Bolivia has the highest prevalence of cervical cancer in South America and the prevalence of viral sexually transmitted infections (STIs) among people in urban cities is increasing. Little is known about the prevalence of viral STIs in rural communities, which generally have limited access to health care. In order to study the prevalence of viral STIs in rural Bolivia, we recruited women from villages and towns in the Department of La Paz in Bolivia.2 test was used to compare variables between the populations and binary logistic regression was used to identify risk factors associated with the positivity of the tests.Three hundred ninety-four female participants were assessed for IgG-antibodies to herpes simplex virus type 2 (HSV-2), human immunodeficiency virus (HIV) and hepatitis B virus , as well as for the presence of HBV surface antigen (HBsAg) in dried blood spots. The prevalence of 12 high-risk types of human papillomavirus (HPV) was assessed by qPCR in dried cervicovaginal cell spots from 376 of these women. χThe seroprevalence of HSV-2 was 53% and of HBV 10.3%. HBAg was detected in 15.8% of women with anti-HBV antibodies indicating chronic infection. The frequency of high-risk HPV infection was 27%, with the most prevalent high-risk HPV types being HPV 56, 39 and 31 followed by HPV 16 and 18. Finally, none of the 394 women were seropositive for HIV, and about 64% of the studied population was positive for at least one of the viral infections.Women in Bolivian rural communities in La Paz show a high prevalence of HBV, HPV and, in particular, HSV-2. In contrast, none of the women were HIV positive, suggesting that the HIV prevalence in this population is low. The pattern of high-risk HPV types differed from many other countries with a predominance of HPV-types not included in the Gardasil vaccine which was officially introduced in Bolivia in April 2017. To investigate and report the prevalence of viral sexually transmitted infections (STIs) other than HIV is important for the introduction or improvement of a wide range of health policies and programs in all regions. It is known that more than 30 microorganisms are sexually transmitted including herpes simplex virus type 2 (HSV-2), hepatitis B virus (HBV), human papillomavirus (HPV) and human immunodeficiency virus (HIV). Estimations according to the World Health Organization (WHO) indicate that more than 1 million STIs are acquired every day.Almost 300 million people are infected with HPV, which if becoming persistent may cause cervical cancer . More thBolivia has a population of around ten million people and 40 to 70% are self-identified as indigenous peoples . An ongoHSV-2 infection is a risk factor for the acquisition of HIV in people who practice unsafe sex, and it is known that the virus is more prevalent in women compared to men. In 2012 the general seroprevalence of HSV-2 of people aged 15–49 years in the Americas is estimated to be 14.4%, while the highest world-wide prevalence is in African populations with an overall estimated prevalence of 31.5% [The Amazonas is an area of high endemicity of HBV, with reported prevalences ranging from 8 to 25% . CountriIn 2017, UNAIDS reported that about 21,000 people are living with HIV in Bolivia with a general prevalence of 0.3%, and that only 36% of those infected are on treatment. A later report indicates an increase of HIV incidence . The genIn rural areas the poor population have limited information about STIs, little/no access to the national health care system, and no resources for treatment. This study therefore seeks to obtain data about the prevalence and possible risk factors of viral STIs in women living in rural areas on the way to the Amazonas of the Department of La Paz in Bolivia, which will help to improve the screening programs and health policies.Our study population was recruited in the rural provinces of Abel Iturralde  and Caranavi (the adjacent lower highlands at 1000 m above sea level) from the Department of La Paz in Bolivia during five field trips; three in the Abel Iturralde province during the dry seasons (July to October) between 2015 and 2017 and two in Caranavi in March 2018 and May 2019. Our research group, a unit working at the Universidad Mayor de San Andrés (UMSA), visited the three villages Tumupasa, San Silvestre and Santa Rosa de Maravilla (mostly indigenous population below 1200 inhabitants) , the smaN = 394) received extended oral and written information regarding STIs and signed an informed consent form. In the case of women under the age of 18 informed consent was signed by their guardians. Demographic data was collected through a questionnaire and a personal interview. Blood samples (N = 389) and cervicovaginal cell samples (N = 376) were collected from female volunteers.Participants were recruited either by direct invitations to small mother groups, unions, local authorities and indigenous leaders or via general invitations by radio and television. The examination and collection of samples was done in the nearest local health center or hospital by laboratory technicians from UMSA. Women who were menstruating or were more than 12 weeks pregnant were excluded from the study. Eligible participants (Because of the lack of sanitary services (including electricity) in some of these areas, sampling was performed using filter papers that preserve the biological material and allowed the transportation and assessment of the samples. Whole blood samples were therefore collected as Dried Blood Spots (DBS) in Whatman 903 filter papers (Protein Saver™ 903 Card) for the evaluation of antibodies against HSV-2, HBV and HIV as well as for HBV antigen. Exfoliated cervicovaginal cells were collected by swabbing the lateral walls using sterile cotton swabs that were then transferred in 1 mL of essential D-MEM medium  and kept at 4 °C. At the laboratory in La Paz city the samples were centrifuged at 1500 rpm for 10 min at 4 °C and suspended cells in 150 μL of medium were transferred and applied on 2 × 2.5 cm Nucleic-card color matrix spots  as dried cervicovaginal cell spots (DCCS). DBS and DCCS were kept at − 20 °C until their further transport to and analysis in Sweden. Data was managed anonymously according to the ethical permission CEI-UMSA 0215 obtained from the Ethical committee at UMSA, La Paz, Bolivia.Blood proteins were extracted from DBS by punching one bloodstained circle of 5 mm diameter from the filter paper as previously described , 15, TheDNA was extracted and purified from DCCS using QIAGEN mini kit as described , One spoElutions of DBS were used to assess antibodies for HSV-2, HBV, and HIV using commercial ELISA kits; HSV-2 , anti-HBV anti-core antibodies , and HIV . In addition, we measured the presence of HBV surface antigens in eluted DBS using ELISA . As the dried blood samples contain lysed red blood cells, which can interfere with ELISA readout and give false-positive results, we increased the cut-off values provided by the manufacturers of the ELISA kits by multiplying with a factor of 1.5 , 18.Equivocal and low positive samples for HSV-2 by FOCUS ELISA were confirmed with the detection of antibodies to the mature portion of glycoprotein G-2 using Western blot as described . BrieflyT) for β-globin below of 37 were included in the analysis.Purified DNA from DCCS were assessed by a Taqman real-time PCR assay which identifies 12 high-risk  and two low-risk (6 and 11) types, by targeting segments of the E6/E7 region . The amp2 test comparing among groups using PRISM 7.0® from GraphPad Software Inc., San Diego, CA. A p value below 0.05 was considered statistically significant.Descriptive data are presented as percentages, median, prevalence estimates and 95% confidence intervals (CIs). Statistical analyses were calculated using χp < 0.1 were included in the adjusted models as in other studies [The associations between the dependent variable  and the independent variables; age, occupation, number of children, current family planning methods, residence and coinfections were tested by binary logistic regression. This analysis was used to estimate crude and adjusted odds ratios and 95% CIs for each category compared to a reference category (Ref). Variables or categories that showed association with the outcome at  studies . Data anWe investigated the prevalence of viral STIs in women from two provinces of the Department of La Paz, which are inhabited mainly by rural and semi-rural indigenous population. Demographic data was taken from the 394 participants through a questionnaire and an interview. The study population Table  was diviThe seroprevalence of HSV-2 was assessed by two methods; all samples were first analyzed using an HSV-2-specific ELISA. Equivocal and low positive samples were confirmed using the “gold standard”, western blot. More than 74% of the samples were positive for HSV-2-specific antibodies using ELISA, but after confirmation using western blot the prevalence was determined to 53% (Table Thirty-eight women out of 389 tested) had HBV core-specific antibodies. Six of these 38 women (i.e. 15.8%) also had detectable HBsAg in their blood indicating a chronic infection. In addition, we found two acute cases of HBV infection, i.e. women that had detectable HBsAg in their blood but no antibodies. Having in total 40 cases, the prevalence for HBV was 10.3%  and 2 low-risk (LR-HPV). Three of the DCCS were excluded as no DNA  was detected. For the remaining 376 samples, 27% were positive for at least one high-risk HPV type Table . Women bThe number of viral STI in the 371 women where all ongoing viral evaluations were performed  was assessed and is summarized in Table . None ofIn Bolivia, the prevalence of viral STIs has increased during the last 10 years, but this has mainly been investigated in larger towns and cities. In the present study, we assessed the presence of viral STIs in 394 women living around villages and towns in the north of the Department of La Paz and found that the burden of HSV-2, HBV and HPV is higher than in larger cities.The HSV-2 seroprevalence varies between South America and Caribbean countries and relate to behavioral and social conditions. It increases with age , 23, andIn female African populations, acquisition of HSV-2 infection is associated with risk factors such as prostitution, limited access to health care, and unnegotiable unsafe sex with their partners due to economic dependence . We haveTwenty-seven percent of the women in this study had an ongoing infection with one or several HR-HPV. This is higher than the 8 to 18% previously reported in rural and urban regions of Bolivia, which indicates that the prevalence of HPV in rural north of La Paz might be higher than in other regions of Bolivia –33. HPV The 12 high risk HPV types we analyzed are the most important ones due to their association with the development of cervical cancer. These genotypes represent the class I carcinogens for cervical cancer according to the (WHO/IARC), and the most common high-risk HPV types we identified were HPV 56, 39 and 31. Previous studies from Bolivian small towns have identified HPV 31 and 58 as the most common HPV high-risk types , were moAlmost 10% of the women in this study had antibodies to HBV, which is similar to the 8% reported in other South American countries such as Colombia and Brazil, and thus confirms the high seroprevalence of HBV in the Amazonas region , 39. NatNo positive cases for HIV was found, which is in agreement with the low estimates by UNAIDS with only a 0.3% of prevalence in adults aged 15 to 49 years, and zero cases from a study of 885 healthy women mostly urban populations in Bolivia . The proAlmost 70% of the rural women included in this study were positive for at least one of the four viral STIs. Approximately 15% of the women had more than one viral STI, and the majority of these co-infections involved HSV-2 and HPV. We did not find a positive association between HSV-2 and HPV infections indicating that these infections do not predispose for each other. However, several studies show that HSV-2 infection is an important risk factor for the development of invasive cervical cancer in HPV-infected women –44. ThusThere are certain limitations to this study. First, STIs are stigmatizing in which might have generated a bias in the recruitment process. Second, many women from villages were afraid to participate because they reported that the Pap smear test was painful, and many of them have never encounter a cytological inspection by medical staff. Third, due to the high rate of illiteracy we could only collect data through oral interviews which might have produced some bias in our data.We conclude that there is an unusually high prevalence of HSV-2 infection in women from villages and towns in the Department of La Paz in Bolivia, and that both HPV and HBV infections are common. In addition, we note that the pattern of high-risk HPV types differ both from what is found in Europe and included in the HPV vaccine introduced in Bolivia in 2017.Additional file 1 Table 1. Types of human papilloma virus detected in cervical samples of 103 participants with HR-HPV and LR-HPV.


The World Health Assembly has adopted a global strategy to eliminate cervical cancer. However, neither the optimal pathway nor the corresponding economic and health benefits have been evaluated. We take China as an example to assess the optimal pathway towards elimination and the cost-effectiveness of tailored actions.A validated hybrid model was used to assess the costs and benefits of alternative strategies combining human papillomavirus vaccination, cervical screening, and treatment of pre-invasive lesions and invasive cancer for females with different immunization history. All Chinese females living or projected to be born during 2015–2100, under projected trends in aging, urbanization, and sexual activity, were considered. Optimal strategies were determined by cost-effectiveness efficiency frontiers. Primary outcomes were cervical cancer cases and deaths averted and incremental cost-effectiveness ratios (ICERs). We employed a lifetime horizon from a societal perspective. One-way and probabilistic sensitivity analyses evaluate model uncertainty.The optimal pathway represents an integration of multiple tailored strategies from females with different immunization history. If China adopts the optimal pathway, the age-standardized incidence of cervical cancer is predicted to decrease to fewer than four new cases per 100,000 women  by 2047 . Compared to the status quo, the optimal pathway would avert a total of 7,509,192  cervical cancer cases and 2,529,873  cervical cancer deaths in 2021–2100, with the discounted ICER being $− 339 (− 687 to − 79) per quality-adjusted life-year.By adopting an optimal pathway from 2021  onwards, cervical cancer could be eliminated by the late 2040s  while saving net economic costs in China.The online version contains supplementary material available at 10.1186/s12916-021-01930-9. Following the call from the World Health Organization (WHO)’s Director-General for action towards the elimination of cervical cancer as a public health problem, several modeling studies suggested that the goal of elimination is within reach globally in the twenty-first century –3. All oChina contributed to 20.2% of the global burden of cervical cancer, and the incidence showed a significant rise of up to 10.5% per year . The meaAlthough there is great optimism about eliminating cervical cancer in China , the optThe results were reported following the Consolidated Health Economic Evaluation Reporting Standards Statement (CHEERS) , gender, sexual activity , and age group .We updated the hybrid model which was developed to evaluate cervical cancer prevention strategies in China . Please Models were calibrated using epidemiological data of high-risk HPV prevalence, cervical incidence and mortality in 2015, HPV type distributions in women with normal cervical cytology, low-grade cervical precancerous lesions, high-grade cervical precancerous lesions, and invasive cervical cancer  in China . The cosIn the base-case analysis, status quo strategy and optimal strategy were evaluated in the model to estimate the year of cervical cancer elimination, averted cervical cancer cases and deaths, and the incremental cost-effectiveness ratios (ICER) for urban and rural areas, respectively. The ICER was calculated as incremental cost per additional QALY gained between optimal strategy and status quo.We calculated age-standardized annual incidence and mortality rates using Segi’s world standard population. Elimination of cervical cancer as a public health problem was defined as the first year when the age-standardized incidence is below 4/100,000 women.Using the calibrated model, we assessed the costs and benefits of all alternative scenarios in birth cohorts with different HPV immunization history , different target ages at vaccination and coverage, and different cervical screening characteristics . A five-stage analytic process was involved to determine the optimal pathway  of model results.The optimal pathway towards the elimination of cervical cancer in China is to integrate the tailored optimal strategies of different birth cohorts under the constraints of available resources  Fig. . A totalNet costs would be positive in 2021–2035 by adopting the optimal pathway, while from 2036 onwards, annual net costs would be negative, due to reductions in the cost of invasive cervical cancer treatment   [Detailed country-level analyses, taking into account specific local factors important for the effective delivery of vaccination and screening interventions, will be key to maximize the use of scarce resources to accelerate efforts to eliminate cervical cancer, and should be viewed as an important complement to global and regional analyses . The spe review) .Our study has three major strengths. First, we employed health economic evaluation to assess the costs and benefits of the different strategies for cervical cancer elimination, which makes a strong case for investment by the policymakers in this area. Second, we have developed optimal strategies for a different population from the perspective of health economic evaluation, which makes it possible for China to achieve the goal of cervical cancer elimination while saving net economic costs. This approach highlights the importance of developing the pathway to elimination rather than simply examining the timeframe to achieve elimination. Third, we have fully considered the accessibility of healthcare resources and preferences of policy marking in China when we develop the strategies. As such, the optimal pathway in our study is more likely to be adopted by policy-makers and then applied to the population.Our study has three major limitations. First, we did not consider the scenario of vaccination for boys and the benefits gained from preventing other HPV infection-related diseases. If the only goal is cervical cancer prevention and elimination, then vaccination for boys is an indirect and less cost-effective means of reaching this goal . We did China can achieve the goal of cervical cancer elimination by the late 2040s  while saving net economic costs by adopting the optimal pathway of interventions we propose from 2021  onwards. To achieve the goal of elimination, China needs to increase investment for cervical cancer prevention during 2021–2035 and improve investment efficiency. Such investment is worthwhile both from the perspective of health economic evaluation and public health services, because it will eventually save China about $100 billion of costs and avoid 7.5 million cervical cancer cases and 2.5 million cervical cancer deaths in 2021–2100.Additional file 1. CHEERS Checklist.Additional file 2: Table S1. Cervical cancer screening costs. Table S2. Model inputs. Table S3. Population size in China, 2015. Table S4. All-cause mortality in China, 2015. Table S5. Cervical cancer incidence and mortality in China, 2015. Table S6. Prevalence and type distribution of HPV infection in China. Table S7. ICER of strategies that lie on the efficiency frontier compared with next-best strategy: a) for 2021–30, b) for non-vaccinated cohort, c) for bivalent vaccinated cohort and d) for 9-valent vaccinated cohort. Table S8. ICERs of switch 9-valent vaccination from 2031 onwards compared to continuing bivalent vaccination. Table S9. Lifetime costs, effectiveness, and incremental cost-effectiveness for optimal pathway (use GDP per capita as threshold) vs. status quo. Table S10. Lifetime costs, effectiveness, and incremental cost-effectiveness for optimal pathway using GDP per capita as threshold vs. optimal pathway using median income as threshold. Table S11. Estimated cervical cancer cases and deaths averted for optimal pathway (use GDP per capita as threshold) vs. status quo. Figure S1. Model structure. Figure S2. Model calibration output: a) high-risk HPV prevalence, b) HPV type distribution and c) cervical cancer incidence and mortality. Figure S3. Efficiency frontier of all alternative strategies: a) for 2021–30, b) for non-vaccinated cohort, c) for bivalent vaccinated cohort and d) for 9-valent vaccinated cohort. Figure S4. Probabilistic sensitivity analyses for optimal pathway vs. status quo: a) 0% discount and b) 3% discount. Figure S5. Deterministic sensitivity analyses for optimal pathway vs. status quo: a) in China, b) in urban area and c) in rural area. Figure S6. Annual costs of optimal pathway: a) 0% discount and b) 3% discount. Figure S7. Annual costs of status quo: a) 0% discount and b) 3% discount. Figure S8. Annual incremental benefits of optimal pathway compared to status quo: a) 0% discount and b) 3% discount. Figure S9. Optimal pathway towards cervical cancer elimination in China (use GDP per capita as threshold). Figure S10. Age-standardized cervical cancer incidence and mortality by adopting optimal pathway (use GDP per capita as threshold). Figure S11. Annual costs of optimal pathway (use GDP per capita as threshold): a) 0% discount and b) 3% discount. Figure S12. Annual incremental benefits of optimal pathway (use GDP per capita as threshold) compared to status quo: a) 0% discount and b) 3% discount.


This study shows, for the first time, that the evolution of a simple behavior, scrounging, at the individual level can have effects on populations, food chains, and community structure. In particular, the addition of scrounging in consumer populations can allow multiple consumers to coexist while exploiting a single prey. Also, scrounging in the top predator of a tritrophic food chain can stabilize interactions between the top predator, its prey, and its prey's prey. This occurs because the payoffs to scrounging for food in a population are negative frequency dependent, allowing scroungers to invade a population and to coexist with producers at a frequency which is density‐dependent. The presence of scroungers, who do not search for resources but simply use those found by others (producers) reduces the total amount of resource acquired by the group. As scrounging increases with group size, this leads to less resource acquired per individual as the group grows. Ultimately, this limits the size of the group, its impact on its prey, and its ability to outcompete other species. These effects can promote stability and thus increase species diversity. I will further suggest that prey may alter their spatial distribution such that scrounging will be profitable among their predators thus reducing predation rate on the prey. Scrounging, a behaviour which can be expected to evolve when animals forage together, can impact both population dynamics and community structure. The fact that scrounging evolves under frequency‐dependent selection and has density‐dependent effects is key to stabilizing interactions with competitors and with prey. These effects can cause top‐down stabilization of a food chain and can promote species diversity. The defense of territories limits the number of individuals who have access to resources and thus sets limits to population density  This predator interacts with its prey under a Lotka‐Volterra predator–prey model. It is well known that, without scrounging, this parsimonious model produces only neutral stability (limit cycles) between predator and prey. Coolen et al. , perhaps but not necessarily, because their food occurs in patches. The Coolen et al.  + (a/F)) is the proportion of each group, and thus of the whole population, which produces (searches for food) rather than scrounging. Collen et al. (G) + (a/F)) in each group of G individuals based on the ESS frequency of producers in Vickery et al.  Here, I extend the Coolen et al.  model byn et al.  model isn et al.  derive ty et al. . We replH), to the Coolen et al.  The eigenvalues of Js are the roots of its characteristic polynomial:A set of differential growth equations has a stable equilibrium if the real parts of the eigenvalues of its Jacobian matrix, evaluated at the equilibrium, are negative. For the tritrophic system with scrounging in the top predator, the Jacobian of the three growth equations evaluated at the equilibrium point is as follows:x33>0andx23x32>0andx12x21x33>0. Clearly, all three conditions are true because all the xij are positive. Therefore, the eigenvalues of the matrix Js all have negative real parts. Thus, the coexistence equilibria of this model are stable.All the terms of the characteristic equation are greater than zero, which is a necessary condition for its roots to be less than zero. Routh‐Hurwitz criteria for this equation to have roots with only negative real parts are as follows: g/P) + (a/F)) by 1 in the above model.) Mathematically, this system of equations has an equilibrium at which all three species go extinct, another in which only the top predator goes extinct and a third in which resources go extinct and herbivores coexist with a negative abundance of top predators. Thus, without scrounging the model has no three‐species equilibrium; the addition of scrounging has the potential, for some parameter values, to stabilize the tritrophic interaction.The stabilizing effect of scrounging can be seen by comparing the above results with an analysis of a tritrophic Lotka‐Volterra food chain without scrounging.  decrease. On the other hand, as the frequency of scrounging decreases , equilibrium abundances of resources and top predators increase up to a threshold value beyond which the tritrophic system becomes unstable.  of the resource require high scrounging frequencies in order to prevent instability on the system : A high frequency of scrounging is required to stabilize the system. Conversion efficiency of resources to herbivores has no effect on stability. Finally, as the mortality rate of herbivores μ increases so does the equilibrium abundance of resources but this has no effect on the abundance of top predators. As the mortality rate ϑ of the top predator increases, the frequency of scrounging which can be tolerated decreases. At low mortality rates, higher scrounging frequencies are necessary in order to stabilize the system.When there are many predator groups, frequent scrounging will be needed in order to stabilize the system Figure b. When oN2 to the model choosing parameter values which ensure that this competitor is less efficient than the original one and thus loses in competition with the original predator, N1 . Finally, I add scrounging to the original predator in the same way as for the food chain model above. This gives the system of growth equations:Having shown that scrounging can have a stabilizing effect further down the food chain, I now ask if it might also affect interactions with competitors. To do this, I once again start with a Lotka‐Volterra model of predator–prey interactions with no scrounging. I add a competitor (a second predator), This system of growth equations has an equilibrium at:μe2β>eαϑa/F and rμe2β>μe2β+reϑa/F.Every set of positive equilibria for these three species is stable Box . EquilibBOX 2ijx are positive and negative signs indicate negative components in the Jacobian matrix. The characteristic polynomial is λ3+x22λ2+x12x21+x13x31λ+x13x31x22. As with tritrophic model, it is clear that all the terms of this equation are greater than zero. Routh‐Hurwitz criteria for this equation to have roots with only negative real parts are as follows: x22 > 0 and x12x21 > 0 and x13x13x22 > 0. Thus, all the eigenvalues of the system have only negative Real parts. Therefore, all positive equilibria of the model are stable.We can derive the Jacobian of the model for two competitors exploiting a single resource from the model given in the main text. At equilibrium the Jacobian has the structureWhen scrounging has invaded two of the competitors, but not the third, the Jacobian of the system of growth equations is as follows:We can substitute the equilibria values for population size into the matrix and reduce it to a structural matrix as before:Js=0-x12-x13-x14x21-x2200x310-x330x41000where all the xij are positive and negative signs in the matrix indicate a negative differential effect for a given component at the equilibrium.  The characteristic polynomial of this matrix is as follows:x14x41x22x33>0 and x22+x33>0 and x222x33+x12x21+x332x22+x13x31x33/x22+x33>0 and (x13x223∗x31∗x33+x12x21+x13∗x31∗x332+x12x21x13∗x31+x14∗x41∗x222+x12x21x332+x122x212+x14∗x21∗x41∗x12+x13∗x31∗x13∗x31+x14∗x41x22∗x33+x13∗x31∗x332x12x21+x14x41)/x222∗x33+x12x21+x332∗x22+x13∗x31∗x33>0.From the signs of the coefficients listed above, we can see that all the terms in the characteristic polynomial are positive. Routh‐Hurwitz criteria for this equation to roots with only negative real parts are as follows: Because all the coefficients in each inequality are positive, the four conditions are all true.Thus, the positive equilibrium of the three competitor system is stable.Now that scrounging has allowed a less efficient competitor to coexist in this system, we can push the analysis one step further by asking if both these competitors incur scrounging will a third, less efficient, competitor be able to coexist with them. The system of growth equations becomes:This set of equations also has an equilibrium:μe3α3>ρe1α1a1/F and νe3α3>ρe2α2a2/F and r is sufficiently large to outweigh the negative impact of the second and third terms in the equation for the equilibrium value of N3. Once again, every equilibrium in which all four species have positive abundances is stable (Box α1 or α2).This equilibrium involves positive abundances for all four species provided that g1 shown in Figure g2 not shown) has a smaller effect on coexistence with fewer groups in a given consumer species allowing lower frequencies of scrounging in that species.Low resource growth rate may be insufficient to support all three consumers regardless of scrounging Figure a. Even hIncreasing encounter rates between a consumer and its resources requires higher scrounging frequency (in the given species) to stabilize the system. This result holds for the two most efficient foragers  within a population of one species can have a substantial impact on the diversity of species in a community.The point here is that evolution at the individual level within a population has the potential to stabilize a population, a food chain, or a community. I do not contend that scrounging will always stabilize population dynamics, food chains, and competitor interactions. In fact, the stability analyses show that only certain parameter values will produce stability. In other cases, the arrival of scrounging in a population might, when scrounging becomes too prevalent, actually push the population to extinction. Other factors  may have stronger effects which can completely obscure the effects of scrounging. In any case, the presence of scrounging in a population will decrease the growth rate of a population as the abundance of that species increases because increases in group size will increase the proportion of scroungers in the species and thus decrease the rate at which food is found. An alternate to my model might be a case in which producers compensate for the food lost to scroungers by foraging over a longer time period. They could, in theory, forage until they consumed as much food as they would have if no scroungers were present. However, in this case the producers and the scroungers would be exposed to predators longer and would expend more energy while they are foraging. The resulting costs would then decrease survival, and probably birth rates, in the population resulting in density‐dependent effects and the same conclusions which I have drawn from the above model.I use exponential growth and Lotka‐Volterra models as a base line in my analysis not because I believe that they represent exact models of intraspecific and interspecific dynamics in nature but rather because they are simple models which capture the essentials of population growth  These models are parsimonious and not inherently stable. Thus, they serve as a convenient null model to which one can add effects which may stabilize, or not, the dynamics being studied. The neutral stability of the two‐species Lotka‐Volterra predator–prey model is particularly useful for determining whether an added factor increases or decreases stability in the interaction. While the tritrophic Lotka‐Volterra model has no three‐species equilibria, the fact the scrounging can produce a stable equilibrium demonstrates the power of the density dependence produced by scrounging.Others  rather than using the exact values of the Jacobian of my model. The latter would show that the particular model which I have adopted produces stability. By analyzing the matrix structure , I show that not only my model, but also any community producing this matrix structure, will be stable, a more general conclusion.My analysis shows that scrounging has the possibility of stabilizing a tritrophic interaction. It should be easy to show that the stabilizing effect in the food chain can be passed on to lower levels. Thus, I surmise that scrounging in a top predator species can have a stabilizing effect, which passes all the way down the food chain. It should be noted that this effect does not pass up the food chain. When I introduced scrounging in the intermediate predator population (results not shown here), the dynamics of its interaction with the top predator were not stabilized because of a lack of negative feedback on prey consumption by the top predator. I also suggest that if scrounging allows three competing species to coexist the effect can be extended to four or more competitors provided that scrounging invades the most efficient (in terms of finding food) competitors.My analysis is similar to that of Fryxell and Lundberg  in that Gil, Hein, Spiegel, Baskett, and Sih  showed tWhile scrounging is a behavior which changes over a shorter time scale than population size, I argue that the two should be modeled together because of the feedback between them. That scrounging can persist in populations over long time periods and respond to population size has been shown by Aplin and Morrand‐Ferron .Australomisidia ergandros. Recently, Kimmel, Gerlee, Brown, and Altrock . The reduction in resource consumption will contribute stability to the interaction between predators and resources.Overall, my analysis suggests that scrounging, a social foraging adaptation, can have a stabilizing effect on interactions between the species in which it occurs and both its prey and competitors. Further, the stabilizing effect can be passed down through the food chain and may even induce distributional changes among prey which can feed back to increase scrounging frequencies in the consumer species.


Background: Certain high-risk (hr) types of human papillomavirus (HPV) can cause cervical cancer in women and penile cancer in men. Hr-HPV can also cause cancers of the oropharynx and anus in both sexes. In the anal and cervical region, a contribution of co-infections with Ureaplasma spp. on the persistence of the hr-HPV infection by a profound inflammatory state is suggested. Here, we investigated if non-HPV sexually transmitted infections are associated with oropharyngeal carcinoma (OPC). Materials and Methods: In this case-control study, a brush test directly from the tumor surface of OPC patients (study group) and from the oropharynx of healthy volunteers (control group), both groups matching in age and sex, was performed. HPV subtypes were detected using a commercially available test kit. For non-HPV sexually transmitted infections , a multiplex nucleic acid amplification approach was performed. Results: In the study group, 96 patients , with histologically confirmed OPC and in the control group 112 patients , were included. Oropharyngeal hr-HPV-positivity was detected in 68% (65/96 patients) of the study group and 1.8% (2/112 patients) of the control group (p < 0.001). In three patients in the study group, Ureaplasma spp. was detected, whereas no patient was Ureaplasma spp. positive in the control group (p = 0.097). Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium were negative in both groups. Conclusion: Based on the current study, the prevalence of oropharyngeal Ureaplasma spp. among patients with OPC is low and does not support a role in oropharyngeal cancer. However, the detection of the pathogen only among OPC patients but not in the healthy individuals might indicate a potential role and needs further elucidation. Changes in sexual behavior in the last decades, like a high number of oral sex partners, seem to play an important etiological role in the development of human papillomavirus (HPV) positive oropharyngeal carcinoma (OPC) by HPV transmission . Once anTherefore, it is of high importance to understand which factors and mechanisms may contribute to the persistence of an oropharyngeal HPV-infection and lead to the development of OPC.Co-factors like smoking and immunosuppression were reported to play a meaningful role in the process of HPV-persistence ,4. StudiMycoplasma and Ureaplasma, a distinguished form of bacteria characterized by their minute size and total lack of a cell wall, were reported to play an important role in HPV infections, abnormal cervical cytopathology, and cervical cancer. Ureaplasma urealyticum and Mycoplasma genitalium may increase the risk of a high-risk (hr) HPV infection, while Ureaplasma urealyticum, Ureaplasma parvum, and Mycoplasma hominis may increase the risk of abnormal cervical cytopathology .p = 0.01) [The bacteria are widespread in nature and well known as human parasites, often causing chronic asymptomatic infections. Mycoplasmas usually exhibit a rather strict host and tissue specificity, and the primary habitats are the mucous surfaces of the respiratory and urogenital tracts, the eyes, alimentary canal, mammary glands, and joints . Because = 0.01) . Barykov = 0.01) . Mizuki  = 0.01) . The sub = 0.01) . Other c = 0.01) ,27,28.Colleagues of our study group collected recent anal brush samples in 222 HIV-positive men who have sex with men (MSM) for the detection of Chlamydia trachomatis, Neisseria gonorrhea, Ureaplasma spp., Mycoplasma, and HPV genotypes. Out of these participants, 73% were hr HPV-positive, and 19.4% harbored Ureaplasma spp. Hr HPV-infection was significantly associated with the co-presence of Ureaplasma spp.  .Given the similar routes of transmission, the co-presence of HPV with other STIs is not a surprise even in the oropharyngeal region. Although previous studies reported on the frequency of Mycoplasma and Ureaplasma spp. detection in the oral cavity , data onThe aim of the study was to evaluate the prevalence of HPV and non-HPV sexually transmitted infections among patients with a pathologically confirmed malignant tumor of the oropharynx. To further validate the results, outcomes were compared to a control group of volunteers without head and neck squamous cell carcinoma (HNSCC). The null hypothesis was that there is no difference in the prevalence of non-HPV sexually transmitted infections among patients with and without OPC.nOPC = 96 and nhealthy = 112) were included. The mean age (SD) of the study participants was 61.9 (10.1) years. There was no significant difference in the age distribution between OPC patients and healthy controls, 61.9 (9.7) versus 62.1 (10.5) years, respectively. In the study group, the proportion of female patients (23.9%) was slightly higher than in the control group (17%) (p = 0.006), had lower T-stage (p < 0.001), and lower ASA scores (p < 0.001). P16 was in 88.5% of the HPV-associated OPC patients positive (p < 0.001)  . Further< 0.001) .OPC = 52), followed by HPV 18 (nOPC =4), HPV 33 (nOPC =3) and HPV 35 (nOPC =3). Moreover, the HPV types HPV 31, HPV 40, HPV 56, HPV 58, HPV 61, HPV 62, HPV 66, HPV 70, HPV 73 and HPV 82 were detected as a single infection or additionally to HPV 16 as a multiple infection  of the OPC patients were positive for HPV DNA. The most common genotype was HPV 16 (nnfection . In the nfection .p = 0.097) (Three OPC patients (3.1%) were tested positive for Ureaplasma spp., which was detected in two patients as a co-infection with HPV 16, and in one patient with an HPV-negative OPC. All other non-HPV sexually transmitted infections  were negative in the study group. In the control group, all investigated non-HPV sexually transmitted infections were tested negative. The difference between the frequency of the Ureaplasma spp. infections in the study group (three patients) versus the control group (zero patients) did not reach statistical significance (= 0.097) .To the best of our knowledge, this is the first study to examine the presence of HPV in combination with non-HPV STIs in oropharyngeal samples of patients with histologically confirmed OPCs.In our study, we found that the prevalence of HPV-positivity was high (68%) in the 96 OPC patients. HPV-positive OPC patients were younger and had a lower ASA score, which indicates a lower rate of comorbidities  as compaIn the control group, only two patients (1.8%) were HPV-positive. The lack of hr HPV among the control group in our study may be of high diagnostic value. Although hr HPV negativity may not exclude the presence of OPC, based on our study, older adults with hr HPV in the oropharynx may be suspicious of having a head and neck malignancy. These patients may probably be referred to the department of otorhinolaryngology for clinical examination. There is currently no evidence-based implementation of an OPC screening . Additiop = 0.097).The use of a multiplex nucleic acid amplification approach enabled the search for the co-existence of bacterial infections, namely, Chlamydia trachomatis, Ureaplasma spp., Mycoplasma hominis, and Mycoplasma genitalium, out of a single brush sample. We used a highly sensitive and well-validated extraction and amplification assays, which make the finding in this study a robust one. Our data show that Ureaplasma spp. was detected in two HPV-positive OPC patients and in one HPV-negative OPC patient. Unfortunately, this low prevalence rate of Ureaplasma spp. makes it impossible to assess the potential role of non-HPV STI in HPV associated malignancy in the oropharynx. With only three OPC patients in the study group and none of the control group testing positive for Ureaplasma spp., as well as none testing positive for the other bacterial pathogens, the prevalence of non-HPV STIs was low in our study  clinic. The authors detected HPV in 18.8%, N. gonorrhoeae in 15.6%, C. trachomatis in 4.2%, M. genitalium in 5.2%, and Ureaplasma spp. in 16.0% of the oral samples . In contAlthough a previous study went further to analyze the role of non-HPV STI in oral swab samples among patients with oral dysplastic lesions, similar data among OPC patients is nonexistent. Mosmann and coworkers examined benign oral lesions or potentially malignant disorders, including oral cancer patients. They found a prevalence of 34% for HPV, 16% for C. trachomatis, and 3% for HSV. They failed to test for Ureaplasma and Mycoplasma spp. . By goinEpidemiological surveys confirm that oral sexual practice significantly declines with increasing age ,46. SincProspective studies need to elaborate on the clinical and epidemiological significance of this colonization. If other studies confirm a differential predominance of Ureaplasma spp. among patients with OPC, the issue of early detection and appropriate antibiotic therapy or eradication might be a topic. Due to the low prevalence, there was no clear association between Ureaplasma spp. with HPV-positivity among these patients in our study.In this prospective case-control study, consecutive patients scheduled for oropharyngeal tumor diagnosis at the outpatient unit of the Department of Otorhinolaryngology, Medical University Innsbruck, Austria, were invited to participate. The admission period was between May 2014 and April 2019. The control group of healthy volunteers was recruited from patients presenting for dentoalveolar procedures or control examinations at the outpatient clinic of Oral and Maxillofacial Surgery, Medical University Innsbruck, Austria, between October and December 2019.This project was conducted in accordance with STROBE guidelines for observational studies . WrittenInclusion criteria for participation in the study group comprised of a minimum age of at least 18 years and a histologically confirmed OPC. For the control group, healthy volunteers with an age of over 45 years and without previous or current HNSCC were included.® HC2 DNA Collection Device, Qiagen, Hilden, Germany) and rinsed in digene Specimen Transport Medium. Particular attention was paid to perform the brush precisely from the tumor surface without the brush coming into contact with the mucosa of the oral cavity. Oropharyngeal brush samples from control patients were collected by the same method.For sample collection, a validated brush test was used as described in a previous publication . For OPC® easyMAG®, Biomerieux, Marcy-l’Étoile, France) according to the manufacturer’s instructions. In brief, out of 500 µL of the original sample, 110 µL of purified nucleic acid was extracted using magnetic silica particles. This method is a highly sensitive approach since it allows the capture of all nucleic acid available in a sample, and the separation from silica leads to no loss of extracted material.Nucleic acid extraction was conducted in a fully automated manner , genotyping followed using allele-specific reverse line-blot hybridization of the PCR products. These biotinylated PCR products then bind with target-specific probes that are bound to a nylon membrane (strip), permitting the differentiation of 40 high-risk (hr-HPV) and low-risk HPV genotypes. HPV genotypes detectable in this assay include types 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68a/b, 69, 70, 71, 72, 73, 81, 82, 83, 84, 87, 89, and 90. Beta-globin was used as an internal control assuring the validity of the test by controlling for sample quality, the performance of the extraction, and the validity of nucleic acid amplification. Moreover, the presence of the dUTP/UNG system within the reagents of the kit help prevent carry-over contaminations. .® easyMAG®, Biomerieux) was used for the amplification of Ureaplasma spp., Mycoplasma genitalium, Mycoplasma hominis, and Chlamydia trachomatis DNA using a validated multiplex nucleic acid amplification kit  according to the thermocycling conditions recommended by the manufacturer. The kit is equipped with negative and positive controls, as well as an internal control system verifying the extraction and the amplification steps.Ten µl of DNA extract . Frequency data were tabulated and analyzed with Fisher’s exact test or with the Kruskal-Wallis test for ordered alternatives. No statistics were computed for Chlamydia trachomatis, Mycoplasma hominis, and Mycoplasma genitalium because these are constants in both groups [p-value of < 0.05 was considered statistically significant.Data were analyzed using SPSSh groups . For conh groups . A p-valOur study shows that the prevalence of non-HPV sexually transmitted infections among patients with OPC is low. Although Ureaplasma spp. has been implicated as a potential HPV-associated carcinogen in anogenital cancers, the low frequency in this study (both in the HPV-positive and HPV-negative patients) does not support a role in oropharyngeal cancer. However, beyond the obvious predominance of hr-HPV, the detection of Ureaplasma spp. only among OPC patients but not in the age and sex-matched control group represents an interesting finding. Given the fact that Ureaplasma spp. were previously shown to be associated with hr-HPV infection or HPV-associated dysplasia, further evaluation of a potential link between a HPV and Ureaplasma spp. co-infection in the pathogenesis of oropharyngeal carcinoma should be evaluated in larger studies.


Human papillomavirus (HPV) genotyping and cytology have been recommended for colposcopy triage, but it is unclear which combinations of high-risk HPV (hrHPV) types and cytology with various thresholds provide clinically useful information for the triage after primary HPV screening on self-collected samples.Chinese Multi-site Screening Trial (CHIMUST) database focused on self-collected samples was reviewed using the results of Cobas4800 HPV assay. Absolute risks of each genotype for cervical intraepithelial neoplasia 2 or worse/ 3 or worse (CIN2+/CIN3+) were calculated. Triage of atypical squamous cells of undetermined significance (ASCUS) or worse cytology was used as the comparator, and diagnostic accuracy for paired comparisons between algorithms was obtained using McNemar’s test.A total of 10, 498 women were included, the overall prevalence of hrHPV, HPV16, HPV18, and Other hrHPV genotypes were 13.7%, 2.4%, 0.8%, and 10.5%, respectively. HPV16-positive women had the highest absolute risk among various genotypes for CIN2+/CIN3+ whether in normal or abnormal cytology (ASCUS or worse) and among all age groups. When compared with the comparator, combining HPV16 positivity and/or high-grade squamous intraepithelial lesion (HSIL) or worse yielded higher specificity , similar sensitivity  for detection of CIN3+, and a decrease in colposcopy referral rate from 3.5% to 2.7%, similar results were found for CIN2+. Positivity for HPV16 and/or (ASCUS or worse), and positivity for (HPV16 and/or HPV18) and/or (ASCUS or worse) achieved favorable sensitivity compared with the comparator , these algorithms would reduce the colposcopy referral rate to 5.0% and 5.6% respectively, compared with 13.7% of that for HPV alone.Triage of HPV-positive women on self-collected samples by combining HPV16 or HPV16/18 genotyping with different thresholds of cytology could provide tradeoffs in sensitivity for detecting cervical lesions and colposcopy referral rates, and tailor management in various circumstances of clinical practice. Cervical cancer has caused estimated 311,365 deaths worldwide in 2018, with 90% occurring in developing countries[HPV test has been proved as a cost-effective primary screening method worldwide , 4, whicMost women find HPV self-sampling to be more convenient, less embarrassing, and less painful than clinician-sampling, but are concerned about test accuracy. When usCytology and genotyping are the most common methods used for triage of HPV positive patients . CytologIn the present study, we reviewed the Chinese Multi-site Screening Trial (CHIMUST) database, and focused on self-collected samples, to explore the performance of HPV16 alone or HPV16/18 combined with different cytological cut-offs as methods of risk-stratification to triage patients after primary HPV screening.We reviewed the data from CHIMUST, a population-based study that was conducted in Beijing and 5 Provinces in China from Aug 2016 to Jan 2018 . A total of 10,885 non-pregnant women, aged 29 to 60 years, with an intact uterus, without history of pelvic radiation, and without cervical cancer screening within 3 years were recruited. Briefly, CHIMUST is a primary HPV testing cervical cancer screening trial, all self-collected and clinician-collected samples were tested with the PCR-based hrHPV assays: Cobas4800 and SeqHPV . Patients with HPV-positive results from any HPV assay on either self-collected or clinician-collected samples were randomly referred to colposcopy and biopsy. Cytology was used only for analysis and not for colposcopy referred requirements . This st® solution . Self-collected samples were prepared for the Cobas4800 assay (Roche) per the manufacturer’s instructions. Results from Cobas4800 testing are either HPV16 positive, HPV18 positive, other 12 types of hrHPV (Other hrHPV) positive, or HPV negative. Hierarchical typing results ranked as HPV16, HPV18, Other hrHPV, and negative.All women who participated in the screening provided a self-collected vaginal sample. The participants were requested to place the sampling brush into the top of the vagina and then rotate it 3 times. After sampling, the brush with specimen was rubbed on a solid specimen processing (SSP) card, followed by placing it into a small bottle containing 6mL of PreservCyt® solution for testing on Cobas4800, SeqHPV, and cytology test . Cytology slides were interpreted by senior cytopathologists in PUSH according to the Bethesda classification system [After self-sampling, cervical exfoliated cell samples were obtained at the squamocolumnar junction of the cervix by prior-trained clinicians with a sampling brush which was subsequently placed into a 20mL PreservCytn system .Patients with HPV positive results from any HPV assay in CHIMUST  were called back for colposcopy and biopsy. Colposcopy-directed biopsies were performed according to the Preventive Oncology International (POI) protocol . HistoloP values of <0.05 were considered statistically significant.Histologically confirmed CIN3 or worse (CIN3+) and CIN2 or worse (CIN2+) were used as the study endpoints. The absolute risks (ARs) of high-grade cervical disease were determined for different HPV types, and the respective 95% confidence intervals (CIs) for ARs were estimated by bootstrapping  . CombinaOut of 10,885 women offered self-sampling for hrHPV testing in CHUMUST, 58 women were excluded because invalid cytology, and 2 because invalid HPV, 265 because of not having histological results after HPV-positive results, 62 because HPV negative on all assays and cytology≥ LSIL therefore without histopathology, leaving 10,498 cases available for analysis . The rattrend<0.0001). Among women aged 50 to 60 years old, the prevalence of hrHPV positivity was highest of 15.4%, and the prevalence of HPV16 and/or 18 was highest of 3.7% among various groups (trend<0.0001).Among the 10,498 women, the overall prevalence of hrHPV, HPV16, HPV18, and Other hrHPV genotypes were 13.7%, 2.4%, 0.8%, and 10.5%, respectively . The oves groups . HierarcThe estimated ARs were dependent on hrHPV types, and HPV16 positivity achieved the highest ARs among various types for CIN2+/CIN3+ whether in normal or abnormal cytology (≥ASCUS) and in all age groups. The ARs for CIN2+ in women with hrHPV positivity/normal cytology, ranged from 1.6% (95% CI = 1.6–6.3%) for women positive of HPV18 to 9.7% (95%CI = 5.2–14.8%) for women positive of HPV16 . The ARstrend <0.0001).We investigated various combinations of genotyping for HPV16, or HPV16/18 with different thresholds of cytology for the triage of HPV-positive women. The characteristics of all 18 strategies  for detecting CIN3+ lesions are detailed in Notably, of the 17 triage strategies, the one with positivity for HPV16 and/or ≥ASCUS cytology (Strategy 7) and the one with positivity for (HPV16 and/or HPV18) and/or ≥ASCUS cytology (Strategy 13) achieved favorable sensitivity compared with strategy 2 , these algorithms would reduce the colposcopy referral rate to 5.0% and 5.6%, respectively, compared with 13.7% of that for HPV alone.Furthermore, HPV16 positivity and/or ≥HSIL (Strategy 11) showed an improved specificity of 97.5% (95%CI = 97.2–97.8) at a similar sensitivity of 92.6% (95%CI = 82.1–97.9) for CIN3+ relative to the comparator, and achieved a referral rate of 2.9% and 6.1 colposcopies to detect one CIN3+. These findings were replicated for the endpoint of CIN2+. In addition, HPV16 positivity and/or ≥LSIL cytology (Strategy 9) showed a similar specificity and a comparable sensitivity for detecting CIN2+/CIN3+ to the comparator. However, (HPV16 and/or 18 positivity) and/or ≥LSIL as triage (Strategy 15) revealed comparable sensitivities and worse specificities for detecting CIN2+/CIN3+ compared with the comparator.Strategy 3 raised the threshold to LSIL, yielding a favorable specificity and a comparable sensitivity for detection of CIN3+ to the comparator, but leading to a worse sensitivity for detection of CIN2+ with misdiagnosis of more high-grade diseases. None of the other strategies showed improvement in specificity without a decreased sensitivity for the detection of CIN2+/CIN3+ as compared to the comparator. Among them, HPV16 alone or HPV16/18 positivity, yielded lower sensitivities for the detection of CIN3+ than the comparator .In the current study, the prevalence rate of hrHPV was 13.7% on self-collected samples. The high prevalence of hrHPV not only leads to unnecessary colposcopy or follow-up burden, but alsRisk stratification has important implications for the personalized risk management of HPV positive women. For instance, optimizing triage strategies to decide whether referring the patients to immediate colposcopy or follow up. Even afMorphological cytology and molecular HPV genotypes are two most common triages used in clinical practice. DiffereAlthough several strategies such as dual staining and methylation makers are under consideration in some countries, “cytology ≥ASCUS” is currently one of the most common triage strategies in clinical practice, 13, andThe medical resources required and health care professionals, as well as healthy perceptions of women, are key factors that should be addressed to ensure effective cervical screening programs . Of the Of the 17 triage strategies, combining HPV16 positivity and/or LSIL or worse achieved similar specificity and comparable sensitivity for detection of CIN2+/CIN3+ to the comparator. However, a prior study  showed tOne limitation of this substudy is that there might be a verification bias since not all the women underwent biopsy, for instance, some women negative of HPV didn’t meet the requirements of colposcopy referring. However, several HPV assays including cobas4800 and Seq HPV either on self-collected or clinician-collected samples were performed, and all the hrHPV-positive women were suggested to be referred to colposcopy-guided biopsy according to standard POI protocol as well as a high compliance rate of colposcopy referral in HPV-positive women , which rEfficient cancer prevention is based on detecting and treating precancers before they become cancer. Implementing this effectively and still avoiding overtreatment should be the primary goal of cervical cancer screening. In seveIn conclusion, the study revealed that combinations of HPV16 and the threshold HSIL improves the colposcopy referral rate, cytology testing rate and the specificity for detecting CIN3+ lesions while maintaining adequate sensitivity compared with the triage of cytology ≥ASCUS, thus could be used as a preferred screening strategy for young and fertile women. Combinations of HPV16 or HPV16/18 with ASCUS or worse could improve sensitivity and cytology rate compared with triage of cytology ≥ASCUS, and reduce substantial colposcopy referrals compared with HPV testing alone. Sequential triage algorithms that combinations of HPV16 or HPV16/18 and different thresholds of cytology provide guidance for individualized management of HPV-positive women in clinical practice, and offer practical alternatives for organizing HPV-based screening programs, particularly in low-resource areas.S1 File(XLSX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.


Human papillomavirus (HPV) associated invasive cervical cancer (ICC) is common in Zimbabwe, disproportionately affecting women living with HIV (WLHIV). Understanding high-risk HPV (hrHPV) infection in relation to cervical disease is important for ICC prevention amongst WLHIV.To describe the prevalence of cervical hrHPV, type distribution, associated risk factors and ICC screening outcomes in an urban cohort of Zimbabwean women.In this cohort study, WLHIV were tested for hrHPV infection using the Cepheid Xpert® HPV assay and followed up for incident cervical disease. Follow-up assessments were done by visual inspection with acetic acid (VIA). Descriptive statistics and logistic regression were used to describe hrHPV burden and association between hrHPV and potential risk factors. Incidence rates (IR) and rate ratios of cervical disease by hrHPV infection status were also calculated.n = 80). Fifty-two of these women (65%) were positive for hrHPV types other than 16 or 18/45. Younger age (22–29 years), early sexual debut (13–16 years) and antiretroviral therapy (ART) regimen (second-line ART) were independently associated with hrHPV positivity. Positive VIA IR ratio between hrHPV-positive and -negative women was 12.57 . Only women with hrHPV infection had incident cervical disease . There were no ICC cases by the end of the 2-year follow-up.Amongst 321 WLHIV recruited, hrHPV prevalence was 24.9% (There was a high prevalence of hrHPV infection other than 16 and 18/45 in this cohort. Integrating HPV testing in cervical cancer screening programmes may increase screening intervals in hrHPV-negative women, reducing costs for programmes. We recommend further research into cross protectivity of the bivalent and quadrivalent HPV vaccines against these other hrHPV types. High-risk human papillomavirus co-infection with HIV is associated with decreased clearance, increased HPV persistence and progression to precancerous lesions and cervical cancer.5 Invasive cervical cancer (ICC) is the most common female malignancy in Zimbabwe and is the leading cause of female cancer-related deaths with an age-standardised mortality rate of 46 per 100 000 women per year.6Zimbabwe is one of the countries with the highest human immunodeficiency virus (HIV) burden in sub-Saharan Africa. In 2018, the HIV prevalence was estimated at 12.7% amongst adults aged 15 to 49 years, with a higher prevalence in women (15.4%) than in men (10.0%).9 The WHO 2013 cervical cancer guidelines recommend primary HPV testing as the preferred method where resources are available, as HPV testing is more sensitive and effective in identifying women at high risk for precancerous and cancerous lesions.11 This modality of screening has not been rolled out in the region because of the prohibitive cost of the test. The diagnostic landscape is changing, and as cost-effective point-of-care HPV DNA tests are becoming more accessible, countries have commenced HPV screening as the preferred primary cervical cancer screening method.13The current recommended cervical cancer screening method in low resource settings such as sub-Saharan Africa is visual inspection of the cervix after application of acetic acid (VIA).14 This, however, has raised questions on the cross protective effect of other hrHPV subtypes, which have been reported to be prevalent amongst women in Zimbabwe.16The Zimbabwean government partnering with GAVI, the Vaccine Alliance in 2018, rolled out a national HPV vaccination programme, as its cervical cancer primary prevention method. The programme targeted the countries’ 800 000 girls aged 10–14 using the bivalent vaccine, which confers protection to hrHPV subtypes 16/18/45.22 In 2017, a Zimbabwean study showed a hrHPV prevalence of 33% in a rural cohort of 123 WLHIV. Types 35, 52 and 58 were found to be amongst the highly prevalent types, in addition to types 16 and 18.15 These geographical differences in HPV burden and type distribution highlight the need to assess the Zimbabwean urban context independently. In this cohort study, we investigated the prevalence of hrHPV, the associated risk factors and VIA outcomes during 2 years of follow-up.Sub-Saharan African studies investigating HPV prevalence in WLHIV have shown a wide variability across different countries from 24% to 64%.23 Sexual reproductive health services form an integral component of HIV care at NC and include cervical cancer screening, diagnosis and treatment of sexually transmitted infections (STIs), and the provision of short- and long-acting reversible contraceptive methods. An HPV vaccination programme was also introduced at the clinic in 2015. In this year alone, 517 adolescents and youth 12–22 years old  were vaccinated using the quadrivalent HPV vaccine. The vaccination of children, adolescents and young adults still continues to date at the clinic as part of the clinic’s effort to prevent a potential burden of HPV-related cancers in these young people as they mature.This analytic cohort study was conducted amongst WLHIV at Newlands Clinic (NC), in Harare, Zimbabwe. The NC was established in 2004 in partnership with the Ministry of Health and Child Care (MoHCC) and provides comprehensive HIV care to approximately 6500 men, women and children.Women registered in care at NC attend routine annual cervical cancer screening where the VIA method is used as guided by the Zimbabwean Ministry of Health. The procedure is performed by a team of three nurses who have been trained in this technique. Women with a positive VIA screen are treated with either cryotherapy, loop electrical excision procedure (LEEP) or referred for specialist management depending on the type and extent of the cervical lesion. Visual inspection with acetic acid and cryotherapy are conducted by the nurses. The LEEP procedure is performed by a gynaecologist, and the excised tissue is sent to an external laboratory for histological examination.We invited women attending cervical cancer screening between 01 September 2017 and 21 November 2018 to participate in the study. Sexually active, HIV-positive women above the age of 18 years who consented to participate in the study were recruited. Potential participants with a positive pregnancy test were excluded. Baseline information including sexual history and demographic information were collected and stored in a Microsoft Access database.® HPV test does not distinguish between types.24 Positive hrHPV results during the study period did not alter VIA follow-up intervals which were determined by VIA results only. We followed up participants with VIA screening for a median of 26 months (interquartile range [IQR]: 24–28), which was up to April 2020. Participants with incident HPV-related disease as high-grade vulva intraepithelial neoplasia (VIN3) were censored from further follow-up.At the baseline visit, we screened participants using VIA, the study nurses collected endocervical swabs for the HPV DNA tests. Women who screened positive by VIA were reviewed six monthly, and those who screened negative, annually. For the HPV DNA tests, we collected endocervical swabs using the Cervexbrush25 and deposited the samples into Preservcyt50 transport medium. We used Xpert® HPV kits for testing on the GeneXpert machine located at the onsite NC laboratory. The test detected 14 high-risk HPV with callouts for HPV 16, HPV 18/45 and ‘other hrHPV’. Amongst the ‘other hrHPV’ subtypes are HPV 31, 33, 35, 39, 51, 52, 56, 58, 59, 66 and 68. The 14 HPV types are detected in five fluorescent channels, each with individual parameters for target detection and validity; channel 1: HPV16, channel 2: HPV18/45, channel 3: HPV31/33/35/52/58, channel 4: HPV51/59, channel 5: HPV 39/56/66/68. For channels in which more than one type is detected, the XpertWe collected additional patient data including antiretroviral therapy (ART) medication history, VIA screening results and laboratory results from the clinic’s electronic database. None of the women in the study cohort had an HPV vaccination history.p < 0.05 considered significant and 95% confidence intervals [CI] used. In summary, our descriptive, univariate and multivariate analysis were based on all data 100% (n = 321). Follow-up data was based on 96% (n = 308) women with hrHPV test results and without incident cervical disease.We used Stata 13.1  for data cleaning and analysis. We used proportions and medians for descriptive statistics, logistic regression and the associated Wald test for measures of association between hrHPV test and potential risk factors, and Wilcoxon Rank-Sum (Mann Whitney) test differences between continuous variables. We assessed all potential risk factors in univariate and multivariable logistic regression models to determine independent associations. Our final logistic regression model did not include VIA data as HPV infection is known to precede VIA status. Incidence rates (IR) and IR ratios for cervical disease defined as VIA positivity, high-grade squamous intraepithelial neoplasia (HGSIL) and cervical cancer were assessed with the follow-up data. All statistical tests were two-tailed with The study was approved by the Newlands Clinic Research team and the Medical Research Council of Zimbabwe .n = 95) were widowed. Two-thirds of the women  were educated to high-school level . Most women  reported sexual debut between 17 and 21 years, and 13.4% (n = 43) were 16 years or below at sexual debut. Regarding duration on ART, 233 (70.8%) had been on ART for more than 5 years . In total, 252 (78.5%) were on a first-line ART regimen (1 Non-nucleoside Reverse Transcriptase Inhibitor [NNRTI] + 2 Nucleoside/Nucleotide Reverse Transcriptase Inhibitor [NRTI]) and had a median CD4 count of 525 cells/mm3  reported that they were unaware of their partner’s HIV status and 15.6% (n = 50) were in HIV sero-discordant relationships. Amongst the 310 women who had HIV viral load results, 91.2% (n = 283) had undetectable viral loads (below 50 copies/mL) and 2.9% (n = 9) had a viral load above 1000 copies/mL (We recruited 321 women with a median age of 44 years (IQR: 38–50). One hundred and thirty-eight (43.0%) women were married and 29.6%  had HPV 16 and other hrHPV coinfections, and five (6.3%) had HPV 18 and other hrHPV. There were no co-infections with HPV 16 and HPV 18/45. Data for specific channels positive for other hrHPV-positive samples were available for 56/61 samples (91.8%). Amongst these 56 samples, 40 (71.4%) were positive in channel 3 (HPV31/33/35/52/58), 5 (7.1%) in channel 4 (HPV51/59) and 15 (26.8%) in channel 5 (HPV 39/56/66/68). One was positive in both channels 3 and 4, whilst two were positive in both channels 3 and 5  were positive for any hrHPV. Human papillomavirus 16 positivity without other coinfections was in 9 (11.2%) women, 10 (12.5%) were positive for HPV 18/45 alone, 52 (65%) for  3 and 5 . Of the p = 0.02), women with a positive VIA within 2 years prior to HPV screening , women on second-line ART  and those with a positive VIA at time of HPV screen  were more likely to test positive for hrHPV. Having a detectable viral load at the time of screening and sexual debut between the age of 13 and 16 years were also significantly associated with hrHPV positivity . However, no statistical significance for hrHPV positivity was observed for CD4 count < 200 cells/mm3 . In the multivariate analysis, only younger age (22–29 years), , ART regimen  and early sexual debut at ages 13–16 years  showed evidence of association with hrHPV positivity  participants with negative VIA at the time of hrHPV screen were followed up for a median of 2 years . Follow-up was made to determine incident VIA positivity, incident HGSIL and incident cervical cancer (confirmed by LEEP biopsy) by HPV infection status at baseline. The VIA positivity IR in hrHPV-negative women was 0.79 per 100 person-years (95% CI: 0.30–2.11). In hrHPV-positive women, the VIA positivity IR was 9.97 per 100 person-years (95% CI: 5.90–16.83). Incident rate ratio between the two groups of women was 12.57 (95% CI: 4.14–38.19). There was no evidence of incident cervical disease (HGSIL) in women who tested negative for hrHPV infection. Amongst women with hrHPV infection, the IR of HGSIL was 6.41 per 100 person-years (95% CI: 3.33–12.32). During the follow-up period, there was no incident of cervical cancer regardless of hrHPV infection status .Of the 14 incident VIA-positive women at follow-up, eight (57%) at baseline were positive for other hrHPV subtypes (four being channel 3 subtypes and the others having missing channel data), two were positive for HPV16, one was positive for HPV 16 and other hrHPV subtypes (channel 5). Two were positive for hrHPV 18/45 only and one for hrHPV 18/45 and other (channel 3). None of the women had 16/18/45 coinfections at baseline. None of the women with positive channel 4 subtypes had incident cervical disease at follow-up.15 but lower than that observed in other regional studies from Malawi, Burundi, Kenya and South Africa, which range from 45% to 64%.26 The difference in reported prevalence rates between studies may be because of several factors including the heterogeneity of the study populations. Our study describes prevalence in an urban cohort of women with well-controlled HIV (95% VL < 1000 copies/mL). The majority of the women were receiving their first-line ART regimen for a median of 7 years and had previous cervical cancer screening.We detected hrHPV infection in 24.5% of WLHIV attending routine cervical screening. The prevalence of types 16 and 18/45 was relatively low, with a predominance (65%) of the non-16/18/45 HPV subtypes. Our observed overall hrHPV prevalence is similar to the 33% prevalence reported in a cohort of WLHIV in rural Zimbabwe,27 In our study, 35% of women with hrHPV had either HPV 16 or 18/45, whilst 65% had ‘other’ high-risk types. These findings are consistent with data from other studies in the region, including a world regional HPV survey, which describes an increased probability amongst WLHIV to harbour other hrHPV types such as 31, 33, 35, 52 and 58, often in the absence of cervical disease (HGSIL or ICC).30. Cumulative risk and annual rate of progression to cancer varies depending on HPV type in immunocompetent women.31 In a longitudinal study of 11 573 HIV-negative, hrHPV-positive women, Demarco et al. reported that 21.5% of women at Kaiser Permanente in Northern California, United States of America, with baseline HPV 16 had progressed to precancer/cancer at 7 years and women with HPV 33 also showing high cumulative risk with 18.4% progression at 7 years.31 Our study’s limited follow-up time inhibits us from making comments on the progression potential of the observed non-16/18/45 hrHPV subtypes. WLHIV with hrHPV are, however, at an increased risk of rapid progression to cervical disease.5 More robust epidemiological data in WLHIV are required to clearly define this risk according to hrHPV type with longer follow-up periods, in order to inform and optimise cervical screening programmes in WLHIV.Globally, HPV types 16 and 18 predominate and are responsible for most anogenital HPV-related cancers in women.32 Cross protection from the bivalent vaccine for other non-vaccine high-risk types as in our cohort has been demonstrated. Van De Weele et al. noted significant reductions in incident and/or persistence of certain types , following exposure to the bivalent vaccine in a cohort of young Dutch women.33 In view of the dominance of subtypes other than HPV 16 or HPV 18/45, it is unclear whether the bivalent vaccine currently being administered in the Zimbabwe national programme will provide cross protection against these subtypes. An understanding of the degree of cross protection from context-specific data is warranted. This can be achieved through country-specific vaccine evaluation studies in the vaccinated cohort.Human papillomavirus vaccination programmes are a key component of primary prevention to reduce cervical cancer-associated morbidity and mortality. The WHO currently recommends both bivalent and quadrivalent vaccines, which confer protection against hrHPV types 16 and 18.34 Van Aardt et al. postulate that the higher hrHPV prevalence in younger women may be partially explained by the lack of natural immunity in the initial stages of sexual activity.35 Literature also provides evidence that over 35% of women contract HPV within the first 2 years of sexual debut8 and that early sexual debut is also associated with a greater number of sexual partners and an increased risk of STI infection.37 Research to further elucidate clearance and progression to cervical dysplasia in younger women is also necessary.Early sexual debut and younger age were significant predictors of hrHPV infection in our cohort. Women with an early sexual debut (13–16 years) were at least three times more likely to test positive for hrHPV when compared with those whose sexual debut was after 21 years. In keeping with these findings, a cohort analysis of 1445 urban women in South Africa showed a peak in hrHPV prevalence in women younger than 25 years and a gradual decrease of hrHPV infection with increasing age of women.3 increases the risk of hrHPV infection.38 In our context, women on second-line ART often have a history of severe immunosuppression necessitating the switch to second-line ART.Despite most women in our study being on first-line ART and 95% having Viral load (VL) < 1000 copies/mL, women on second-line therapy were twice as likely to test positive for hrHPV. In a systematic review of the association between HPV infection and ART, Menon et al. indicate that severe immuno-suppression of CD4 counts < 200 cells/mm39 In low-income countries, less-frequent cervical cancer screening, once every 3 years, for hrHPV-negative WLHIV will have both the potential to reduce costs and divert scarce resources to hrHPV-positive women who are at higher risk of developing cervical cancer and in women who have never been screened. This resource optimisation may translate to greater screening potential in settings where coverage is still low like in Zimbabwe.8 However, a key component of the potential success of this screening programme that utilises HPV testing is the development and availability of low-cost HPV assays.After a median of 2 years follow-up, the incident rates for both VIA positivity and HGSIL were significantly higher in the women with hrHPV infection. No cases of HGSIL were observed in hrHPV-negative women. These data are consistent with findings from large longitudinal studies. Data from the Kaiser Portland cohort of over 20 000 women and more than 15 years of follow-up demonstrate a low risk of precancer or cancer in HIV-negative women with a single negative hrHPV result. The high negative predictive value of HPV DNA testing is now well established, hence the adoption by many global cervical screening programmes as the primary screening tool.® HPV kits limited our ability to describe individual hrHPV types in the cohort apart from HPV 16. Secondly, the duration of follow-up was short and because of the nature of the pathogenesis of HPV infection, there was limited time for disease progression to occur. Thirdly, hrHPV infection was only assessed at baseline, therefore questions of HPV persistence and clearance could not be addressed. Despite these limitations, the information from this study can be used to provide background data for prospective cohort studies to ascertain persistence of HPV infections in women with controlled HIV infection.As reported in the methodology, the use of the XpertOur study highlights key epidemiological information on hrHPV infection in an urban cohort of HIV-infected women in Zimbabwe. There was a lower than expected overall prevalence of hrHPV infection in the study cohort, but a higher prevalence of hrHPV subtypes other than HPV 16 or 18/45. This raises some important vaccine effectiveness questions regarding the current roll-out of the prequalified bivalent and quadrivalent HPV vaccine, particularly regarding the level of cross-protection against other hrHPV types, which are prevalent in our setting. Our follow-up data highlights the potential benefits of integrating primary HPV testing, in cervical cancer screening programmes amongst WLHIV, which may lead to reduced screening intervals in hrHPV-negative women and potentially result in cost reduction.


Men perform a higher percentage of winning smashes than women, mainly in the flat smash (p = 0.02). Furthermore, with regards to direction, flat and off the wall smashes are predominantly down the line strokes and women perform significantly more cross court topspin smashes than men (p = 0.005). The results shown could be used to design tasks and exercises by padel coaches at professional players.The aim of this study was to analyze the distribution and effectiveness of the different types of smash in professional padel according to the area and direction of the strokes and the gender. Through systematic observation, 1.015 smashes from eight finals (four men’s and four women’s) of the professional matches were analyzed. The smashes were categorized into four types of smash: tray, flat, topspin and off the wall. The results showed both men’s and women’s that the tray is the most used smash by padel players, presenting a percentage of point continuity of almost 90%. The flat and topspin smashes are the strokes that achieve the highest percentage of winning points (near 60%), although this efficiency decreases significantly when the players move away from the net area ( Padel is a racket sport that was born in Mexico approximately 50 years ago  and has These studies, carried out on professional players, have determined that there are two basic tactical positions in padel: the offensive position, where the players play close to the net and the defensive position, where the players play near the baseline of the court . PreviouThere is a continuous dichotomy during the development of the point, where players who are at the net try to keep this advantageous position, while the backcourt players try to recover it ,25. PlayFollowing the review conducted, there is research related to a performance analysis in padel, but mainly in male players. Research focused only on a female padel player is scarce . In relaTray: Offensive stroke, without a bounce, which is made over the head and on the dominant side of the player. In this shot, before hitting the ball, the player opens the face of the racket pointing upwards and hits with a slice effect. The impact point on the ball is lower than in the other smashes.Flat smash: Offensive stroke, without a bounce, which is made over the head and on the dominant side of the player. In the execution of this shot, the player hits the ball with a lot of power at the highest possible point, with a flat stroke (no effect), so that after bouncing on the opposite side, the ball could go out of court or return to the other side after rebounding against the wall.Topspin smash: Offensive stroke, without a bounce, made over the head and hitting the ball from the non-dominant side (behind the player’s head). In the execution of this shot the player hits the ball with a lot of power, with a topspin effect, accelerating the shot by arching the back so that, after bouncing the ball on the wall of the opposite side, it goes out over one of the sides walls of the court.Off the wall smash: Offensive stroke, with a bounce, which is made above the head and on the dominant side of the player. This shot is made when the player, after receiving a lob, lets the ball bounce on his/her side and waits for the bounce on his/her back wall to make a smash. Depending on the player’s aim, this shot can be done with a flat or slice effect.Type of smash: The different types of smash were classified into four shots, following the classification proposed by other authors in padel research ,22:TrayShot effectiveness: The classification proposed by Courel-Ibáñez and Sánchez-Alcaraz (2017) was used to determinate smash effectiveness, distinguishing between the winner (the attacking player wins the point by making a smash), error (the attacking player fails the smash and loses the point) or continuity (the point continues after the smash).Hitting zone: The court was divided into six zones, depending on the court side (right or left) and the distance to the net  when the player hit the ball . BaselinShot direction: Two possible trajectories were distinguished: down the line and cross court .It is a descriptive and observational study of quantitative methodology. The sample included 1.015 smashes corresponding to eight finals (four men’s and four women’s matches) of the official circuit World Padel Tour 2019 held in Barcelona, Valladolid, Madrid, Santander and Murcia (Spain). The analyzed smashes were made by 20 professional padel players: 10 men (age = 32.35 ± 6.28 years old) and 10 women (age = 29.62 ± 5.91 years old) and the study was conducted in accordance with the Declaration of Helsinki of 2013. The following variables were analyzed:https://www.worldpadeltour.com/) [Data were collected through systematic observation, carried out by two observers who have a degree in Sports Science and are specialized in padel. Observers were specifically trained in the use of the observational instrument during two weeks. The training focused on the clear identification of the variables  and the use of the observational instrument software. At the end of the training process, each observer analyzed the same two sets in order to calculate the inter-observer reliability through the Multirater Kappa Free , obtainiur.com/) , from whur.com/) .n) and percentage (%) were calculated on the whole sample. A comparison was made of the statistics of distribution and efficiency of the smashes according to gender and the playing side of the court using Pearson’s Chi-Square test. Column proportions were compared using Z tests on the effectiveness of the smash according to the area and gender of the players. A significance level of p < 0.05 was established, which was adjusted according to Bonferroni in the Z tests. The associations among the categories of the variables were performed with corrected standardized residuals (CSR). The effect size was calculated using Crammer’s V [Firstly, a descriptive analysis of the data was carried out and the mean (M), standard deviation (SD), frequency . The female player performed significantly more tray strokes than male  and top-spin smashes (CSR = 3.0) than female players. Depending on the area of the court, most of the smashes were made in the middle area of the court for both genders. In relation to the direction of the smash, male players performed significantly more down the line strokes than female .2 = 2.371; gl = 2; p > 0.05; V = 0.065). By contrary, in the right side of the court male and female players played different . Male players made more smashes in the net (CSR = 1.8) and in the baseline (CSR = 1.5), and females played more smashes in middle area (CSR = 2.4).Depending on the hitting side, there was a trend towards a higher percentage of smashes in the middle zone in both genders. On the left side of the court, the smashes made in the different areas of the court were similar between male and female . The men performed a significantly higher percentage of winning flat smashes (CSR = 2.7) and less percentage of continuity of this stroke than the women (CSR = −2.8). No significant differences were found according to gender for the tray , topspin  and off the wall smashes . Furthermore, the flat smash and topspin smash were the two smashes that produced more winners, while the tray and off the wall smashes were the smashes recording a higher percentage of continuity. The smash with the highest percentage of errors was the off the wall smash.The division by the type of smash  showed d2 = 7.203; gl = 1; p < 0.01; CSR = 2.7; V = 0.31). Thus, while men equally distributed the direction of their topspin smashes, women performed more than 80% of their topspin smashes cross court. No significant differences were found between men and women in the direction of the flat smash , tray  and off the wall smash . In general, both men and women hit a higher percentage of down the line flat and off the wall smashes, while the tray was directed equally down the line and cross court.Smash stroke is the game actions that produce the highest percentage of winner shots in padel ,27 and hPrevious studies in professional padel have shown that players who are in defensive positions predominantly use the lob stroke to recover the net ,26,35. HGender differences showed that men made a significantly higher percentage of winners than women . These results could be due to the anthropometric and strength differences between elite men and women players ,38. The In line with our hypothesis, males and females use one type of spike more than another, and with different performance (mainly in flat and top-spine strokes). The results of this study have important practical applications for the training of padel players, facilitating the design of tasks and exercises, as well as preparing them for competition taking into account the differences between the men’s and women’s categories. Moreover, knowledge of the effectiveness of the different types of smash depending on the court area in which the player is located will allow the training of perceptual and decisional mechanisms during the game by the player and the application of feedback about the behaviors by the coach ,40. HoweThe tray was the most commonly used smash by padel players. Female players used more tray and less flat and topspin smashes than male players. Tray represents a percentage of point continuity of almost 90%. The flat and topspin smashes were the shots that achieved the highest percentage of winners, although this efficiency decreased significantly when the players moved away from the net area, especially in the flat smash. Regarding gender, men performed a significantly higher percentage of winning smashes than women. In addition, with regard to direction, flat smashes and off the wall smashes were predominantly down the line strokes and women performed significantly more cross court topspin smashes than men.


To assess the benefits and harms of the human papillomavirus (HPV) vaccines.Clinical study reports obtained from the European Medicines Agency and GlaxoSmithKline from 2014 to 2017.Randomised trials that compared an HPV vaccine with a placebo or active comparator in healthy participants of all ages.Two researchers extracted data and judged risk of bias with the Cochrane tool (version 2011). Risk ratio (RR) estimates were pooled using random-effects meta-analysis.Clinically relevant outcomes in intention to treat populations—including HPV-related cancer precursors irrespective of involved HPV types, treatment procedures and serious and general harms.P = 0.05, I2 = 67%) and HPV-related treatment procedures . The HPV vaccines increased serious nervous system disorders  and general harms  but did not significantly increase fatal harms  or serious harms .Twenty-four of 50 eligible clinical study reports were obtained with 58,412 pages of 22 trials and 2 follow-up studies including 95,670 participants: 79,102 females and 16,568 males age 8–72; 393,194 person-years; and 49 months mean weighted follow-up. We judged all 24 studies to be at high risk of bias. Serious harms were incompletely reported for 72% of participants . Nearly all control participants received active comparators . No clinical study report included complete case report forms. At 4 years follow-up, the HPV vaccines reduced HPV-related carcinoma in situ  and general harms. As the included trials were primarily designed to assess benefits and were not adequately designed to assess harms, the extent to which the HPV vaccines’ benefits outweigh their harms is unclear. Limited access to clinical study reports and trial data with case report forms prevented a thorough assessment.https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20170030.pdf. Two protocol amendments were registered on PROSPERO on November 2017: https://www.crd.york.ac.uk/PROSPEROFILES/56093_PROTOCOL_20171116.pdf. Our index of the HPV vaccine studies was published in Systematic Reviews in January 2018: 10.1186/s13643-018-0675-z. A description of the challenges obtaining the data was published in September 2018: 10.1136/bmj.k3694.CRD42017056093. Our systematic review protocol was registered on PROSPERO in January 2017: The online version of this article (10.1186/s13643-019-0983-y) contains supplementary material, which is available to authorized users. The approved human papillomavirus (HPV) vaccines—GlaxoSmithKline’s Cervarix™ and Merck Sharp and Dohme’s Gardasil™ and Gardasil 9™—are considered safe and effective –3. Recen+) infected with an HPV vaccine-specific HPV type, such as HPV types 16 and 18 that are associated with the majority of HPV-related cancers ” ” ), which The clinical study reports, their informed consent forms and corresponding journal publications  were only included in the trials if they had no history of immunological or nervous system disorders  for 61,331 participants  and general harms. As the included trials were primarily designed to assess benefits and not adequately designed to assess harms, the extent to which the benefits outweigh the harms is unclear. Limited access to clinical study reports and trial data with case report forms prevented a thorough assessment. An independent assessment of the complete individual participant data is needed. If granted access to the complete data set with individual participant data, we will update this systematic review. A large industry-independent multicentre trial of two doses of Gardasil 9 vs. saline placebo would likely be informative in identifying a more accurate benefit-harm balance, but we recognise that such a trial will be considered unethical in most settings.Additional file 1:Benefits and harms of the HPV vaccines—PRISMA 2009 checklist. (DOCX 31 kb)Additional file 2:Benefits and harms of the HPV vaccines—characteristics of included studies. (DOCX 121 kb)Additional file 3:Benefits and harms of the HPV vaccines—list of excluded studies. (DOCX 63 kb)Additional file 4:Benefits and harms of the HPV vaccines—meta-analyses. (PDF 26103 kb)