Importin 13-dependent axon diameter growth regulates conduction speeds along myelinated CNS axons.

Axon diameter influences the conduction properties of myelinated axons, both directly, and indirectly through effects on myelin. However, we have limited understanding of mechanisms controlling axon diameter growth in the central nervous system, preventing systematic dissection of how manipulating diameter affects myelination and conduction along individual axons. Here we establish zebrafish to study axon diameter. We find that importin 13b is required for axon diameter growth, but does not affect cell body size or axon length. Using neuron-specific ipo13b mutants, we assess how reduced axon diameter affects myelination and conduction, and find no changes to myelin thickness, precision of action potential propagation, or ability to sustain high frequency firing. However, increases in conduction speed that occur along single myelinated axons with development are tightly linked to their growth in diameter. This suggests that axon diameter growth is a major driver of increases in conduction speeds along myelinated axons over time.

Exploring self-care and cervical cancer prevention attitudes and practices among Moroccan and Pakistani immigrant women in Catalonia, Spain: a comparative qualitative study.

BACKGROUND: Self-care and preventive health strategies may trigger health inequities when individuals' cultural values and health beliefs are not fully understood and considered. In the case of cervical cancer (CC) screening programs immigrant women have shown lower attendance compared with native women, which increases the risk of late diagnosis and, consequently, a lower probability of survival. HPV self-sampling for CC screening has been recently added to the World Health Organization's (WHO) list of self-care interventions as a promising tool to reduce this disparity and improve screening coverage. In Catalonia, Spain, the introduction of HPV self-sampling as a part of the new population-based CC screening program, is a significant step. However, there is a lack of research addressing self-care and prevention among immigrant populations in this region. This study aims to fill this gap exploring self-care and prevention attitudes and practices among Moroccan and Pakistani women. METHODS: We conducted focus groups and individual interviews with 36 Moroccan and 37 Pakistani women in Barcelona, Spain. The topic guide of the focus groups included case vignettes to stimulate the discussion and a semi-structured questionnaire was used for the interviews. RESULTS: Our findings show that most Moroccan and Pakistani women do not prioritize self-care and prevention. They seek care for symptom treatment rather than disease prevention. In this sense, they reported not having the habit of doing regular check-ups and their self-care and prevention attitudes and practices seemed to be conditioned by cultural values. The implementation of an effective call and recall system could enhance the engagement of these populations with CC screening services. CONCLUSION: This study provides evidence on how universal concepts of self-care and prevention may not aligned with more collectivist societies, emphasizing the limited applicability and motivation of global self-care interventions guidelines for individuals with different cultural backgrounds and values. Therefore, the successful implementation of CC screening programs or any other self-care intervention requires the adoption of culturally appropriate strategies.

Everything causes cancer? Beliefs and attitudes towards cancer prevention among anti-vaxxers, flat earthers, and reptilian conspiracists: online cross sectional survey.

OBJECTIVE: To evaluate, using an online non-probability sample, the beliefs about and attitudes towards cancer prevention of people professing vaccination scepticism or conspiracy theories. DESIGN: Cross sectional survey. SETTING: Data collected mainly from ForoCoches (a well known Spanish forum) and other platforms, including Reddit (English), 4Chan (English), HispaChan (Spanish), and a Spanish language website for cancer prevention (mejorsincancer.org) from January to March 2022. PARTICIPANTS: Among 1494 responders, 209 were unvaccinated against covid-19, 112 preferred alternative rather than conventional medicine, and 62 reported flat earth or reptilian beliefs. MAIN OUTCOME MEASURES: Cancer beliefs assessed using the Cancer Awareness Measure (CAM) and Cancer Awareness Measure Mythical Causes Scale (CAM-MYCS) (both validated tools). RESULTS: Awareness of the actual causes of cancer was greater (median CAM score 63.6%) than that of mythical causes (41.7%). The most endorsed mythical causes of cancer were eating food containing additives or sweeteners, feeling stressed, and eating genetically modified food. Awareness of the actual and mythical causes of cancer among the unvaccinated, alternative medicine, and conspiracy groups was lower than among their counterparts. A median of 54.5% of the actual causes was accurately identified among each of the unvaccinated, alternative medicine, and conspiracy groups, and a median of 63.6% was identified in each of the three corresponding counterparts (P=0.13, 0.04, and 0.003, respectively). For mythical causes, medians of 25.0%, 16.7%, and 16.7% were accurately identified in the unvaccinated, alternative medicine, and conspiracy groups, respectively; a median of 41.7% was identified in each of the three corresponding counterparts (P<0.001 in adjusted models for all comparisons). In total, 673 (45.0%) participants agreed with the statement "It seems like everything causes cancer." No significant differences were observed among the unvaccinated (44.0%), conspiracist (41.9%), or alternative medicine groups (35.7%), compared with their counterparts (45.2%, 45.7%, and 45.8%, respectively). CONCLUSIONS: Almost half of the participants agreed that "It seems like everything causes cancer," which highlights the difficulty that society encounters in differentiating actual and mythical causes owing to mass information. People who believed in conspiracies, rejected the covid-19 vaccine, or preferred alternative medicine were more likely to endorse the mythical causes of cancer than their counterparts but were less likely to endorse the actual causes of cancer. These results suggest a direct connection between digital misinformation and consequent erroneous health decisions, which may represent a further preventable fraction of cancer.

HPV vaccination introduction worldwide and WHO and UNICEF estimates of national HPV immunization coverage 2010-2019.

WHO/UNICEF estimates for HPV vaccination coverage from 2010 to 2019 are analyzed against the backdrop of the 90% coverage target for HPV vaccination by 2030 set in the recently approved global strategy for cervical cancer elimination as a public health problem. As of June 2020, 107 (55%) of the 194 WHO Member States have introduced HPV vaccination. The Americas and Europe are by far the WHO regions with the most introductions, 85% and 77% of their countries having already introduced respectively. A record number of introductions was observed in 2019, most of which in low- and middle- income countries (LMIC) where access has been limited. Programs had an average performance coverage of around 67% for the first dose and 53% for the final dose of HPV. LMICs performed on average better than high- income countries for the first dose, but worse for the last dose due to higher dropout. Only 5 (6%) countries achieved coverages with the final dose of more than 90%, 22 countries (21%) achieved coverages of 75% or higher while 35 (40%) had a final dose coverage of 50% or less. When expressed as world population coverage (i.e., weighted by population size), global coverage of the final HPV dose for 2019 is estimated at 15%. There is a long way to go to meet the 2030 elimination target of 90%. In the post-COVID era attention should be paid to maintain the pace of introductions, specially ensuring the most populous countries introduce, and further improving program performance globally.

Quantifying the under-reporting of uncorrelated longitudal data: the genital warts example.

BACKGROUND: Genital warts are a common and highly contagious sexually transmitted disease. They have a large economic burden and affect several aspects of quality of life. Incidence data underestimate the real occurrence of genital warts because this infection is often under-reported, mostly due to their specific characteristics such as the asymptomatic course. METHODS: Genital warts cases for the analysis were obtained from the Catalan public health system database (SIDIAP) for the period 2009-2016. People under 15 and over 94 years old were excluded from the analysis as the incidence of genital warts in this population is negligible. This work introduces a time series model based on a mixture of two distributions, capable of detecting the presence of under-reporting in the data. In order to identify potential differences in the magnitude of the under-reporting issue depending on sex and age, these covariates were included in the model. RESULTS: This work shows that only about 80% in average of genital warts incidence in Catalunya in the period 2009-2016 was registered, although the frequency of under-reporting has been decreasing over the study period. It can also be seen that this issue has a deeper impact on women over 30 years old. CONCLUSIONS: Although this study shows that the quality of the registered data has improved over the considered period of time, the Catalan public health system is underestimating genital warts real burden in almost 10,000 cases, around 23% of the registered cases. The total annual cost is underestimated in about 10 million Euros respect the 54 million Euros annually devoted to genital warts in Catalunya, representing 0.4% of the total budget.

Morphometric analysis of developing zebrafish embryos allows predicting teratogenicity modes of action in higher vertebrates.

The early identification of teratogens in humans and animals is mandatory for drug discovery and development. Zebrafish has emerged as an alternative model to traditional preclinical models for predicting teratogenicity and other potential chemical-induced toxicity hazards. To prove its predictivity, we exposed zebrafish embryos from 0 to 96 h post fertilization to a battery of 31 compounds classified as teratogens or non-teratogens in mammals. The teratogenicity score was based on the measurement of 16 phenotypical parameters, namely heart edema, pigmentation, body length, eye size, yolk size, yolk sac edema, otic vesicle defects, otoliths defects, body axis defects, developmental delay, tail bending, scoliosis, lateral fins absence, hatching ratio, lower jaw malformations and tissue necrosis. Among the 31 compounds, 20 were detected as teratogens and 11 as non-teratogens, resulting in 94.44 % sensitivity, 90.91 % specificity and 87.10 % accuracy compared to rodents. These percentages decreased slightly when referred to humans, with 87.50 % sensitivity, 81.82 % specificity and 74.19 % accuracy, but allowed an increase in the prediction levels reported by rodents for the same compounds. Positive compounds showed a high correlation among teratogenic parameters, pointing out at general developmental delay as major cause to explain the physiological/morphological malformations. A more detailed analysis based on deviations from main trends revealed potential specific modes of action for some compounds such as retinoic acid, DEAB, ochratoxin A, haloperidol, warfarin, valproic acid, acetaminophen, dasatinib, imatinib, dexamethasone, 6-aminonicotinamide and bisphenol A. The high degree of predictivity and the possibility of applying mechanistic approaches makes zebrafish a powerful model for screening teratogenicity.

Impact of a single-age cohort human papillomavirus vaccination strategy in Catalonia, Spain: Population-based analysis of anogenital warts in men and women.

Extensive multiple-age cohort human papillomavirus (HPV) vaccination has proved to be highly effective. We aimed to determine the 8-year population impact of a female single-age cohort HPV vaccination programme on the incidence of anogenital warts (AGW). In 2008, Catalonia initiated a school-based quadrivalent HPV vaccination programme targeting 11-year-old girls, achieving coverage over 80%. Data on diagnoses of AGW and genital herpes were obtained from a population-based database of electronic health records covering 74% of the population. The annual incidence rates from 2009 to 2016 were calculated, stratified by age and sex using Joinpoint regression to estimate trends and annual percentage changes (APC). Among women aged 16-19 years, the AGW incidence decreased by 61% from 2012 to 2016 (APC -19.4%; 95% CI: -30.0 to -7.3). In contrast, the incidence of genital herpes in same-aged women increased throughout the study period (APC 11.1%; 95% CI: 7.2-15.2). Among men aged 20-22 years, the increasing incidence of AGW shifted to a downward trend in 2013 (APC 2009-2013: 17.0%; 95% CI: 8.2-26.5; and APC 2013-2016: -4.5%; 95% CI: -14.6 to 6.9). A similar pattern was observed among men aged 23-25 years (APC 2009-2014: 16.0%; 95% CI: 12.0-20.2; and APC 2014-2016: -6.0%; 95% CI: -18.4 to 8.3). In contrast to AGW, among men aged 20-25 years, the incidence of genital herpes increased over this period. Our study strongly suggests that a single-cohort HPV vaccination strategy with high vaccine uptake not only provides direct benefit in the vaccinated cohorts but also extends protection through a herd effect to unvaccinated men.

Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b.

Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons.

Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.

Selection of the correct targets for myelination and regulation of myelin sheath growth are essential for central nervous system (CNS) formation and function. Through a genetic screen in zebrafish and complementary analyses in mice, we find that loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies, without affecting targeting to axons. In addition, loss of Neurofascin reduces CNS myelination by impairing myelin sheath growth. Time-lapse imaging reveals that the distinct myelinating processes of individual oligodendrocytes can engage in target selection and sheath growth at the same time and that Neurofascin concomitantly regulates targeting and growth. Disruption to Caspr, the neuronal binding partner of oligodendrocyte Neurofascin, also impairs myelin sheath growth, likely reflecting its association in an adhesion complex at the axon-glial interface with Neurofascin. Caspr does not, however, affect myelin targeting, further indicating that Neurofascin independently regulates distinct aspects of CNS myelination by individual oligodendrocytes in vivo.

Human papillomavirus vaccine disease impact beyond expectations.

Since 2006, 115 countries and territories have introduced human papillomavirus (HPV) vaccination programs. Several efforts have been undertaken to evaluate the impact of HPV vaccines. Many countries, mainly high-income and with high screening coverage, are already reporting a visible impact of the HPV vaccine on HPV-related diseases. Others, largely low-income and middle-income countries, are introducing HPV vaccine to control HPV diseases that will undoubtedly generate a similar impact. In this review, we will summarize the compelling evidence of the impact of vaccines in reducing the burden of HPV-related disease. The data support additional efforts to make HPV vaccines widely available to adolescent girls in the countries that bear the vast majority of cervical cancer-related morbidity and mortality.

Comparison of Zebrafish Larvae and hiPSC Cardiomyocytes for Predicting Drug-Induced Cardiotoxicity in Humans.

Cardiovascular drug toxicity is responsible for 17% of drug withdrawals in clinical phases, half of post-marketed drug withdrawals and remains an important adverse effect of several marketed drugs. Early assessment of drug-induced cardiovascular toxicity is mandatory and typically done in cellular systems and mammals. Current in vitro screening methods allow high-throughput but are biologically reductionist. The use of mammal models, which allow a better translatability for predicting clinical outputs, is low-throughput, highly expensive, and ethically controversial. Given the analogies between the human and the zebrafish cardiovascular systems, we propose the use of zebrafish larvae during early drug discovery phases as a balanced model between biological translatability and screening throughput for addressing potential liabilities. To this end, we have developed a high-throughput screening platform that enables fully automatized in vivo image acquisition and analysis to extract a plethora of relevant cardiovascular parameters: heart rate, arrhythmia, AV blockage, ejection fraction, and blood flow, among others. We have used this platform to address the predictive power of zebrafish larvae for detecting potential cardiovascular liabilities in humans. We tested a chemical library of 92 compounds with known clinical cardiotoxicity profiles. The cross-comparison with clinical data and data acquired from human induced pluripotent stem cell cardiomyocytes calcium imaging showed that zebrafish larvae allow a more reliable prediction of cardiotoxicity than cellular systems. Interestingly, our analysis with zebrafish yields similar predictive performance as previous validation meta-studies performed with dogs, the standard regulatory preclinical model for predicting cardiotoxic liabilities prior to clinical phases.

Multiplex Analysis Platform for Endocrine Disruption Prediction Using Zebrafish.

Small fish are an excellent experimental model to screen endocrine-disrupting compounds, but current fish-based assays to detect endocrine disruption have not been standardized yet, meaning that there is not consensus on endpoints and biomarkers to be measured. Moreover, exposure conditions may vary depending on the species used as the experimental model and the endocrine pathway evaluated. At present, a battery of a wide range of assays is usually needed for the complete assessment of endocrine activities. With the aim of providing a simple, robust, and fast assay to assess endocrine-disrupting potencies for the three major endocrine axes, i.e., estrogens, androgens, and thyroid, we propose the use of a panel of eight gene expression biomarkers in zebrafish larvae. This includes brain aromatase (cyp19a1b) and vitellogenin 1 (vtg1) for estrogens, cytosolic sulfotransferase 2 family 2 (sult2st3) and cytochrome P450 2k22 (cyp2k22) for androgens, and thyroid peroxidase (tpo), transthyretin (ttr), thyroid receptor α (trα), and iodothyronine deiodinase 2 (dio2) for thyroid metabolism. All of them were selected according to their responses after exposure to the natural ligands 17ß-estradiol, testosterone, and 3,3',5-triiodo-L-thyronine (T3), respectively, and subsequently validated using compounds reported as endocrine disruptors in previous studies. Cross-talk effects were also evaluated for all compounds.

Strength in numbers: Collaborative science for new experimental model systems.

Our current understanding of biology is heavily based on a small number of genetically tractable model organisms. Most eukaryotic phyla lack such experimental models, and this limits our ability to explore the molecular mechanisms that ultimately define their biology, ecology, and diversity. In particular, marine protists suffer from a paucity of model organisms despite playing critical roles in global nutrient cycles, food webs, and climate. To address this deficit, an initiative was launched in 2015 to foster the development of ecologically and taxonomically diverse marine protist genetic models. The development of new models faces many barriers, some technical and others institutional, and this often discourages the risky, long-term effort that may be required. To lower these barriers and tackle the complexity of this effort, a highly collaborative community-based approach was taken. Herein, we describe this approach, the advances achieved, and the lessons learned by participants in this novel community-based model for research.

The natural history of human papillomavirus infection.

Human papillomavirus (HPV) is a small double-stranded DNA virus that commonly infects humans. The oncogenic characteristics of HPV derive from the oncoproteins E6 and E7 that act inhibiting p53 and pRB tumor suppressors. About 5% of all cancers worldwide are attributable mainly to those known as high-risk, including HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. Infection with HPV is common after sexual initiation, but the majority of HPV infections do not cause symptoms or disease and are cleared within 12-24 months post-infection. Only a small fraction of those infections that persist or progress to a preneoplastic lesion result in cancer. Persistence of HPV infection is needed to start the oncogenic process. Clearance of infection is common in young adults. Viral load and viral type are the main cofactors for progression from infection to cervical intraepithelial lesions and cancer. Smoking, hormonal exposure, and HIV are additional exposures that increase the risk of progression to cancer. The adverse health effects of HPV infections can be largely controlled through vaccination and screening.

Epidemiology and burden of HPV-related disease.

Human papillomavirus (HPV) infection is recognized as one of the major causes of infection-related cancer in both men and women. High-risk HPV types are not only responsible for virtually all cervical cancer cases but also for a fraction of cancers of the vulva, vagina, penis, anus, and head and neck cancers. Furthermore, HPV is also the cause of anogenital warts and recurrent respiratory papillomatosis. Despite the availability of multiple preventative strategies, HPV-related cancer remains a leading cause of morbi-mortality in many parts of the world, particularly in less developed countries. Thus, in this review, we summarize the latest estimates of the global burden of HPV-related diseases, trends, the attributable fraction by HPV types, and the potential preventative fraction.

[Factors Associated with Sexual Risk Behaviour Among Young People in Catalonia]. / Determinantes de las conductas sexuales de riesgo en jovenes de Cataluña.

BACKGROUND: Sexual behavior in young people is influenced by external factors that may increase their vulnerability. OBJECTIVE: to describe sexual behavior and other indicators of sexual and reproductive health among young people (16 to 24 years) in Catalonia and to identify factors associated with sexual risk behaviors. METHODS: Cross-sectional study in 2012 carried out by an online survey from a panel of population (n=800). Factors associated with not using a condom at last sexual intercourse were evaluated using multivariate logistic regression models. RESULTS: 76.1% of boys and 83.3% of girls reported having had complete sexual intercourse (p=0.012). The proportion of boys and girls who reported casual partners was 39.7% and 22.5%, respectively. 31.4% of boys and 10.3% of girls reported having contacted partners through Internet. Not using a condom at first sexual intercourse showed significant association with reporting not using a condom in the last sexual intercourse, for both, boys (OR= 2.50) and girls (OR= 3.18). Having contacted partners through the Internet (OR=2.29) was associated with this risky sexual behavior in boys, and having used the emergency contraception 3 or more times (OR=3.38) was associated in girls. CONCLUSIONS: There are differences in the sexual behavior of young people by sex, being condom use at first sexual relationship a good predictor of condom use at last sexual intercourse. Boys show a higher number of casual partners than girls, as well as a higher use of the Internet to contact sexual partners.

Patterns and trends in human papillomavirus-related diseases in Central and Eastern Europe and Central Asia.

This article provides an overview of cervical cancer and other human papillomavirus (HPV)-related diseases in Central and Eastern Europe (Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, and the Former Yugoslav Republic [FYR] of Macedonia) and Central Asia (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, the Russian Federation, Tajikistan, Turkmenistan, Ukraine and Uzbekistan). Despite two- to three-fold variations, cervical cancer incidence rates are high in many countries in these two regions relative to other populations on the European and Asian continents. In Central and Eastern Europe, Romania and the FYR of Macedonia had the highest rates in 2008 alongside Bulgaria, Lithuania and Serbia, while in Central Asia, rates are elevated in Kyrgyzstan (the highest rates across the regions), Kazakhstan and Armenia. In each of these countries, at least one woman in 50 develops cervical cancer before the age of 75. The high cervical cancer burden is exacerbated by a lack of effective screening and an increasing risk of death from the disease among young women, as observed in Belarus, Tajikistan, Kyrgyzstan, Armenia, Azerbaijan, Ukraine, the Russian Federation and Kazakhstan. In several countries with longstanding cancer registries of reasonable quality (Belarus, Estonia and the Russian Federation), there are clear birth cohort effects; the risk of onset of cervical cancer is increasing in successive generations of women born from around 1940-50, a general phenomenon indicative of changing sexual behaviour and increasing risk of persistent HPV infection. There are limited data for other HPV-related cancers and other diseases at present in these countries. While options for reducing the HPV-related disease burden are resource-dependent, universal HPV vaccination with enhanced screening would maximally reduce the burden of cervical cancer in the countries within the two regions. It is hoped that the expanded second edition of the European Guidelines will finally kick-start effective interventions in many of these countries that still lack organised programmes. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Central and Eastern Europe and Central Asia Region" Vaccine Volume 31, Supplement 7, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.