The histopathology is addressed regarding its indications, main findings and limitations, as a complementary diagnostic method largely used by dermatologists. Electron microscopy is briefly reviewed, along with its contribution to the accumulated knowledge on HPV, as well as the relevance of research in using this technology for future advances in diagnosis and treatment. Molecular information about the virus is continuously increasing, and the practical applications of HPV serology, molecular identification and genotyping are discussed. Vaccines are a valuable tool in primary HPV infection prevention and are now available in many countries; their composition, indications, and adverse effects are revisited. Local and systemic treatment options are reviewed and off-label prescriptions are discussed. Finally, health education focusing on HPV infection as a sexually transmitted infection of worldwide relevance and the many barriers to improve primary and secondary prevention are addressed.In this nonsystematic review, the complementary diagnosis, treatment, prevention, and control of  In a previous article, aspects of epidemiology, pathogenesis and the main clinical manifestations of the Human Papilloma Virus (HPV) infection were discussed.This non-systematic review article addresses the topics of complementary diagnosis, treatment and preventive measures.The histopathological analysis of lesions caused by HPV should be considered whenever there is doubt regarding the differential diagnosis and also when malignancy is suspected, both on the skin and on the mucosal membranes. Oncotic colpocytology remains recommended as a periodic examination for Cervical Cancer (CC) screening.HPVs are known to infect epithelial cells and depend on epithelial cells differentiation to complete their life cycle.The histopathological characteristics of verruca vulgaris or common warts are evident in the epidermis, where the presence of acanthosis, papillomatosis, marked hyperkeratosis, and parakeratosis columns can be observed on the top of the epithelial cones, with the absence of the granular layer that is accentuated in the valleys between adjacent cones.The three histopathological features that are used to differentiate the common wart from other papillomas include the presence of foci of vacuolated cells, known as koilocytes, vertical columns of parakeratosis and dense foci of keratohyalin granules. These characteristic epidermal alterations are best seen in young warts.koilos/cavity), which are characteristic of HPV infection, are observed in the upper stratum of Malpighian layer and in the stratum granulosum; they are characterized by small, round and dense basophilic nuclei, surrounded by a clear halo with pale cytoplasm. Sometimes, these lesions can resemble seborrheic keratoses due to the loss of their characteristic shape. Dermal alterations are usually minimal in the common wart. Approximately 8% are inflamed and show a lichenoid infiltrate. Filiform warts show much more evident papillomatosis with marked hyperkeratosis, dilated capillaries in the dermis and, sometimes, small hemorrhagic foci.Koilocytes  lesions are characterized by stratum corneum with basket-weave appearance and keratinocyte edema. Keratinocytes have a pale appearance, are slightly basophilic and keratohyalin granules of variable size and shape, and are grouped in the granular and spinous layers of the epidermis which resembles the flat wart, but they can occupy the whole length of it. These cells have small, pyknotic nuclei, like a loose balloon in a cell vacuole . It has 7Lesions located in the anogenital region include condyloma acuminatum, giant condyloma or Buschke-Lowenstein tumor, Bowenoid papulosis, Bowen's disease and Queyrat's erythroplasia. Lesion classification into low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs) has been used to designate them according to their histopathological characteristics and clinical behavior.kondulos/condyle and Latin acuminatum) as having an undulated and moderately acanthotic surface.Fazel et al. describe the epidermis in condyloma acuminatum  The giant condyloma acuminatum of Buschke–Löwenstein exhibits mild vacuolization of keratinocytes and marked epidermal papillomatosis, with bulbous extensions of well differentiated squamous epithelium extending into the deep dermis. Keratinocytes are minimally atypical.in situ, into which it can evolve.In the microscopic sections, the epidermis shows psoriasiform hyperplasia and hyperkeratosis. The keratinocytes appear in clusters and show larger, hyperchromatic, pleomorphic nuclei, dyskeratosis and loss of epidermal stratification. There is an increase in the number of mitotic figures, some of them atypical, seen in all layers of the epidermisTwo different types of proliferative lesions can appear in the cervix, the precursor lesions of cervical intraepithelial neoplasia (CIN) and invasive carcinoma. The knowledge of precursor lesions that show well-defined morphological characteristics allows an early diagnosis before the neoplastic invasion occurs. Clinically, they appear as acetowhite lesions A under cIn Situ (CIS). Subsequently, the division of the lesions into two groups was proposed: the LSILs, which would correspond to the NIC-I, encompassing epithelial alterations suggestive of HPV infection (koilocytosis) even without dysplasia; and HSILs, comprising CIN-II and III and CIS.They were called CIN and subdivided into CIN-I (mild dysplasia), CIN-II (moderate dysplasia) and CIN-III (severe dysplasia) in the same category of Carcinoma On histopathology, the precursor lesions of neoplasia show alterations in cell proliferation and maturation and loss of epidermal stratification, whith varying degrees of atypia. In cases of mild dysplasia, the alterations are found in the lower third of the epithelium, which shows mild cellular atypia and discrete loss of cell polarity. In moderate dysplasia, atypia and loss of polarity, in addition to cell differentiation, are more intense and comprehend half of the epithelial thickness. Mitoses are more frequent. Marked dysplasia shows alterations in the entire thickness of the epithelium with loss of stratification and the presence of typical and atypical mitoses. The finding of koilocytosis is an indicative of HPV infection B and C.1According to Betz, HPV-related benign oral cavity lesions comprise the common wart, squamous papilloma, condyloma acuminatum and multifocal epithelial hyperplasia.Squamous papilloma is described as the most common benign lesion seen on the oral mucosa, both in children and adults.The histopathological presentation in the mucosa is identical to that in the skin.11In condyloma acuminatum, the lesions are papillomatous and exophytic under microscopy and, unlike squamous papilloma, the base is enlarged. The epithelium shows moderate to severe acanthosis and papillomatosis. Thick parakeratosis is often identified, with invaginations that fill up the crypts between the papillae. Similar to what has been described for anogenital condyloma acuminatum, the koilocytes are seen at the top of the spinous layer and predominate in the valleys between the papillae.11Irregular epithelial hyperplasia with mild parakeratosis is observed in focal epithelial hyperplasia. The acanthotic epithelium shows elongated, anastomosed and thickening rete ridges. Clear keratinocytes in the upper layer and binucleated cells in the medium layer are the observed histological characteristics. Ballooning degeneration can be prominent. Frequently, there is a slight lymphocytic infiltrate in the corium. Electron microscopy shows particles arranged in a crystalline pattern.11Electron microscopy (EM) is the technique that allows the observation of the virus in tissues. However, since the introduction of molecular biology techniques for detecting HPV DNA, these are preferred when it is necessary to prove the presence of the virus. EM is of great importance in several types of research, such as the pathogenesis of the infection, which includes considering the need for new interventions against the virus.In EM, the amount of viral particles is variable in different types of lesions, being frequently absent in common warts and in lesions that have developed into CIS or even invasive carcinoma.Viral DNA replication occurs with basal cell proliferation. The proteins of the capsid structure appear in mid-epidermis and in the upper epidermis the mature viral structure of HPv is found. The viral particles appear as spherical bodies, with a diameter of 50 nm. Each particle consists of an electron-dense nucleoid with the aspect of an appendage surrounded by the less dense capsid.The viruses in the warts multiply in the nucleus, where they appear as particles in dense crystalloid aggregates . In planThe host's humoral immune response to HPV infection occurs in around 50–60% of individuals with infection demonstrated by a positive HPV-DNA detection test. Since it is not possible to isolate the virus using conventional culture methods, HPV identification is based on molecular methods.According to the World Health Organization (WHO), antibody screening is indicated in population-based epidemiological studies, aimed at defining pre-vaccination strategies for groups and age groups with the greatest exposure and when assessing vaccine efficacy. The use of serology as a diagnostic tool is not recommended.Cervista, approved in 2009, identifies 14 types of HR HPVs; the Cobas HPC, approved in 2011, identifies HPV-16, HPV-18 and other 12 types of HR HPVs in a single reaction, and in 2014 the Cobas 4800, a fully automated test, was the first to be approved by the FDA as the first line screening for cervical cancer risk in women aged 25 or older; the Aptima HPV Assay, approved in 2011, focuses on the identification of HPV E6/E7 oncogenes through the detection of messenger RNA of 14 types of HR HPV and, finally, the Onclarity, approved in 2018, also detects the oncogenes E6 and E7 of 14 types of HR HPV. All of these tests show high sensitivity and specificity.https://consultas.anvisa.gov.br/#/saude/q/?nomeProduto=HPV.The first test to assess HR HPVs was approved by the Food and Drug Administration (FDA) of the United States of America in 1999, with an emphasis on the evaluation of cervical cancer. Since then, several tests have been introduced and approved and several studies involving other anogenital and oropharyngeal neoplasms have been carried out. The following tests have been approved by the FDA to evaluate cervical cancer: the Qiagen Hybrid Capture-2, approved in 2003, is a test that identifies 13 types of HR HPV: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68; the According to the WHO, HR HPV detection tests are indicated for the screening of women aged 30 years or older, either alone or in combination with cervical cytology for the prevention of cervical cancer. These tests are more sensitive than cytology and have a higher negative predictive value. They are used for the screening of women with minimal cytological abnormalities to avoid unnecessary follow-up, to monitor women with persistent/recurrent disease and as a post-treatment test-of-cure. The WHO does not recommend testing for Low-Risk (LR) HPV.There are currently no recommendations regarding the use of screening tests for HR HPV infections in the anal, vulvar, vaginal, penile and oropharyngeal regions.in situ hybridization or PCR, especially in tumors of the oropharynx  can be useful, as those associated with HPV have better therapeutic response, higher survival rates and lower risk of recurrence when compared to HPV-negative patients.21The identification of HPV in head and neck SCCs, by Not all women with persistent HR HPV infection or precursor lesions in the cervix, even without treatment, will progress into cancer, suggesting that the identification of HR HPV alone does not define the evolution.in situ hybridization of RNA is capable of detecting E6/E7 mRNA and allows the observation of transcriptional viral activity in tumor cells and seems to be the most specific test for HPV.Moreover, regarding head and neck carcinomas, In relation to cervical cancer, emergent biomarkers include the identification of mRNA for proteins E6/E7, screening for p16 protein, aberrant S-phase induction markers, detection of chromosomal and miRNA abnormalities; combined with advanced genotyping methods. They can be useful to differentiate those women with precancerous conditions who would need urgent treatment or diagnostic colposcopy.According to the Brazilian Guidelines for Cervical Cancer Screening, cytopathological examination is the recommended screening method for cervical cancer and its precursor lesions.Speculative treatments for treating warts, especially cutaneous warts (CW) or verrucae, are widespread among the population. Successful lay experiences are suggested with absolute confidence, such as the act of blessing the region, exfoliating the lesions with coarse salt or green banana peel, acupuncture, destroying the “mother” wart so that the others will disappear, among others. The search for unusual therapies, in some situations, could be due to the esthetic appeal. The manipulation of the lesions can cause an inflammatory process and the regression of the warts, but it can also lead to rapid growth and dissemination due to trauma. The success of these approaches may be due to the spontaneous regression that is described in a significant percentage of cases, a fact that must be considered in the evaluation of any therapeutic method.Several therapeutic modalities have been used to treat HPV infections. The choice of treatment should take into account factors such as age, location, number and size of the lesions, clinical subtype and the patient's immunological status.Topical treatments include predominantly destructive modalities, such as cryotherapy, chemical cauterization, surgical methods and laser removal. They can be divided into three categories: destructive, cytotoxic agents and immunotherapy.Otherwise, the majority of systemic treatments are based on the attempt to improve the individual's immune response to HPV. Overall, the studies are scarce and, in some situations, show controversial results. In addition, the use of these treatments ends up being made through an off-label prescription, for which the doctor must be aware and follow the necessary guidelines.Considering this scenario, the proposal is not to exhaust the subject, but to list part of the evidence available in the literature and to offer dermatologists material that helps them in the routine care at outpatient clinics and medical offices. Formulations containing salicylic acid (SA) are considered the first line of treatment for CW by some authors.Cryotherapy is usually performed by applying Liquid Nitrogen (LN) on the lesion. Freezing causes tissue damage, damaging the cells and their blood supply.27Although several studies have failed to show its superiority over placebo and SA, patient satisfaction was significantly higher in the group treated with cryotherapy.5-Fluorouracil (5-FU) has antineoplastic and antimetabolic properties that inhibit DNA and RNA synthesis, and this is believed to be the mechanism responsible for stopping aberrant epithelial proliferation.Bleomycin is an antineoplastic drug with label indications for the treatment of Hodgkin's disease and non-Hodgkin's lymphomas, malignant pleural effusion, some types of testicular carcinoma and SCCs of the oropharynx, genitals (including cervix) and skin. It is known that many SCCs, especially mucosal ones, are associated with HPV.27Cure rates vary widely between studies (16–94%). This variation could not be associated with any drug concentration, method of application or total dose.Imiquimod is an immunomodulatory drug that acts on the innate and adaptive response, induces the production and release of Interferon (IFN)-alpha, tumor necrosis factor-alpha and interleukin-12, in addition to promoting the activation of natural killer cells, promoting the interruption of viral replication.Tretinoin is the main retinoid used in the treatment of CW, usually at a dose of 0.05% in a cream base. Its use is generally reserved for cases with multiple recalcitrant lesions or patients with flat warts.Podophyllin is an antimitotic agent that can cause tissue necrosis. It must be applied by the physician, at concentrations of 10–25%. Systemic effects may occur if it is applied on large body surfaces. It is contraindicated during pregnancy. Although it is used in GWs, it is not yet well established in CWs. Podophyllotoxin can be administered by the patient and causes less irritation than podophyllin.Cantharidin is a vesicant agent that causes acantholysis. Due to its mechanism of action, it carries a reduced risk of scarring. Its application is practically painless, and the discomfort appears only 24 h later. It is highly toxic if administered systemically, so it must be applied in the medical office. The most often used concentration is 0.7%.Cidofovir is a nucleotide analog that works by inhibiting viral DNA polymerase. The treatment is carried out with monthly intralesional injections. There are studies underway to evaluate the use of a cream-based formulation. Only local side effects have been reported: pain, burning, pruritus and erythema.Topical immunostimulatory agents have been studied for decades in an attempt to elucidate their therapeutic role in the treatment of recalcitrant warts. Dinitrochlorobenzene has been used in the past with promising results, but it is no longer indicated due to its mutagenic potential.Candida sp. antigen, triple viral vaccine (MMR), topical zinc sulfate, among others. However, further studies are needed to determine their role in the management of cases.28Several other substances have been described as possible immunotherapy agents that can be applied in the treatment of CWs: PPD, Surgical excision is a method that removes CWs using a curette, scalpel or electrocautery.2 laser is described as a destructive method with potential for use in CWs, as well as the pulsed dye laser; however, more studies are needed to determine the effectiveness of these methods.The use of photodynamic therapy with aminolevulinic acid to treat plantar warts has been described, but studies have shown contradictory results regarding the effectiveness of this intervention.2 laser.The treatment of GWs can be carried out in a single session, using destructive methods such as electrocoagulation, surgical excision or COTrichloroacetic Acid (TAA) (80–90%), podophyllin 10–25%) and cryotherapy are options for treatments that require multiple applications at the medical office.0–25% and2 laser and, in selected cases, Mohs micrographic surgery. Imiquimod also seems to be a viable option. The use of radiotherapy for malignant and pre-malignant lesions associated with HPV is not recommended.In the therapeutic approach, it should be kept in mind that although histopathology shows many atypias, the evolution of these lesions is favorable in most cases. Spontaneous regression frequently occurs, especially in young and male individuals. It can be more aggressive in the elderly and immunocompromised individuals.Minimally invasive surgery, together with local therapy, is adequate for patients with small lesions or high intraoperative risk. Likewise, the association of cryotherapy with topical chemotherapy can be considered. Mohs micrographic surgery can also be indicated. The main treatment remains an extensive surgery, with broad resection and often reinterventions to complete the excision. Complementing the surgical treatment for small lesions can be carried out with laser application and local or intralesional treatments with 5-FU and bleomycin, associated with cisplatin and methotrexate; TAA, cidofovir and imiquimod are other described options. In addition to these, systemic immunotherapy with IFN-alpha and systemic chemotherapy with several drug combination regimens have been used in selected cases. The use of radiotherapy is controversial.39TAA is the treatment of choice for pregnant women with localized lesions, and cryotherapy with LN is also indicated. For patients with extensive affected areas, surgical treatment is the preferred conduct.The management of immunosuppressed patients is a challenging situation. Treatment may not result in the complete healing of the lesions, but it helps to reduce their size and the esthetic impact. Therapeutic options are the same as those previously reported; however, variation and association of methods may be necessary.Cimetidine, an H2 receptor antagonist antihistamine, has been used in several clinical studies for CW, with conflicting results, some showing significant improvement and others showing disappointing results.Levamisole, which has several immunomodulating effects, has been used in a few controlled studies for the treatment of CWs with conflicting results. Its side effects include: nausea, dysgeusia, skin rash, alopecia and the flu-like syndrome.Zinc, an important trace element in the body immune function, was compared to a placebo, at a dose of 10 mg/kg/day, in a few studies for the treatment of resistant CWs: some with good results, showing an improvement of up to 87% and others with similar results between the drug and the placebo.A prospective, double-blind, randomized Brazilian study compared cimetidine 35 mg/kg/day (maximum 1200 mg/day) and zinc sulfate 10 mg/kg/day (maximum 600 mg/day), during three months for the treatment of CWs in 18 patients. Zinc sulfate was more effective than cimetidine, with complete response in 62.5% of patients and partially in 25%. The study limitation is the small sample size.Selenium has been studied as prophylaxis for the appearance of HPV-related lesions in Solid Organ Transplant (SOT) recipients but it has not been shown to be effective.Asteraceae family, has three species with therapeutic properties: E. purpurea, E. angustifolia and E. pallida. It is used for the prevention and treatment of upper airway infections, and it has also been tested for the treatment of CWs in a few studies, with conflicting results.Echinacea, a perennial herbaceous plant that belongs to the p < 0.000001), but the systemic use did not .IFN, a cytokine produced by T lymphocytes, fibroblasts and other cells, has immunomodulatory, antiproliferative and antiviral properties and can be used to treat HPV lesions using topical, intralesional or systemic formulations. A systematic review carried out in 2009 included 12 controlled and randomized studies that comprised 1445 patients with genital warts treated with INF. When compared to the placebo, the topical use of IFN showed a statistical difference  in the treatment of HPV-related skin lesions of patients with EV. The response is variable, being good in some cases, but showing recurrence after treatment interruption. As for etretinate, reports have shown a minimal or transient response.Cidofovir, an acyclic nucleoside phosphonate that acts on viral DNA polymerase, which has been approved for systemic use in cytomegalovirus (CMV) retinitis in HIV-positive patients, has had reports of topical and intralesional use in the treatment of anogenital lesions caused by HPV in transplant recipients; moreover, there have been reports of improvement of refractory skin lesions in HIV-positive patients with its topical use, albeit with high rates of recurrence.In recurrent respiratory papillomatosis, it has been used through several application routes: intralesional, systemic and inhaled. Although widely used, the treatment results are variable and refer to its combined use with surgical treatment. Systemic use is limited by the effects of renal toxicity and risk of oncogenicity. Other adverse reactions described are: skin rash, headache and vocal cord scarring.The use of bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF) receptors, has had several reports on the improvement of recurrent respiratory papillomatosis, with both intralesional and systemic use. Controlled, randomized clinical trials and studies with larger case series must be carried out to assess its efficacy and safety.A relevant aspect to be considered concerns the immunosuppressant used in transplant recipients: calcineurin inhibitors, such as cyclosporine, pimecrolimus and tacrolimus, are associated with the development of warts, especially if associated with azathioprine, while mTOR inhibitors, such as sirolimus, temsirolimus and everolimus, are related to the improvement and reduction of warts and associated malignancies. There are reports of kidney and liver transplant recipients with warts that showed improvement when these immunosuppressive medications were changed.New drugs targeting molecular pathways have been studied in the treatment of HPV-related diseases: molecular inhibitors directed at the DNA binding activities of HPV proteins E1 and E2 or at the anti-apoptotic activities of oncogenes E6 and E7; proteasome and histone deacetylase inhibitors in addition to E6 and E7 therapeutic protein vaccines.The off-label prescription of medications is characterized by the use of a drug, by the physician, when its use has not been approved by the health agencies in situations that are not included in the package insert, for instance, regarding its dosage, interval between doses, age group, diseases and even the stages of the same disease. Indications for using a certain medication vary from country to country and throughout the time of drug use, new indications may be authorized by agencies based on scientific evidence.In Brazil, ANVISA draws attention to the fact that this type of prescription is carried out at the risk and discretion of the physician who prescribes it, which may eventually characterize a medical error. However, it also points out that, in most cases, it is an essentially correct use, which has just not been approved yet.Regarding the treatment of HPV manifestations, many of the treatments will be carried out through an off-label prescription. Physicians should be aware of this possibility and should always share this information with their patients and, preferably, ask them to sign the free and informed consent form for the medication use.The relationship between HR HPV and cervical cancer (CC) has been well established, and this is one of the most common neoplasms in women from low- and middle-income countries.It is considered that almost all cases of CC are caused by HPV infection, which also occurs in 90% of anal neoplasms. Moreover, HPV is related to neoplasms of the vagina, penis, vulva and oropharynx, with varying percentages, and is the cause of GWs and recurrent respiratory papillomatosis.47All three prophylactic vaccines currently available against HPVs are obtained by recombinant DNA technology from the viral L1 protein, which will constitute the virus-like particles, or VLP.In Brazil, the quadrivalent vaccine was introduced in the SUS  network for girls between 9 and 14 years of age in 2014. In 2017, the use was extended to boys, and it is currently recommended for the age range between 11 and 14 years old in this group.The three vaccines are considered safe and among the associated adverse effects are episodes of syncope, attributed not to the components of the vaccine itself, but to the vaccination process. Especially among the younger population, syncope has been described with the application of other vaccines, blood collection and parenteral administration of medication.49There is robust evidence of individual and population benefit in reducing both benign lesions and lesions caused by HR HPVs after HPV vaccination.47A major challenge is to maintain vaccination coverage at levels considered to be adequate, even for the first dose. In Brazil, there was a reduction of almost 23% in the coverage of the target population (girls) between the years 2014 and 2015 for the first dose of the vaccine (92% × 69.5%). In 2017 the data showed percentages below 80% for girls at the first dose (79.2%) and only 48.7% at the second dose. For boys in that same year, the coverage at the first dose was of 43.8%.The vaccination of individuals older than 26 is not recommended for all individuals. However, some adults between the ages of 27 and 45 may decide to take the HPV vaccine based on discussion with their physician, if they have not been adequately vaccinated when they were younger. In this age group, vaccination offers fewer benefits, for the abovementioned reasons. The vaccination prevents new HPV infections but does not treat existing infections or diseases.51Saccharomyces cerevisiae yeasts present in its composition. People with acute illnesses with moderate to severe conditions should have their vaccination postponed.The vaccine is contraindicated during pregnancy. If pregnancy occurs after the first dose, or if it is inadvertently administered during pregnancy, the subsequent dose should be suspended and the vaccination schedule should be completed after delivery. Breastfeeding does not contraindicate vaccination.The difficulties in implementing HPV vaccination are many, which have different and sometimes dynamic characteristics, with specific situations that require prompt intervention so that myths and misinformation are not disseminated.In health education aimed at HPV prevention, it is necessary to consider not only its relevance due to the prevalence/incidence in the populations, but also its transcendence. The burden of individual suffering associated to morbidity and mortality should be highlighted, which leads to feelings of fear and the experience of stigma for many individuals. Moreover, it translates into high costs for public health.When considering health education focused on skin manifestations, one should bear in mind that in immunocompromised patients, skin cancer develops at an earlier age, is more aggressive and carries a greater risk of metastasis, which implies the need to adopt effective preventive measures for this population.Knowledge about the sexual behavior of the population in which one intends to develop health education activities is essential. Regarding sexuality, a population survey carried out in Brazil that included 12,000 people aged between 15 and 64 years old aiming to assess the knowledge, attitudes and practices related to STIs and viral hepatitis, showed that a quarter of them reported having started sexual activity before the age of 15, 34.9% of men and 15.4% of women.In relation to HPV, health education should cover the dissemination of knowledge about infection, related diseases and their possible consequences, more specifically, the oncogenic potential of the virus. Considering the existence and availability of the quadrivalent vaccine in SUS and the evidence of its efficacy in reducing genital warts and pre-malignant lesions related to HPV, it is essential to ensure, during this process, the acceptance and access to the specific vaccination.The fundamental points highlighted in studies on the subject are the knowledge, attitudes and practices related to sexuality, especially among adolescents and young adults, who constitute the most vulnerable group for STIs/HPV, as well as for early pregnancy.57Knowledge about HPV is insufficient in several studies, both in Brazil and in other countries.55As with several other diseases, lower schooling is related to less knowledge, which translates into greater vulnerability according to Fontes et al.The adoption of a safe behavior in sexual relationships implies previous knowledge about what constitutes risk. Knowing the importance of using condoms, being able to negotiate their use with sexual partners, or even having the option to postpone or abstain from sexual involvement are behaviors, attitudes and practices that are learned and necessary for the prevention of STIs and pregnancy.58The interventions to disseminate/consolidate knowledge about STIs and lead to safer attitudes and practices are relevant, and in recent years they have gained an ally with great potential for reaching these individuals, through digital technologies.58Another meta-analysis that evaluated 63 studies and included almost 60,000 individuals in several countries showed that almost 75% of the interventions were based on health promotion theories.The stigma related to STIs can hinder the search for treatment and protection methods, in addition to increasing the individual's burden of suffering. It is admitted that individuals with little knowledge feel more stigmatized when they are diagnosed with HPV infection.Regarding the vaccine, the knowledge about HPV goes beyond the target population itself, since most of them should be vaccinated in childhood or early adolescence.The lack of information by parents and guardians about the importance of vaccination in the pre-pubertal stage coupled with the belief that the vaccine could lead to early sexual initiation or promiscuous behaviors can lead to the postponement of the vaccine or even non-vaccination. However, these arguments are known to have no scientific basis.51The anti-vaccine movement should not be underestimated. Coping strategies on several fronts need to be permanently worked on, considering the multi-causality of these barriers. The importance of the role schools and health professionals have for vaccination success is recognized and needs to be encouraged. The physician must use all medical care opportunities to check and/or indicate HPV vaccination.61None declared.Marcelo Grossi Araújo: Study conception and design; literature search and critical reading of the articles; writing of the manuscript; critical review of the manuscript and final approval of the submitted version.Geraldo Magela Magalhães: Study conception and design; literature search and critical reading of the articles; writing of the manuscript;, critical review of the manuscript and final approval of the submitted version.Lucas Campos Garcia: Study conception and design; literature search and critical reading of the articles; writing of the manuscript; critical review of the manuscript and final approval of the submitted version.Érica Cristina Vieira: Study conception and design; literature search and critical reading of the articles; writing of the manuscript; critical review of the manuscript and final approval of the submitted version.Maria de Lourdes Ribeiro de Carvalho Leite: Study conception and design; literature search and critical reading of the articles; writing of the manuscript; critical review of the manuscript and final approval of the submitted version.Antônio Carlos Martins Guedes: Study conception and design; literature search and critical reading of the articles; writing of the manuscript; critical review of the manuscript and final approval of the submitted version.None declared.


This study aimed to determine whether blood loss and fibrinogen can differentiate amniotic fluid embolism (AFE) from postpartum haemorrhage (PPH). This retrospective case–control study included nine patients with clinical AFE (“AFE group”) and 78 patients with PPH managed at our tertiary care perinatal centre between January 2014 and March 2016. Patients meeting the Japanese diagnostic criteria for AFE were stratified into cardiopulmonary collapse-type AFE and disseminated intravascular coagulation (DIC)-type AFE groups. The relationship between blood loss and fibrinogen at onset was examined to compare DIC severity. Vital signs at onset were not significantly different. The AFE group had significantly less blood loss at onset , significantly more blood loss 2 h post-onset  and more severe coagulopathy and fibrinolysis. The blood loss/fibrinogen (B/F) ratio at onset was significantly higher in the DIC-type AFE group . AFE was complicated by catastrophic DIC irrespective of blood loss at onset. Fibrinogen exhibited the strongest correlation among test findings at onset. The B/F ratio may help differentiate PPH from DIC-type AFE and diagnose clinical AFE, facilitating optimal replacement of coagulation factors during the early stages. AFE reportedly causes 24.3% of all maternal deaths in Japan5.Amniotic fluid embolism (AFE) is a rare, severe maternal complication with an incidence of 0.001–0.013%3. Definitive diagnosis of AFE comprises conventional autopsy findings of amniotic fluid/foetal components in maternal lung and uterine tissue, and interstitial oedema with inflammatory cell infiltration related to anaphylactic reactions7. Because autopsy results take time to produce definitive diagnoses, timely practical diagnostic criteria are needed to improve maternal life expectancy.AFE likely results from amniotic/foetal component-triggered physical embolism and an anaphylactoid reaction5. The perinatal committee of the Japanese Society of Obstetrics and Gynaecology described clinical features of uterine-type AFE to clarify the concept8.Recent analyses by Japan’s Maternal Death Exploratory Committee and the Amniotic Fluid Embolism Registry have raised the “concern that AFE is implicated in massive obstetric haemorrhage”. Disseminated intervascular coagulation (DIC) [uterine]-type AFE causes critical obstetric haemorrhage. Reports on this subject are increasing10. However, there are problems with the current AFE diagnostic criteria. Although “severe bleeding of unknown origin within 2 h of delivery” and “DIC” are important diagnostic criteria, it is difficult to differentiate AFE and early-stage postpartum haemorrhage (PPH) unrelated to AFE (“non-AFE PPH”) without symptoms of cardiopulmonary collapse. DIC causes secondary atonic bleeding due to the relaxation of uterine smooth muscle. Excessive blood product resources and personnel may be utilised when atonic bleeding secondary to DIC and DIC secondary to atonic bleeding are conflated, and a diagnosis of DIC (uterine)-type AFE is reached. In non-AFE PPH, the amount of coagulation factors needed generally correlates with the amount of bleeding, whereas in DIC (uterine)-type AFE, severe coagulopathy should be anticipated from the early stages after its onset. Prompt replacement of much larger amounts of coagulation factors, specifically fibrinogen concentrates and cryoprecipitates, may be necessary.Diagnostic criteria for clinical AFE were proposed based on the clinical presentation of cardiopulmonary collapse or DIC triggered by amniotic/foetal component inflow into maternal blood . The requirement for informed consent was waived because this was a retrospective medical chart review. We compared nine cases of clinical AFE (“AFE group”) and 78 cases of PPH excluding clinical AFE (“non-AFE PPH group”) from the 2385 patients that our department managed for delivery and postpartum transport between January 2014 and March 2016  non-coagulable bleeding accompanied by marked coagulopathy immediately after placental delivery; (2) soft uterine muscle, with the uterine fundal height reaching two or more fingers above the navel; and (3) uterine atony that does not respond to uterine contraction agents15. These patients subsequently underwent haematological testing, and any patients with diseases  that could have caused coagulation factor disorders or placental abruption, leading to a consumption coagulopathy similar to AFE, were excluded.The AFE group comprised patients who met the Japan consensus criteria for the diagnosis of AFEThe “(time of) onset” was regarded as the point in time when diagnostic, criteria-based symptoms of clinical AFE were observed in the AFE group and the point in time when blood loss of 1500 mL or more was detected in the non-AFE PPH group. The vital signs at onset , blood loss at onset , blood loss at 2 h after onset, haematological findings, and obstetric DIC scores were examined.16. To determine the total amount of blood loss, real-time measurements of the amount of blood extracted into the aspirator and the weight of blood that infiltrated into the absorption pads and gauze were measured every 20 min. The weight of blood that infiltrated into the surgical drapes was also measured after each procedure.Measurements were taken by several expert nurses trained in the management of bleeding during labour and surgery, similar to our previous studiesThe blood loss (B) was divided by the fibrinogen levels (F) at onset to calculate the B/F ratio (mL dL/mg) and to compare the extent of consumption coagulopathy at onset.Statistical analysis was performed using JMP v13.0 . The Kruskal–Wallis and chi-square tests were used to compare the two groups, with the significance level set to a p-value less than 0.05.Within the study period, 2385 patients were managed for delivery and postpartum at our department, of whom the records of 128 patients indicated massive blood loss of 1500 mL or more. After applying the exclusion criteria, 87 patients’ cases were used in the analysis. None of these patients received anticoagulant or antiplatelet therapy.The AFE group included nine patients, with three cases of cardiopulmonary collapse-type AFE patients 1–3) and six cases of DIC-type (uterine-type) AFE (patients 4–9). The patients’ backgrounds are shown in Table –3 and siPatients 4–9 all survived after massive blood losses subsequent to delivery (during Caesarean section) or 2 h after delivery (post-Caesarean section). All nine patients fulfilled every clinical feature of DIC-type AFE, including non-coagulable bleeding immediately after placental delivery. At the time of onset, the main symptom was non-coagulable bleeding accompanied by marked coagulopathy immediately after placental delivery and uterine atony that did not respond to uterine contraction agents.The 78 pregnancies in the non-AFE PPH group were complicated by twin pregnancies, uterine atony, low-lying placenta/placenta previa/placenta accreta, and birth canal lacerations. Supplementary Table There were no significant differences in vital signs at onset between the two groups. The AFE group had significantly lower amounts of blood loss at onset  but had significantly higher amounts of blood loss at 2 h after onset   in the group diagnosed with clinical AFE Table . The greWhen the cut-off values were calculated for each coagulative function test value, with respect to AFE positivity and using a receiver operating characteristic (ROC) curve based on the Youden index (sensitivity + specificity − 1), those of the tests with top three AUC values were 132 mg/dL (fibrinogen), 1.44 (PT-INR), and 80.0 μg/dL (fibrinogen degradation products [FDP]). The predictive power (PP), defined as (true positive + true negative)/total, was evaluated using the optimum cut-off value selected. The PP values for fibrinogen, PT-INR, and FDP were 0.9673, 0.9767, and 0.9512, respectively , those with blood loss equivalent to group III but with lower fibrinogen levels (group II), and those who maintained their fibrinogen levels (group III) Fig. . The patCompared to the PPH group, the AFE group had a significantly lower concentration of extrinsic coagulation factors, a representative example is fibrinogen. Fibrinogen exhibited the strongest correlation with AFE in our analysis, with a cut-off value at 132 mg/dL. Although the AFE group had significantly lower amounts of blood loss at onset than the PPH group, the extent of coagulopathy was severe, suggesting that the B/F ratio could be used to differentiate between these two diseases, both of which present with massive bleeding. Interestingly, despite similar amounts of bleeding being noted at onset, the fibrinogen level was significantly lower in patients with DIC-type AFE than those with non-AFE PPH. All patients in the AFE group exhibited DIC, and even patients that did not have bleeding developed severe consumption coagulopathy.The nonparametric density estimation showed a group that exhibited a relatively small amount of bleeding, not accompanied by systemic symptoms, which were labelled “group II”, believed to consist of patients of the DIC (uterine)-type. However, only 6 out of 11 patients (54.5%) with extreme hyperfibrinogenaemia met the existing diagnostic criteria for clinical AFE. Conversely, the fact that five patients (45.5%) did not fulfil those diagnostic criteria suggests that the current diagnostic criteria for clinical AFE may not be adequate. In this disorder, which requires intensive treatment from its early stages, determining blood loss and quickly measuring fibrinogen could promote more accurate diagnosis and treatment.12. Of the predictive factors for cases with massive bleeding, fibrinogen showed the strongest correlation, even more than the shock index or obstetrical DIC score. Fibrinogen is also reportedly useful as a criterion for assessing the severity of consumption coagulopathy14. The cut-off value for fibrinogen at which six or more units of RBC transfusion are needed is 155 mg/dL. In our analysis, fibrinogen exhibited the strongest correlation with AFE, consistent with previous reports, but the AUC, which shows the strength of the correlation, was higher, and the cut-off value was lower than in previous reports. The AFE group experienced more severe coagulopathy and differentiation according to their fibrinogen levels, a marker that appears to be more accurate than findings of massive bleeding or placental abruption, which was used in previous reports.We previously reported the usefulness of fibrinogen levels for predicting massive obstetrical haemorrhage17. When an anaphylactoid reaction occurs, factor XII and factor XI are activated, and plasminogen is activated in the fibrinolytic system. The kinin-kallikrein system is also activated, and bradykinin is produced by the plasmin-associated degradation of high-molecular-weight kininogen. Anaphylatoxins are activated as well as the complement system, which produces anaphylatoxins such as C3a and C5a. Because bradykinin acts as a smooth muscle relaxant19, it lowers blood pressure and worsens atonic bleeding. The entry of amniotic fluid tissue factors into the maternal bloodstream also activates the extrinsic system. Tissue thromboplastin is found in the amniotic fluid, and it is one possible cause of consumption coagulopathy20. When tissue thromboplastin enters the bloodstream, it results in excessive conversion of fibrinogen into fibrin, creating microthrombi. In the process, tissue thromboplastin forms a complex with factor VII and is consumed, thus lowering its concentration in the blood21. With this type of coagulopathy, the cause of DIC is different from the dilutional coagulopathy caused by infusion or transfusion or the loss of coagulation factors due to massive bleeding. Therefore, severe DIC can develop even if there is no massive bleeding caused by vascular collapse. The anaphylactoid reaction also includes a pathway wherein proteases derived from inflammatory cells, a representative example is granulocyte elastase, which directly breaks down fibrinogen without passing through fibrin. It is also possible that the anaphylactoid reaction contributes to the rapid decrease in fibrinogen.The mechanism by which AFE triggers DIC is based on the flow of amniotic fluid into the maternal blood. AFE occurs if there is a maternal anaphylactoid reaction to the amniotic fluid. C1-inhibitor plays a central role among the substances that suppress anaphylactoid reactions, and it has been suggested that anaphylactoid reactions occur when amniotic fluid enters the blood of patients with low C1-inhibitor levelsUltrasound and other examination techniques offer relatively rapid diagnosis at the time of onset of placental abruption. However, DIC (uterine)-type AFE with consumption coagulopathy secondary to the entry of tissue factors as described above only shows consumption coagulopathy and uterine relaxation, which are difficult to distinguish from atonic bleeding. Diagnosis in these cases is, therefore, difficult, and delays in diagnosis result in greater severity of the condition and a worse prognosis. Consumption coagulopathy involving these diseases is associated with an inflowing of tissue factors (DAIT). There is a more prominent decrease in fibrinogen associated with blood loss than with atonic bleeding, and the B/F value is higher in the former. In such cases, close attention to the risk of severe consumption coagulopathy and rapid application of haemostatic resuscitation may improve patient prognosis.There were some limitations in this study that must be acknowledged. First, our facility is a high-volume centre for maternal emergencies, and the frequency of AFE, including DIC-type AFE, may have been higher than those reported in the literature. Second, in this study, the measurement limit values for the coagulation profiles included fibrinogen < 70 mg/dL, PT-INR > 5.2, and FDP 80 μg/dL. Because extremely abnormal coagulation/fibrinolysis occurs with AFE, increasing the measurement limits may enable discovering newer and more sensitive coagulative/fibrinolytic markers. Third, the small sample size, particularly for the AFE group, and the retrospective nature of the study may have biased our results; an analysis of cases in the future could shed more light on the differences at onset between AFE and PPH.25, resulting in different diagnostic criteria for each country28. Those criteria are somewhat variable. Although it is being sought, at this time there is no highly specific marker to aid in the diagnosis of AFE at onset32. However, most of the diagnostic criteria for AFE include “coagulopathy”. As coagulopathy develops, focusing on its features imparts the possibility to improve diagnostic accuracy leading to early intervention and improved prognosis.Critical challenges remain in this field. In this study, the onset of AFE was defined as the time at which diagnostic criteria for clinical AFE were observed, but currently, there are no serum markers for a clear diagnosis of AFE in the early stages. Therefore, there is a need for future research to develop serum markers enabling more accurate and rapid assessments of the results. Moreover, a nationwide analysis is needed to establish diagnostic criteria. As this would require specimens from the early stages of the disease, each region would need to have resources such as coagulation tests in place to collect specimens and record the blood loss at the time of onset, followed by the rapid performance of testing and treatment at higher-order medical care facilities. Research on the risk factors of AFE has been conducted in various nationwide studiesIn conclusion, clinical AFE includes severe DIC, even in patients with little (to no) blood loss. Blood fibrinogen levels showed the strongest correlation at onset, with a cut-off value of 132 mg/dL. The B/F ratio has the potential to provide a reference for differentiating between PPH and DIC (uterine)-type AFE, both of which present with massive haemorrhage. The mortality rate associated with AFE remains high, and improvement in its associated prognosis will require earlier diagnosis and therapeutic interventions. In light of our results, fibrinogen may improve early clinical diagnosis to improve the prognosis of AFE via multidisciplinary therapy in the early stages.Supplementary Information.


Background: Video-based interventions have the potential to contribute to long-lasting improvements in health-seeking behaviours. Ghana's upsurge rate of information and communication technology usage presents an opportunity to improve the awareness of HPV vaccination and screening rates of cervical cancer among women in Ghana. This research aimed to assess the impact of video-based educational intervention centred on the Health Belief and Transtheoretical Models of behavioural changes in promoting HPV vaccination, cervical carcinoma awareness and willingness to have Pap smear test (PST) among women in Ghana.Methods: To achieve the intended sample size, convenient, purposive and stratified random sampling techniques were used. SPSS v. 23.0 was used in the data analysis. Percentages and frequencies were used to represent participants' demographic characteristics, knowledge of (1) cervical carcinoma, (2) human papillomavirus vaccine, and (3) Pap smear test. The chi-square test by McNemar was employed to evaluate variations in the post- and pre-intervention responses. A p-value < 0.05 was considered statistically significant. The level of significance was adjusted owing to multiple comparisons by using the Bonferroni's correction.Results: Before the intervention, 84.2% of the participant had some knowledge or information about cervical cancer, but after the intervention, 100% of the participant became aware of cervical cancer which represents 15.8% increment at a P < .001. The willingness to have a pap smear test increased from 35.8% to 94.2%  after the educational intervention. The willingness to be vaccinated increased from 47.5% to 81.7%  after the educational intervention. Six months after the intervention, participants were followed-up. 253 (42.2%) participants had gone for cervical cancer screening (Pap smear test) while 347 (57.8%) participants had not been screened. In terms of HPV vaccination, 192 participants (32.0%) had begun their HPV vaccination cycle.Conclusion: The study results show that health education, using videos, may be influential in perception changing, self-efficacy improvement and the understanding of cervical carcinoma screening and HPV vaccination. The prevalence of cervical cancer (CC) tends to draw the attention of researchers and primary healthcare providers. The Globocan 2018) report rated cervical cancer as the fourth most commonly diagnosed cancer among women with annual new registered cases of 569,847 and 311,365 deaths worldwide . The International Agency for Research on Cancer monographs has categorised 12 distinct types of oncogenes as group 1 carcinogens with HPV 18 and 16 been the predominant once , 4. Othe® as a prophylactic vaccine has demonstrated to protect younger women who are yet to be infected with HPV 18 and 16  established by the World Health Organization has effectively and efficiently increased the availability and accessibility of childhood vaccines. It has attained more comprehensive coverage globally, including African nations. Nevertheless, the lack of knowledge and the low level of awareness on HPV vaccination may have a negative influence on HPV vaccination programs in Africa , 20. HenThe prevention of ailments with significant mortality and morbidity can be achieved through modifying and developing health behaviour . EducatiA video-based educational intervention on smoking prevention and human immunodeficiency virus projects in the United States of America resulted in significant costs reduction , 29. FurFurthermore, Ebu et al. suggested that leaflets, videos and lectures as a form of educational intervention can sharpen an individual's knowledge and perceptions on cervix carcinoma and it's screening . A reseaHowever, to the authors' best of knowledge, no research has exclusively investigated the impact of video-based educational interventions on the awareness and knowledge level on Cervical Cancer, Pap smear and HPV Vaccines. This research aimed to assess the impact of a video-based educational intervention centred on the Health Belief and Transtheoretical Models of behavioural changes in promoting HPV vaccination, cervical carcinoma awareness and willingness to have Pap smear test (PST) among women in Ghana. We hypothesised that an educational intervention using videos would improve participants' knowledge and understanding of Pap smear test, cervix carcinoma and HPV vaccine. We also hypothesised that VBEI can decrease the barriers to cervical cancer screening and HPV vaccination.This population-based cross-sectional survey on the impact of video-based educational interventions on cervical cancer, pap smear and HPV vaccines was carried between the years 2019 to 2020. The sampling methods used in this survey were stratified random sampling, purposive and convenient sampling. Participants were invited to partake in the survey via a formal electronic and paper invitation. The email addresses of those who were reached electronically were collected via a previous exercise conducted within the Municipalities. We used convenient sampling for participants we had their emails. In addition, participants who did not have internet accessibility or for whom we did not have their email addresses were recruited by means of smaller local groups within the communities, home visits and church groups. The population  were categorised into three strata (3) and random sampling was employed so that every individual in the communities, homes and church groups had an equitable opportunity of participating in the survey. The purposive sampling method was used to ensure that all respondents in the survey met the inclusion criteria. The target population were residing at Takoradi, Sunyani, Kumasi and Accra. The selection of the four cities were centered on their population density and also with the objective of achieving a representative sample of the country's population.The inclusion criteria were; (i) any sound-minded female Ghanaian resident (ii) must be 18 years and above, (iii) not deaf and dumb, (iv) women with no history of HPV vaccination and Pap smear test, (v) women who owned and used any ICT device. All participants who did not meet these criteria were excluded from this study. The criteria for exclusion involved females with history of Pap smear test, females diagnosed with cervix carcinoma and individuals who did not give their consent. Responses to the above exclusion query were acquired by asking the respondents in an interview prior to the questionnaire being administered.0.916. The Cronbach's alpha assesses a given dataset's consistency or internal reliability. The questionnaire-based study was conducted after all respondents provided written consent, with their confidentiality and anonymity retained. The sample size was calculated by using the formula of the minimum sample size; thus, “n = Z2P(1-P)/d2; where, n = sample size, Z = z statistic for a level of confidence. For the level of confidence of 95%, which is conventional, the Z value is 1.96. P = expected prevalence or proportion , and d = precision .” The estimated sample size was 382 using an expected prevalence or proportion(p) of 46%; P = 0.46, considering a 95% confidence interval (CI) and a 5% marginal error. To account for heterogeneity in the target group and also ensure that maximum responses were obtained, we increased the sampling size and targeted about 645 participants.The questionnaires employed in this study is a modified version of the one used in our previous study after it was approved by experts . An adviOn the day of administering the questionnaire, all the selected respondents answered a baseline questionnaire. No control group was involved in this study because it was a pre-post-study. Video-based educational interventions were used to educate the participants.The Health Belief Model (HBM) and the Transtheoretical Model (TTM) were the two principal models in health behaviour change theories on which the interventional study was centred. These models have been utilised effectively in a similar setting to promote positive cancer screening attitude . The TraThe respondents were followed-up 6 months after staging the intervention to complete the endline questionnaire to assess their attitude and knowledge on cervix carcinoma, pap smear test and HPV vaccination. Interviews and the questionnaire were used to evaluate the impact of the VBEI on HPV vaccination and cervical cancer screening.The questionnaire design and group selection were centred on Triadic Impact theory (TTI)  and Soci2,” “Family history of cervical cancer,” “Having sexually transmitted infections,” “Multiple sexual partners (≥3)”] and symptoms  of cervical carcinoma was assessed. PST knowledge was assessed with the phrase, “Have you heard about the Pap smear test?,” “What is a Pap Smear test used for?” “Is there a need for Pap smear test after receiving the HPV vaccine” and “Have you ever had a Pap smear or Pap test?.” The knowledge of the HPV vaccine was assessed in a similar way. Some previous studies have reported these questions  and sociodemographic. The section for cervical cancer was subcategorised into (a) cervical cancer knowledge, (b) symptoms of cervical cancer, and (c) cervical cancer risk factors. If a respondent replied that they were knowledgeable of cervical cancer by saying that they had learned or knew about it, their knowledge of the disease was assessed. Awareness of the risk factors by the respondent included [“Can HPV infection cause cervical cancer,” “long term use of oral contraceptives pills,” “smoking,” “unprotected sexual practices,” “multiparity,” “Immunocompromised/HIV-AIDS,” “early age at marriage,” “Body mass index ≥ 25 kg/muestions . Other ruestions  in assesp-value <0.05 was considered statistically significant. The level of significance was adjusted owing to multiple comparisons by using the Bonferroni's correction.SPSS v. 23.0 was used in the data analysis. The respondents' sociodemographic characteristics, knowledge of HPV vaccine, cervical carcinoma, and Pap smear test were represented by percentages and frequencies. The chi-square test by McNemar was employed to evaluate variations in post- and pre-intervention responses. A A total of 645 participants answered the survey questions; however, 45 answered the questionnaire incompletely. The remaining 600 participants representing 93.0% response rate, were included in our final analysis. P < 0.001. Again, most of the respondents understood that “All women are at risk of developing cervical cancer” with a significant increase in correct responses from 325 (54.2%) to 560 (93.3%) indicating 39.1% rise in correct responses (P < 0.001). Regarding Pap smear test, 55.8% responded “Yes” to “Do you know about Pap smear test?,” but after the intervention, 100% responded “Yes” to the same question with the correct responses going up by 44.2% at a significant P < 0.001. The willingness to have a pap smear test increased from 35.8 to 94.2%  after the VBEI. We observed an increase in the intention to have a pap smear test from pre-intervention to post-intervention, with progress via the Stage of Changes from the pre-contemplation stage to the preparation stage (P < 0.001), corresponding to respondents who stated their willingness to have the Pap smear test within the next 6 months.The impact of the interventional study on cervical cancer awareness and knowledge are presented in on stage . The proP < 0.001 was observed across these symptoms when the post and pre-interventional responses were compared. Majority of the respondents understood that Human papillomavirus (HPV) infection is one of the key risk factor in the development of cervix carcinoma with a significant increase in correct responses from 345 (57.5%) to 595 (99.2%) representing 41.7% increase (P < 0.001). Other correctly identified risk factors with significant rise in knowledge level regarding such factors include “long term use of oral contraceptives pills”, “unprotected sexual practises,” “Early age at marriage,” “Multiparity,” “Body mass index ≥ 25 kg/m2 (Obesity)” and “Family history of cervical cancer” with increment of 45% (from 57.5 to 96.7%), 40.8% (from 53.3 to 94.2%), 40% (from 21.7 to 61.7%), 73.3% (from 20.0 to 93.3%), 55.9% (from 18.3 to 74.2%), and 46.7 (from 50.0 to 96.7%), respectively, with all at a P < 0.001 . Most participants understood that HPV is sexually transmitted  and that HPV infection can go away on its own without treatment . Concerning HPV vaccine, 26.7% responded “Yes” to “Have you heard of the HPV vaccines ?” in pre-intervention while 100% responded “Yes” to the same question in post-intervention representing 73.3% increase at a significant P < 0.001  and also the vaccine can be given to males . The willingness to be vaccinated increased from 47.5 to 81.7%  after the VBEI. We observed an increase in the willingness to be vaccinated from pre-intervention to post-intervention, with progress via the Stage of Changes from the pre-contemplation stage to the preparation stage (P < 0.001), corresponding to respondents who stated their willingness to be vaccinated within the next 6 months. The possible barriers to cervical cancer screening identified by the respondents were “lack of knowledge (70.7%), Poor awareness (59.4%), Lack of understanding about screening procedure (53.4%), Stigma (51.9%), Superstition (37.6%) and family support (30.8%).” Respondent views on the potential use of the videos and their satisfaction with the videos were also evaluated. Our findings showed a high level of video satisfaction among the respondents. Most respondents confirmed that the length of the video is “Right” (89%), and few did not understand some aspect of the video (4.2%).After the intervention, 100% of the participants responded “Yes” to the statement “Have you ever heard of HPV?” compared to the 51.7% who responded Yes to the same question before the intervention, indicating a significant increase of 48.3% in the “Yes” responses  participants had gone for cervical cancer screening (Pap smear test) while 347 (57.8%) participants had not been screened. In terms of vaccination, 192 participants (32.0%) had begun their HPV vaccination cycle.The research was geared toward evaluating the impact of VBEI on improving the awareness and knowledge on cervix carcinoma, Pap smear test and HPV vaccines. We hypothesised that an educational intervention using videos would improve participants' knowledge and understanding of Pap smear test, cervix carcinoma and HPV vaccine. Interestingly, in other to achieve our objectives the effect and impact of the educational intervention were totally validated among the respondents in the study. These findings were consistent with the previous study performed by Gottvall et al.  where a Considering the substantial increase in the level of knowledge about Human papillomavirus as a causative organism of cervix carcinoma, the acceptability of Human papillomavirus vaccination among these women may be easier. Knowing HPV as a high-risk factor of cervix carcinoma may increase HPV vaccination uptake. The HPV vaccines have shown to be safe and very effective in preventing cervical cancer and other HPV cancer types and infections , 49–51. A notable outcome from our analysis was the fact that the video-based educational intervention massively and significantly improved participant's knowledge of cervix carcinoma risk factors and symptoms. This outcome runs contrary to the findings of Ampofo et al. where educational intervention could not improve the respondent's knowledge of cervix carcinoma risk factors and symptoms . The difGottvall et al. reported that educational intervention was unable to change participants' intention of getting a pap smear test and the usage of condom . SimilarIntriguingly, after the video-based educational study, possible barriers to cervical cancer screening such as “lack of knowledge, poor awareness, lack of understanding about screening procedure, stigma, superstition, fear of embarrassment, anxiety, the pain of pap test and lack of family support" was not changed. This result shows that utilising only educational intervention might not be enough to decrease possible screening barriers. Rosser et al. reported that stigmatisation among women, screening acceptability and cervical cancer risk perceptions failed to decrease after an educational intervention was conducted . SimilarNevertheless, screening facilities for cervical cancer might not be adequately developed in some resource-constrained nations like Ghana. Again, details on the availability of screening and in-depth clarification on the procedures for screening, utilising relevant communications , could help decrease barriers. Ornelas et al.  proposedOur results also revealed the comfortability women had while watching the video in varieties of settings and modalities. For instance, the majority of the participants showed their comfortability in watching the videos as a group and also suggested that the videos must be shown to some women associations or groups within their communities. During a period of several conflicting priorities, consistent and regular messaging utilising a range of modalities can aid ensure that pertinent health information's are received by women. The videos could still be beneficial to women who have previously had a pap smear test since all the participants attested to the fact that they learnt something new, as well as considering that there are sometimes myths regarding cervical cancer screening.Besides, a major determining factor in the health belief model is the person's confidence level or self-efficacy. Numerous studies have evaluated its influence on screening for cervical cancer –57. The Our findings indicated significant improvements in the willingness to be vaccinated with the HPV vaccine, an outcome that is comparable to other video-based study, accompanied by a group discussion session for preventing Obesity . AdditioEven though pragmatic measures were put in place to avoid shortfalls and limitations, we still had some limitations. Due to socially perceived value, answers to queries such as willingness-to-be vaccinated and screened may be biased, and might be varied if vaccination and pap smear tests were readily available after the intervention. Again, there was a decrease in our sample size due to the survey being incompletely answered. Nevertheless, we believe that the relevance of our results was not compromised. Additionally, time and budgets constraints did not allow for a longer time of follow-up.Utilising an educational intervention based on theory, substantially improved knowledge of cervix carcinoma symptoms, risk factors, Pap smear test and HPV vaccines, which contributed to the majority of the respondents seeking for the Pap smear test and HPV vaccine after the post-intervention. The study results show that health education using videos may be influential in perception changing, self-efficacy improvement and the understanding of cervical carcinoma screening and HPV vaccination. Regardless of the screening barriers observed in the study, the intervention achieved positive belief concerning screening and high level of knowledge. While respondents may be well-educated, and have improved self-efficacy, it was clear that the barriers such as “lack of knowledge, Poor awareness, “lack of understanding about screening procedure, Stigma, Superstition and family support” among others could discourage qualified women from being screened. Initiatives to decrease the barriers may improve the uptake of screening for cervical cancer within the study population. It is important to establish that educational interventions will help women to determine their susceptibility level and implement actions to minimise the likelihood of contracting the disease. The results of this study are vital in steering health educational interventions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Zhengzhou University and Henan Provincial People's Hospital. The patients/participants provided their written informed consent to participate in this study.HA: data curation. KS: funding acquisition and supervision. CA-B: investigation. CE and CA: methodology. ES: software. ED: writing—original draft. ED and GA: writing—review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein that is expressed in many tissues and in the vast majority of species, although it was first discovered as a component of human cytotoxic T lymphocytes. TIA1 has a dual localization in the nucleus and cytoplasm, where it plays an important role as a regulator of gene-expression flux. As a multifunctional master modulator, TIA1 controls biological processes relevant to the physiological functioning of the organism and the development and/or progression of several human pathologies. This review summarizes our current knowledge of the molecular aspects and cellular processes involving TIA1, with relevance for human pathophysiology. T-cell intracellular antigen 1 (TIA1) is a member of the RNA-binding protein (RBP) family. It is now 30 years since the first report on the cloning and characterization of TIA1 was published by the laboratory of Paul Anderson and colleagues , who ideThe human TIA1 gene is located on chromosomal region 2p13 and consists of 13 exons that, by alternative splicing, can give rise to two major isoforms. At the structural level, TIA1 is similar to other classical RBPs, consisting of three RNA-recognition motifs (RRMs) and a low-complexity glutamine and asparagine (Q/N)-rich carboxyl-terminal domain, which favors protein-protein interactions .The Anderson laboratory later identified TIA1-related/like protein (TIAR/TIAL1), which shares 85% amino-acid sequence similarity with TIA1 in the amino-terminal region but only 51% in the C-terminal region, the expression of which also promotes DNA fragmentation .Caenorhabditis elegans and Drosophila melanogaster, illustrates the high degree of shared identity ? Wang and colleagues argue that this redundancy leads to increased robustness in the regulation of gene expression, although the two proteins may differ in terms of their interactions with other proteins or RNAs and thus regulate some biological processes differently. They may even be post-translationally modified differently, allowing distinct cell-signaling pathways to regulate the activity of TIA proteins and their isoforms. Moreover, the expression pattern of TIA proteins could be distinctly modulated in different tissues .TIA1 is virtually ubiquitous. Although discovered in the immune system, it is expressed in many other cells and tissues A 1,2,3,,3,2,3,20Under steady-state conditions, TIA1 is mainly localized in the nucleus (showing nucleolar exclusion) and, to a lesser extent, in the cytoplasm. TIA1 translocates from the nucleus to the cytoplasm under stress conditions . AlthougGene expression in eukaryotic cells is an orderly process comprising: DNA replication, transcription; post-transcriptional processes, such as processing/splicing of pre-mRNAs; and transport, stability and translation of mature mRNAs. Additionally, post-translational regulatory mechanisms modulate the function, stability and fate of proteins. By virtue of its properties of binding to cellular RNA/DNA, TIA1 participates in the regulation of many of these processes. In the presence of RNA, it binds to small fragments of 3–11 uracil-rich ribonucleotides , but it COL2A1  [IGFBP-3 (insulin-like growth-factor binding protein-3) [PACAP (pituitary adenylate cyclase-activating polypeptide) [PTGS2 (prostaglandin-endoperoxide synthase 2) and IL-6 (interleukin 6) gene transcription was demonstrated [TIA1 was first implicated in transcriptional regulation in 2007, when it was described that the C-terminal domain of RNA polymerase II interacted with components of the spliceosome processing factor snRNP U1 and other proteins, including TIA1  Figure . These itype II) , IGFBP-3otein-3)  or testipeptide)  seem to peptide) . In thisnstrated . Similarnstrated .One of the nuclear functions of TIA1 is to regulate the alternative splicing  of some pre-mRNAs to favor the inclusion ,33,34,35The cellular relevance of TIA1 in the regulation of alternative and constitutive splicing was confirmed through the establishment of a binding map of these regulators to RNA in HeLa cells using in vivo irradiation of cells with ultraviolet light and subsequent immunoprecipitation of RNA-protein complexes (termed iCLIP) . ResultsTIA1 can modulate cellular translation by limiting the availability of the ribosomal machinery and the translational efficiency of specific cellular mRNAs, either under conditions of stress, to safeguard cell viability, or under conditions of homeostasis ,42,43,44In the absence of stress, 48S translation initiation complexes, which include the ternary translation-initiator complex eIF2-GTP-tRNAMet, the small subunit of the ribosome, other translation initiation factors (eIFs) and mRNA, are formed in the cell. When translation is initiated, eIF5 causes hydrolysis of eIF2-associated GTP. The 60S subunit of the ribosome then binds, displacing some eIFs, and the 80S ribosome is formed. However, under stress, the α-subunit of eIF2 is phosphorylated by a family of kinases such that eIF2B cannot exchange GDP for GTP, eIF2-GTP-tRNAMet levels decrease and translation pre-initiator complexes cannot form properly. At this point, TIA1 associates with the complex formed by eIF4E, eIF4G, eIF4A, eIF4B, eIF3 and the small subunit of ribosome in an anomalous 48S complex. These inactive translation pre-initiator complexes associated with mRNAs accumulate in the cytoplasm and, through the aggregation properties of the Q/N-rich domain of TIA1 and PABP (Poly(A) Binding Protein) proteins, bind together, forming large foci of mRNAs and proteins termed stress granules (SGs) ,46,47,48SGs are dynamic structures, and most of their components are in a constant flux of assembly and disassembly ,55,56. Sc mRNA translation [There are many proteins  that have been identified as components of SGs, in addition to RNAs (coding and non-coding). These include the HuR protein   and somenslation ,43 of thnslation  and of tnslation  has alsonslation ,34,35. Inslation ,56,67.TIA1 has the ability to globally and/or specifically inhibit the translation of cellular mRNAs in stress-independent conditions by binding to specific sequences located in the 5′- and/or 3′-UTR region of mRNAs . The firmRNA turnover is the process by which an mRNA is degraded before or after translation. This can occur at the 5′ end of the mRNA through decapping by the activity of DCP1 and DCP2 (dipeptidyl carboxypeptidase 1 and 2) and the exonuclease XRN1 (5′-3′ exoribonuclease 1)  or at thThe multifunctional capacity of TIA1 to modulate gene expression points to an important role of TIA1 in the maintenance of cell homeostasis and in the regulation of several cellular processes with pathophysiological implications .The health of all multicellular organisms depends not only on their ability to produce new cells but also to get rid of unwanted cells . The firAutophagy is an evolutionarily conserved mechanism to eliminate dysfunctional cells or their damaged components, promoting cell regeneration and clearance . TIA1 haTIA1 and TIAR modulate cell proliferation by promoting or inhibiting cell growth . For exaThe mitochondrion is a cytoplasmic organelle unique and essential to eukaryotic cells but with a proteobacteria origin. Mitochondria respond to changes in genetic, metabolic and/or environmental conditions by modifying the dynamics of their morphology and architecture to achieve cellular homeostasis or to initiate mitophagy and/or cell death or apoptosis. TIA1 has been associated with mitochondrial respiration and mitochondrial fission/fusion dynamics ,94,119. D. melanogaster, Rox8 protein expression is increased during the egg-formation process [Bombyx mori, the TIA1 ortholog BmTRN-1 increases the expression of EN86 in the midgut during larvae-pupa metamorphosis [Xenopus laevis embryogenesis, TIA1 is predominantly transcribed during nervous-system development, supporting the notion that TIA1-mediated regulation of gene expression plays an important role in amphibian neuronal development [C. elegans, TIA1 expression is associated with apoptosis of some germ cells to maintain gamete quality [TIA1 expression is not homogeneous in all mouse embryonic tissues and is greater in neuronal tissues, such as brain and retina . Indeed,orphosis . EN86 paorphosis . During elopment . In C. e quality . Overall quality ,36,88,95The relevance of TIA proteins during embryogenesis was addressed in vivo by generating mutant mice deficient in TIA1  and TIARInflammation is one of the immune system’s defense mechanisms against the presence of dangerous agents or toxic products . The essential function of this complex cellular response is to eliminate and repair cellular damage. The involvement of TIA1 in the molecular mechanisms associated with inflammatory processes was discovered in the early 2000s  Figure . The difTIA1-knockout (KO) mice have a profound inflammatory diathesis and are markedly more susceptible to lipopolysaccharide-induced septic shock than wild-type counterparts . MoreoveStress granules are non-membranous aggregates that form from mRNAs arrested at translation initiation and thus contain translation initiation factors, in addition to proteins with both RNA-binding and other functions ,133 Fig. SimilarThe cellular-stress response constitutes one of the first lines of defense against viral infection. Its activation can lead to global translational repression in the host cell, as well as SG formation, processes in which TIA1 is directly involved . Upon inAmyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the cerebral cortex and spinal cord, resulting in severe muscle weakness. Although its cause remains unknown, several genetic mutations have been found that could be related to the progression of the disease. Many of them affect RBPs involved in RNA metabolism found in SGs, as is the case of TIA1 . This haTauopathies are neurodegenerative disorders characterized by the formation of insoluble brain deposits of tau protein. Studies have shown that the pathophysiology of these diseases is also related to the interaction of tau with RBPs . The rolSpinal muscular atrophy (SMA) is caused by deletions or mutations of the survival motor neuron 1 (SMN1) gene. Its cognate gene, SMN2, cannot compensate for this loss due to the predominant skipping of exon 7 during splicing of its mRNA, which involves TIA1. In a recent study analyzing the effect of TIA1 KO in a murine model of mild SMA , the autAvoidance behaviors are adaptive responses to environmental threats. Those related to fear are particularly necessary for survival but can be detrimental when they occur excessively, as is the case in post-traumatic stress disorder. Recently, Rayman and colleagues studied the physiological role of TIA1 in mouse brain, concluding that it bidirectionally modulates stress-dependent synaptic plasticity in the hippocampus . They alHuntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormal expansion of CAG repeats in the huntingtin gene (HTT), which results in polyglutamine expansions in the protein . Mutant SMN2 exon 7, the authors were only able to observe a mild effect of the mutation on the process, in agreement with previous reports [Welander distal myopathy (WDM) is a dominantly inherited autosomal muscular dystrophy that manifests late in life (40–60 years) . Its fir reports ,111. Reg reports ,112. Fin reports . In this reports  , which is essential for glucose-induced insulin synthesis . A recenTIA1 also plays a role in lipid metabolism. Its depletion in nerve tissue increases the expression of genes that are normally induced by fasting and are involved in lipid storage, transport and membrane trafficking and alters lipid-droplet formation . MoreoveThroughout this review, we have detailed the most important discoveries related to TIA1 and its mechanistic implications, as well as the related cellular and pathophysiological processes. Although in recent years, there have been great and relevant advances in this regard, there are still many questions that remain to be answered and that deserve more detailed study. For instance, the differential aspects of the a and b isoforms of TIA1 have been scarcely studied. What we know so far suggests putative differential roles of both isoforms in the regulation of constitutive and alternative splicing, growth suppression, ability to act as proto-oncogenes, regulation of proliferation and cell cycles, etc. Analysis of the interactomes of RNAs and proteins associated with each of the cell-, tissue- and species-dependent TIA1 isoforms would help to address these aspects. The generation of tissue- and isoform-specific animal models with loss- and gain-of-function would also provide very useful information regarding the different activities involving TIA1 isoforms. Moreover, since current technology allows it, obtaining single-cell transcriptomic and proteomic expression patterns could provide novel and much more precise information concerning the role of TIA1 in different cell types.Another feature that remains poorly studied is the one that encompasses the post-translational modification patterns of TIA1, including phosphorylation, methylation, acetylation, sumoylation, etc., which could form another level of regulation of the protein and its isoforms and, consequently, of the processes that they modulate. Finally, profiles of TIA1 gene mutations should also be obtained in order to discern the role of mutated variants in proteostasis or cancer, as is the case of gain-of-function associated with proteotoxic and tumoral responses. This would also be related to the identification of prognostic and therapeutic targets. The ultimate and most important goal should be the development of drugs that enhance or reduce the functionality of TIA1 or interacting proteins, depending on the disease, by modifying their expression patterns or biological activity.