is somewhat depressing and discouraging in itself.” Participant 6 also stated, “great, you service-connected me, awesome, and now I can [be] financially be stable. But now I need you to actually fix me because I can’t work because of these conditions. So, service connection is great and all, being financially [stable] is wonderful, but a long life is even better.” One veteran stated, “that compensation is not just money. That compensation for that soldier is an affirmation to his contract that he signed and earned. And that is bigger than the money” (Participant 6). Another veteran states, “I’m not asking for more money…I need the money now because I can’t work, but I just want care. I want care, empathy, understanding” (Participant 10). While the symbolic nature of benefits was noted as important, another veteran also highlighted, “I need that income to survive, for my family” (Participant 13). Veterans also discussed the benefits process, “I think [VBA] does most of the damage. VHA tries to do a lot of the care, but the damage is done from the benefit side” (Participant 1). Another veteran explicitly stated, “when you into the VBA side of things, you do not get the sense the VA is there to help you. You completely don’t feel that—you know, you don’t feel that the people who is evaluating you are going to try to make sure that you get the benefit” (Participant 13). At the same time, veterans spoke of VBA and VHA as being inextricably linked. Veterans shared that in VHA, they often felt that the notion of connecting their condition to military service was “taboo” and “we can’t talk about it, we can’t look at it” (Participant 4). As Participant 5 stated, “we [veterans] didn’t create the rule that’s called service connection. It was created for us.”Participant 2 described the notion that an “ethically intelligent” organization must also recognize that there is power over individual actors within the organization; for example, employees are dependent upon the organization for their livelihood, and patients in a healthcare organization are dependent upon the organization for their care. This suggests that the organization must also recognize that individuals may not respond in courageous ways due to fear of retribution. This included that an institution made up of humans is inevitably fallible. All actors within institutions will make mistakes, as this veteran states, “I was always taught if you make mistakes you own it. That takes a lot of courage. And I think the VA, our government, they make mistakes. We’re all human. Own it” (Participant 4). Participant 11 described a situation where the provider admitting they were wrong built trust:[my provider] called me to tell me to stop taking that medicine right away, and if I had any further issues I needed to go to the nearest emergency room…she’s doing her job, she’s doing what’s expected of her to do. So there are two sides of that, one is that she took the initiative to call me to say, hey this could be life threatening stop taking it right away. On the other side, basically she was admitting that they are giving me a medicine that I didn’t need for a diagnosis that I did not have.In our quality improvement project, veterans described instances of institutional betrayal both while serving in the military and when seeking healthcare. Veterans described the characteristics of healthcare institutions that are courageous but also, more specifically, how the VA can be a more courageous institution. First, veterans described institutionally courageous systems as having mechanisms of accountability and discussed that the VA as an institution can offer repair for betrayals that occurred during military service. Next, veterans described institutionally courageous healthcare as being proactive, both in terms of providing preventive healthcare but also proactively reaching out to veterans to ascertain their needs. Related to this was the idea that healthcare should be mindful of veterans’ unique needs and avoid a one-size-fits-all approach. Veterans also described the need for a shift in organizational culture within VA surrounding how providers view veterans’ benefits, noting that provider-level stigma surrounding public benefits has resulted in poor experiences with care. Finally, veterans described the importance of advocacy and safety in courageous healthcare systems. This includes self-advocacy, advocacy for patients, and advocacy for VA employees. Veterans described the idea that individuals should feel safe to advocate for others but also safe in admitting to errors or mistakes. and individual responsibility for healthcare has been highlighted in the contemporary professional literature [Veterans often described individuals within institutions as being both responsible for their actions and also beholden to the rules and culture of the institution. This is consistent with the existing literature, which notes that exercising institutional courage in healthcare may be especially fraught. Interactions among healthcare organizations are complicated and interdependent; ethical clinical practice often requires personal risk when confronting structures of power , is inheterature , especiaterature . This juterature ,47. VeteVeterans also described a desire for a change in how the system and individual providers view monetary and healthcare benefits administered by VA. Most of what is known about the veterans benefits process, specifically service connection, is found in the posttraumatic stress disorder (PTSD) and the legal literature. Most veterans view the service connection process negatively  and reseThe theme of being proactive also emerged from our interviews with veterans exposed to airborne hazards. A more reactive approach to health has been closely identified with a disease-focused model . The VA Finally, veterans in our sample discussed the importance of advocacy in organizations in terms of both self-advocacy and speaking up for others. The existing literature discusses fear on the part of healthcare providers to engage in advocacy, as well as the investment of time which advocacy requires. Advocacy often involves interactions with management or systems of power, which can result in adverse consequences for providers, including retaliation or dismissal . There iOur study included several limitations. Our goal was to improve care for a specific group of veterans who seek care in our clinic for a specific exposure concern . Therefore, this quality improvement endeavor should not be construed as generalizable to all veterans, including all veterans with exposure concerns. We approached a small group of veterans to allow for resources to be dedicated to member-checking; additional themes may have emerged from a larger group of respondents.Institutional betrayal occurs through wrongdoing, systematic discrimination, actions of law or healthcare agencies or officials, punitive actions against whistleblowers, and a neglect of workplace hazards ,2,3,4,5.


Diadema antillarum controls reef dynamics by grazing on algae and increasing coral recruitment. Populations of Diadema never recovered after a mass-die off in 1983 and 1984, and numbers were further reduced by a more recent die-off in 2022. To restore grazing pressure and thereby the resilience of Caribbean coral reefs, multiple Diadema restocking efforts have been performed. Although results vary, relatively low retention is one of the reasons restocking is not considered more often. If causes for the low retention can be identified, suitable measures may be able to increase restocking success. In this study, we monitored restocked lab-reared and wild juvenile Diadema on artificial reefs around Saba, Caribbean Netherlands. To assess the retention of Diadema over time, we conducted diver surveys and used underwater photo time lapse during daylight. Retention of uncaged lab-reared and wild Diadema decreased steadily with less than 30% surviving after 10 days. In total, 138 predator-prey interactions were recorded, of which 99% involved the queen triggerfish Balistes vetula, although other potential predators were present in the area. None of the recorded predator-prey interactions was successful, which suggests that artificial reefs with incorporated shelters may be suitable for juveniles as daytime refuge. However, Diadema that were more often attacked during the day were more likely to be absent the next morning. Because queen triggerfish often visited the experimental site in the first or last hour of daylight, it could be that they were more successful in their attacks when it was too dark to see anything on the photos and when Diadema came out to feed or to look for better shelter opportunities. If Diadema migrated off the artificial reef, they were probably predated during the process, because no Diadema were found on surrounding reefs. Wild Diadema were attacked significantly more often than lab-reared Diadema, possibly because the wild urchins were larger, but this did not significantly affect retention. Future restocking should be performed on natural or artificial reefs with deeper shelters, so Diadema can retract farther into their crevice, and should include night-time monitoring to identify the remaining unknown factors that cause low retention, including migration and nocturnal predation. This knowledge is urgently needed to coral reef managers so they can increase Diadema restocking success by selecting reefs with a lower predator density, protect urchins during an acclimatization period and/or conduct temporary predator control measures.The long-spined sea urchin  Diadema antillarum, hereafter Diadema, was once an ubiquitous species on Caribbean coral reefs  on the south coast of Saba, Caribbean Netherlands, within the Saba National Marine Park . Our sturedators .http://www.moreef.com) artificial reef modules  were made from concrete in August 2020. Each Moreef module contained eight tapered blind shelters, two tunnel shelters and numerous tapered micro-shelters . However, even when using the smallest collected recruits, the average (±SD) test size of wild individuals was 32.6 ± 5.5 mm, which was larger than the 24.8 ± 4.0 mm size of lab-reared Diadema. Permission to relocate Diadema for this experiment was given by Kai Wulf from the Saba Conservation Foundation, who was the Saba National Marine Park (SNMP) manager at the time of this study. The SNMP includes the sea and seabed around Saba from the high-water mark to a depth of 60 m.On 13 April 2021, four Diadema 1, 2, 3, 6, 7 and 10 days after restocking between 08:00 and 09:00. To determine behaviour of Diadema and to identify predators, all eight uncaged reefs were monitored with four underwater camera setups during the 10-day period. Each camera setup consisted of a GoPro 8  inside a 10 cm watertight cylinder (Blue Robotics Inc.). Two power banks  with a total capacity of 19,200 mAh per camera were enclosed. The setups were placed on a stand 55 cm above the substrate to which the camera setups could easily be attached and reattached. The cameras setups were installed simultaneously with the introduction of Diadema at the start of the experiment (day 0). The setups used a wide-angle setting with a time-lapse interval of 5 s to photograph the blind shelters with introduced Diadema and a surrounding margin of one meter to record any activity on the sand and in the surrounding water column. No lights were used, so useable images were restricted to daylight (approximately 05:40 to 18:45). Cameras were removed around midday on days 2 and 5 and replaced on day 3 and day 7 . Photos taken within ten minutes after retention surveys or camera deployments were excluded from analysis. Photos taken at night were also excluded as they were entirely black. The remaining 194,400 photos were manually analysed by MDB and AL. Photos collected during tests of the set-up, including restocked Diadema (code 7). Codes 8 and 9 relate to Diadema outside of their shelter space in the abscence of a predator. It was not possible to observe attacks on Diadema within shelters because they would retreat into the shelter and the predator followed, blocking the view of the cameras. We therefore coded these probable attacks as ‘interactions’ (code 4) and defined interaction as “photo with predator snout in shelter”. Photos were only attributed to the highest level code describing the action. For example, a photo with a predator interacting with Diadema in the shelter was only attributed to code 4 and not to code 1, 2 or 3. We installed cameras opposite of each other, so both cameras had two artificial reefs in the front and two in the back of the photo, to account for actions at the back of the artificial reefs. Codes 2–9 were only recorded for the two artificial reefs directly in front of the respective camera, avoiding double counts of the cameras opposite.Photos were coded according to predefined codes of which examples can be seen in Diadema.To determine the presence of predators on the surrounding reefs, a roving diver visual survey was conducted after completion of the retention count on day 6 when cameras were not running. We based the survey on the fish roving diver technique, which considers presence/absence data as well as frequencies of fish species , includiDiadema per artificial reef . Both GLMs were run with artificial reef as replicate, thus using number of photos per artificial reef. Model validation for both models was performed according to A Generalized Linear Mixed Model (GLMM) was used to assess the effect of source (factor: lab-reared or wild), caging (factor: caged or uncaged) and day of the experiment (covariate) on the retention of Because photos were taken only 5 s apart, a predator usually appeared in a sequence of multiple photos. We considered visits as independent only if they were separated from other photos of a conspecific predator by at least 10 min. Running time of the cameras was used to calculate the number of independent visits per hour per day. The time of the first and the last photo in a set were used to calculate the duration per independent visit and the mean duration per day.Diadema at the start of the first or second night of the experiment. The difference in number of Diadema between the start of the night and the next morning was modelled with GLMMs using the glmer function in the R package “lme4”. A binomial distribution was used  as the difference in Diadema at the beginning and end of the night was either 0 or 1 (presence-absence data). Source and total number of interactions were considered as fixed factors. To account for repeated measures, because the same shelter was surveyed multiple mornings, shelter ID was included as a random factor. Model selection was performed based on AIC  and significantly negatively related to day of the experiment . Retention was not significantly affected by source of the sea urchins.Artificial reefs with uncaged wild and lab-reared  10 days . All of Diadema predators and no sightings were recorded of Diadema outside their shelter without a predator present (code 8 and 9). Of all photos with a predator (Diadema (code 4). There was a single sighting of a Diadema outside its shelter, on the sand, with a predator within 50 cm (code 5) and another single sighting of a predator attacking that same individual (code 6). No sightings were observed of a predator feeding on Diadema (code 7). Queen triggerfish was by far the most abundant predator with 589 recorded photos, followed by the spotted porcupine fish with 23 photos, the Caribbean spiny lobster with 22 photos and the Spanish hogfish which was recorded on 11 photos. The bandtail puffer was recorded on two photos and the saucereye porgy was recorded on one photo. Of all predators, only queen triggerfish and Spanish hogfish approached within 10 cm (code 3 and 4). For the Spanish hogfish this was recorded twice, while the other 176 photos concerned the queen triggerfish. Most of these sightings (135) concerned interactions between the queen triggerfish and Diadema. On average, 6.0 ± 4.1 photos of queen triggerfish within 10 cm of a shelter were recorded per artificial reef restocked with wild Diadema. This was not significantly different  from reefs restocked with lab-reared Diadema, where the queen triggerfish was recorded within 10 cm of a shelter on 3.8 ± 2.2 photos per artificial reef module. Interactions of the queen triggerfish with Diadema were observed significantly more often on reefs restocked with wild compared to lab-reared Diadema . In total, we recorded 26.2 ± 15.8 photos per artificial reef with interactions between queen triggerfish and wild Diadema, and 7.5 ± 2.7 between queen triggerfish and lab-reared Diadema.Photo analysis resulted in 648 coded predator photos. All included predator , 189 incIn total, 104 independent predator visits were recorded, of which 82 concerned the queen triggerfish. Queen triggerfish visits were more frequent in the first half of the experiment, where 1.0–1.8 visits per hour were recorded . In the Diadema in that shelter during the following night . Shelters that retained a Diadema at the end of the night (n = 54) had 0.93 ± 1.52 interactions with predators during the previous day whereas shelters that lost their Diadema during the night (n = 22) had 3.48 ± 6.20 interactions with predators. Source had no significant effect on retention and was not included in the best fitting model.Total number of interactions during the day on a particular shelter had a significant relationship to the retention of Diadema predator species were sighted during the roving diver survey. The Caesar grunt was the most abundant with four sightings, followed by two sightings of the spotted spiny lobster. The black margate, Caribbean spiny lobster, queen triggerfish and Spanish hogfish were all sighted once.Six Diadema on the artificial reefs was relatively low, falling to 25–30% by 10 days. This was expected, as the current study is a follow-up on a restocking attempt at a nearby location, where a restocking experiment resulted in a mean retention of 0% after 3 months  or handling were of minor concern and that other factors negatively affected retention. Retention of restocked Diadema is thought to be mediated by predation pressure, habitat, food availability, and behavioural tendencies  suggesting that Diadema do not form a significant dietary proportion of predators in the area. More generalist predators such as the wrasses and grunts could therefore be less attracted by low densities of Diadema. More specialized predators, such as the queen triggerfish, were able to persist after the 1983–1984 Diadema die-off by switching to other prey items in the absence of their primary prey , excluding the possibility that the source treatment became mixed-up by nocturnal movements of the Diadema. The higher number of interactions with wild Diadema did not affect the final retention, which was similar for both sources.Contrary to our hypothesis, wild  urchins . NonetheDiadema during the present study is likely a result of predation and/or migration at night. There are multiple possible explanations for this, but Diadema that were more often attacked by queen triggerfish during the day were more likely to be missing the next morning. It could be that queen triggerfish were more successful in their attacks when it was too dark to see anything on the photos and when Diadema came out to feed or to look for better shelter opportunities. Diadema are known to look for better shelter when attacked, so migration off the artificial reef could still be the result of interactions with queen triggerfish during the day. If this was indeed the case, these Diadema were probably predated during the process, because no Diadema were found on surrounding reefs. No indications were found that lab-reared individuals were less suitable than wild Diadema for restocking practices, although it cannot be ruled out that lab-reared individuals were initially attacked less because of their smaller size. To increase restocking success, future restocking attempts should be conducted on artificial or natural reefs that have shelters more than 20 cm deep, so Diadema can retreat far enough to avoid contact with predators. We recommend monitoring restocked Diadema also at night and at other locations, to determine the causative factors for low Diadema retention, including identification of the most important predators. This information is essential to give coral reef managers the opportunity to increase Diadema restocking success by selecting reefs with a lower predator density, giving restocked Diadema an acclimatization period in a protected environment , camera retrievals (blue triangles pointing down), and retention counts (orange diamonds) were performed over the course of the experiment.Click here for additional data file.


Most of what is known about extra‐pair paternity in hole‐nesting birds derives from studies using artificial nesting sites, such as nestboxes. However, it has rarely been investigated whether inference drawn from breeding events taking place in nestboxes matches what would be observed under natural conditions, that is, in natural cavities. We here report on a variation in promiscuity in blue tits and great tits nesting in natural cavities and nestboxes in an urban forest in Warsaw, Poland. Specifically, we tested whether local breeding density, local breeding synchrony, and extra‐pair paternity (inferred from SNP data generated with a high‐throughput genotyping by sequencing method) differed between birds nesting in natural cavities and nestboxes. In both blue tits and great tits, the frequency of extra‐pair paternity was similar between the two cavity types. In blue tits, we observed shorter nearest neighbor distance, higher neighbor density, and higher synchronous neighbor density  in nestboxes relative to natural cavities. No such pattern was found in great tits. Moreover, we detected a positive relationship between the proportion of extra‐pair offspring in the nest and neighbor density around the nest in blue tits. Our results revealed that the provisioning of nestboxes did not change rates of extra‐pair paternity, suggesting that conclusions drawn from nestbox studies might adequately represent the natural variation in extra‐pair matings in some species or sites. However, the observed differences in spatiotemporal components of breeding dynamics highlight the fact that these parameters should be carefully considered when comparing mating behavior across studies and/or sites. Extra‐pair paternity levels were similar between natural cavities and nestboxes in blue tits and great tits breeding in an urban forest in Warsaw, Poland. We observed differences in spatiotemporal parameters between cavity types in blue tits but not in great tits, namely shorter nearest neighbor distance, higher neighbor density and higher synchronous neighbor density in the nestbox plot compared with the natural cavity plot. Independently of cavity type, the proportion of extra‐pair offspring per nest increased with density of closest neighbors in blue tits. Contrasting hypotheses have been suggested regarding breeding synchrony, thereby synchronous or asynchronous breeding might favor extra‐pair matings  and great tits (Parus major) breeding in natural cavities and nestboxes in the same urban forest in Warsaw, Poland. Blue tits and great tits are small passerine cavity nesters, breeding readily in nestboxes and equally widespread in natural and urban environments. They are socially monogamous with biparental care and varying levels of extra‐pair paternity among populations  and common oaks (Quercus robur). In late January 2018, 65 woodcrete Schwegler 1b nestboxes, with a 32 mm diameter entrance, were set up 50 m apart from each other in the NW part of the forest, in an overall area of 15 ha. A distance of 50 m between nestboxes was chosen to match the grid established in other study sites in Warsaw      according to the manufacturer's protocol, with the modification of overnight incubation at 37°C. DNA concentration and purity was assessed with a DeNovix DS‐11 spectrophotometer. DNA sequencing was outsourced to Diversity Arrays Technology Pty, Ltd  and performed using DArTseqLD, a high‐throughput genotyping by sequencing method that employs genomic complexity reduction using restriction enzyme pairs , we additionally repeated the analysis with radii two and three times larger than the original estimate to identify the most informative distance explaining variation in promiscuity: 192 and 288 m in blue tits and 144 and 216 m in great tits. Our reasoning was that nearest neighbor distance represents the distance to the nearest possible extra‐pair partner, while the other two measures within each radius reflect the number of extra‐pair mating opportunities within the neighborhood of a focal nest. Results for the smallest radius are presented in the main text, while those for the other two are presented in Supplementary  nearest neighbor distance (distance in meters to the nearest conspecific occupied nest); (ii) neighbor density (number of conspecific nests within three different radii around each nest); and (iii) synchronous neighbor density  and the three spatiotemporal parameters on two response variables: occurrence of extra pair paternity in each nest and proportion of extra‐pair young per nest. Occurrence of extra pair paternity for each brood was coded as 0 (no extra‐pair offspring) or 1 (at least one extra‐pair offspring). The three spatiotemporal parameters showed moderate correlations , we used chi‐square tests on the proportion of nests with extra‐pair paternity relative to the overall number of nests and on the proportion of extra‐pair offspring relative to the overall number of nestlings. We also performed a chi‐square test to determine whether the proportion of extra‐pair nests and extra‐pair offspring differed between study years. We used Mann–Whitney U‐tests on the three spatiotemporal parameters to test for differences between cavity types  and between years. In addition, we used Mann–Whitney ns Table  and werens Table . When tens Table  and S10.ns Table . An intens Table  and sex ns Table . It is pns Table , separat33.1n = 25 in blue tits and n = 25 in great tits; Figure n = 7 blue tits and n = 4 great tits; Figure n = 44 in blue tits and n = 50 in great tits; Figure n = 3 nests in blue tits and n = 3 nests in great tits; Figure For blue tits, a total of 118 adults and 497 nestlings were successfully sequenced, together with 114 great tit adults and 402 nestlings. Out of these, 62 (53%) adult blue tits, 226 (46%) blue tit nestlings, 74 (65%) adult great tits, and 207 (52%) great tit nestlings were sampled in natural cavities. In each species, the distribution of GRM values among individuals from the two plots combined together  and 46% in the nestbox plot (n = 17 out of 37) contained at least one extra‐pair offspring. 8% of blue tit nestlings in the natural cavity plot (n = 16 out of 197) and 12% in the nestbox plot (n = 28 out of 237) were extra‐pair offspring  and 62% in the nestbox plot (n = 16 out of 26) contained at least one extra‐pair offspring. 11% of great tit nestlings in the natural cavity plot (n = 20 out of 179) and 16% in the nestbox plot (n = 30 out of 189) were sired by males other than their social father  or in terms of proportion of extra‐pair offspring . Differences between years in the proportion of broods containing at least one extra‐pair offspring lacked statistical support , similarly to differences between years in the proportion of extra‐pair offspring in the population . No brood consisted entirely of extra‐pair young either in blue tits or great tits over the 2 years in either plot. Table p = .867, n = 23) nor in great tits  .Over 2 years, in blue tits we recorded 87 nesting attempts in natural cavities and 46 in nestboxes. Out of the 87 natural cavities, 32 were inaccessible because they were located in very high and/or dry branches, to which climbing was not possible for safety reasons, or because the nest was too deep to reach and extract nestlings; we obtained information on extra‐pair paternity for 30 broods. In great tits, we recorded 88 nesting attempts in natural cavities  and 29 in nestboxes. Nest searches proved to be highly effective, because most nests were found at building also in natural cavities  or between sexes . In great tits, low sample size led to model convergence issues, precluding testing for successful fledging.At the individual level, there was statistical support for an effect of cavity type on the sex‐specific probability of being an extra‐pair blue tit. Thus, female nestlings had higher probability of being extra‐pair in the nestbox plot than in the natural cavity plot Table . In grea4We found no differences in levels of extra‐pair paternity at the plot level in blue tits and great tits breeding in natural cavities and nestboxes within the same urban forest. The analysis of blue tit data indicated that nearest neighbor distance was longer, and neighbor density and synchronous neighbor density were lower in natural cavities compared with nestboxes  breeding in natural cavities and nestboxes , where nestbox studies reported two to three times higher rates of polygyny in nestboxes compared with natural cavities, suggesting that the distribution of cavities and the ability of males to defend their territories might limit levels of extra‐pair paternity ; data curation (lead); formal analysis (lead); investigation ; methodology (lead); writing – original draft (lead); writing – review and editing . Charles Perrier: Conceptualization (supporting); formal analysis (supporting); methodology (supporting); writing – review and editing (supporting). Marta Szulkin: Conceptualization ; formal analysis (supporting); investigation (supporting); methodology (supporting); resources (lead); writing – review and editing . Joanna Sudyka: Conceptualization ; data curation (supporting); funding acquisition (supporting); investigation ; methodology (supporting); writing – review and editing .We declare none.Table S1–S10.Click here for additional data file.