The North Atlantic blue whale was depleted by modern whaling and it is still considered to be highly endangered. Despite its protection in 1954, catches continued in the South European Atlantic Shelf (SEAS) region and immediately adjacent waters until 1979. We compiled catches and investigate abundance trends in the region using original data from whaling (1921–1985) and scientific surveys around the last years of exploitation (1981–1987). The struck and lost rate was estimated at 3.2% for sperm whales and 2.3% for baleen whales. The compiled records include 60 catches, with an additional 1–2 blue whales likely struck and lost. From these, 29 individuals had been correctly reported as blue whales but 31 were mislabelled as fin whales. After correcting for loss rates, the number of blue whales killed in the region was estimated at 61 in 55 years . The data from the 1950s shows some oversized fin whales but it is unclear whether they are due to an incorrect reporting of species or to incorrect measurements, so it cannot be discarded that the actual number of blue whales caught was slightly higher than estimated. Mean body length of reported blue whales was lower than in higher latitudes of the North Atlantic, probably reflecting geographical stratification with higher proportion of immatures in the SEAS. The ratio between catches or sightings of blue whales and those of fin whales was 5.9% in the southern part of the SEAS previous to exploitation, it declined to 0.02–0.18% in the 1920s, and increased thereafter up to 1.6% in the 1980–1990s. Taking as reference the population size of fin whales in the SEAS, that of blue whales at the end of the 1980s can be guessed to be at ca337-497 individuals. Considering accepted population estimates in other areas as well as the observed rates of increase, current abundance is thought to be over a thousand whales in the SEAs and at in the order of 4000–5000 individuals for the whole eastern North Atlantic basin. Balaenoptera musculus) was the most sought after species when modern whaling started its activities in the 1860s. The first catches were made in North Norway, but soon operations extended to other locations of the North Atlantic before they spread in the first years of the twentieth century to the North Pacific and the Antarctic Oceans1. However, in the North Atlantic the blue whale populations were relatively small and catches rapidly plummeted over the course of several decades of exploitation3. International Whaling Commission (IWC) catch statistics, built on the records earlier assembled by the Bureau of Whaling Statistics (BIWS) between 1930 and 1986, and completed and corrected thereafter4, only reflect 10,747 catches in the North Atlantic during 1864–2019, although actual numbers probably ranged between 15,000 and 20,000 because in the first years of exploitation some blue whales were caught and not reported5. Despite these numbers being low compared to those from other species , already at the start of the twentieth century the species was residual in most areas of the North Atlantic Ocean and was substituted by the fin whale as a main target6. When the pioneer Convention for the Regulation of Whaling was signed in Geneva in 1931 there was already a clear perception that several blue whale stocks had been dramatically impacted and, in 1936, exploitation of the species was prohibited between the Equator and 40° S latitude, the fringe of waters where it was believed to reproduce7. In 1946 the International Whaling Commission (IWC) was established, and in its meeting in Tokyo in 1954 approved a ban on the exploitation of blue whales in the North Atlantic Ocean8. Iceland and Denmark initially objected the decision and were the only IWC-member countries that for some years continued carrying out its exploitation. However, blue whales were so scarce that their combined catch was only 5–13 whales per season9. In 1960 these two countries withdrew their objection and agreed to stop killing blue whales, and thus the complete protection of the species in the North Atlantic came into force amongst all IWC member nations10. The few catches of blue whales recorded thereafter were only scattered mistaken captures catalogued as infractions, which totalled 4 individuals during the period 1960–196611.Because of its massive body size and economic profitability, the blue whale (Rey Alfonso (1924–1926), Bas (1924), Congo (1925), and Pioner (1934) floating factories, the Benzú land station (1947–1954), the Setúbal land station (1925–1927 and 1944–1951), the Industria Ballenera SA (IBSA) land stations of Cangas, Caneliñas and Morás (1951–1985), the Sierra unregulated floating factory (1977–1979), as well a number of small land stations in the Azores (1921–1987) and Madeira (1941–1981)14  and their occasional catches of rorquals never included blue whales11. Spain, conversely, had at that time three operating land stations run by the IBSA company  that strongly relied on the exploitation of Balaenopteridae whales and, although besides the sperm whale the main exploited species was the fin whale, they also took sei whales  and, to a lesser extent, blue and humpback whales (Megaptera novaeangliae)14. Not being a signatory to the Convention, Spain did not have to abide by the IWC regulations and thus ignored the prohibition on catching blue whales.At the time that IWC passed its ban on the exploitation of blue whales, all North Atlantic whaling countries adhered to the International Convention for the Regulation of Whaling (ICRW) with the exception of Portugal and Spain. In both countries modern whaling had started in the 1920s and continued with some interruptions until the moratorium on commercial whaling adopted by the IWC came into force in 1986. Operations were conducted from several whaling factories: the Getares land station (1921–1926 and 1950–1959), the 14. As a result, the protection of the species became thereafter fully effective in the North Atlantic and no catches have been recorded since that time.In order to prevent these and other whaling operations from escaping its jurisdiction, in 1978 the IWC agreed that member countries could not import products from non-member countries. Spain, which was then exporting most of its whaling products to Japan, saw its business in danger and was left with no choice but to adhere to the IWC. In 1979 it joined the organization and, from then on, it stopped capturing protected species, including blue whales15. The variation in abundance trends in different areas that had been subject to exploitation, with asynchronous local depletions caused by the excessive takes, suggests that the North Atlantic Ocean metapopulation is structured into different units with at least two discrete subpopulations, one occupying the western basin and another occupying the eastern basin17. Although there are no conclusive evidences to support the separation between these purported populations, photo-ID and satellite tracking studies suggest that mixing between them is very low and that the Icelandic feeding grounds are used by the eastern subpopulation20.In the North Atlantic, blue whales are distributed from the edge of the pack ice to tropical and subtropical waters5. In this context, accurate information on the historical catches, the status of the subpopulations and their trends, is of prime relevance. Here we analyse the information on blue whales from whaling operations and scientific surveys conducted in the South European Atlantic Shelf ecoregion  and immediately adjacent waters to gain an insight into their demographic trends. To do so, we extracted catch data from the internal landing records of the whaling factories, contrasted them for accuracy with catcher boat logbooks and gunner’s notebooks, and compared the resulting data with those contained in the officially compiled IWC catch data set. Also, for the period 1980–1987 we compile the sightings data from the available logbooks of the catcher boats and from scientific sighting cruises that were carried out during the period 1979–1987. Combining these different sources of information, we attempt to assess the relative abundance of blue whales in the last phases of whaling in the area, the potential impact that the unregulated catches had on the population, and their past and current abundance trends.Despite more than 4 decades of complete protection in the North Atlantic, the species has only timidly recovered and its current population appears to be still fragile and is consequently catalogued as Endangered21. The geographical limits of the area covered were: 48° 30′ N (Normandy)–30° 00′ N (southern limit of the Cadis Gulf) and 18° 30′ W (limit of the area covered by the surveys)–5° 30′ E . The Mediterranean Sea is not included because the species does not occur in this water mass22. We analysed several independent data sources:Acaecimientos). Recording was in a format-free style text where whales were in most cases only recorded if caught and were identified as either sperm whales or as baleen whales, in the latter case with no distinction between species. The gunners’ notebooks had been kept just for personal recording of catches and bonuses obtained, and were simple listings of catches with dates and species. These two sources of information were of utility for checking the accuracy of the catch data, but could not be used to investigate schooling behaviour or the relative abundance of blue whales.Standard-type logbooks from the IBSA catcher boats and gunners’ note books: until 1979, the logbooks used by the IBSA whaling fleet had the standard format used in fishing vessels but included with varying degrees of detail the whale catch information in the section of “daily events”  they were also used to examine school size and composition, as well as to investigate abundance relative to fin whales, the most abundant large whale in the region and the main target of the fishery.23, Sanpera et al.25, Sanpera and Jover 26, and Lens et al.27 In combination with the IWC-type logbook data (see above) they were used to examine school size and composition, as well as to investigate abundance relative to fin whales.Sightings data recorded during line transect surveys conducted by the University of Barcelona during 1981–1987 (“UB-surveys”): these cruises were carried out with the objective of obtaining population estimates of fin whales in the area. Details of sightings of all cetacean species were recorded by a crew composed of both whalers and whale biologists, all with experience in species identification, so they are considered to be accurate and reliable. Cruise details can be found in Aguilar et al.14 and checked against the IWC catch dataset4. Those from the three whaling stations that operated in NW Spain during the 1951–1986 period, Caneliñas (1951–1986), Balea (1985) and Morás (1965–1975), were extracted from the internal landing records of the managing company, Industria Ballenera SA (IBSA), and checked for accuracy against the standard format and IWC-type logbooks available from the IBSA catcher boats, and then used to correct Aguilar14 and Allison4 databases. Data from the unregulated operations of the Sierra and the Tonna were taken from published sources28. The distribution of the body lengths collected by the IBSA whaling company during 1974–1985 were compared to those from the database of biological measurements collected by scientists from the University of Barcelona during the same period (UB database) to assess potential biases in IBSA measurements. Data normality of body length distributions was assessed through the Shapiro–Wilk test, and differences between distributions and medians were tested using the U Mann Whitney test and the Mood's median test for independent samples, respectively. Additionally, body length distributions for the different operations and periods were also investigated visually to identify oversized individuals that could indicate inaccuracies in measurements or in the species assignment in databases.Blue and fin whale catch data: catch data from the whaling companies operating between 1921 and 1985 in the region  were taken from a previous review of local data sources conducted by AguilarCompañía Ballenera Española , which conducted whaling during 1921–1927 both in the Straits of Gibraltar and off NW Spain, and AS Hektor /Industrial Marítima S.A., which operated during 1934–1954 in the Gibraltar Straits. This documentation was examined at the Vestfold Museene .Internal correspondence from two Norwegian whaling companies that operated in the region: the The area covered by this compilation, the SEAS, is defined as the marine ecoregion located off the European continent between the South of the British Isles and the North of AfricaThe loss rates of whales that were killed, that is, the proportion of whales that were actually harpooned and secured either to the boat or to a buoy, but were subsequently lost due to bad weather, sinking of corpse, parting of the securing chains, or other reasons, was calculated as a percentage of those that were landed at the whaling stations. The paucity (n = 15) of loss events precluded stratification by period, comparison between catcher boats or companies, or other more sophisticated analyses. Because neither the logbooks nor the gunners’ notebooks reported the loss of whales that had been struck but escaped, or those which were lost before being secured to the boat or to a buoy, we equated the number of whales that were successfully secured to those that were killed. The resulting numbers likely underestimate actual kills but, because the efficiency of harpooning techniques was high, we assume that any difference existing between the number of struck whales, and thus possibly killed, and that of secured whales would be small.29. However, because only juveniles of the species appear to occur in the SEAS (see below) and their body size approaches that of adult fin whales, the effect of such bias is probably reduced. If indeed existing, the bias would tend to slightly increase the catchability rate of blue whales and, with this, the relative abundance of this species in relation to that of fin whales, thus pushing upwards its abundance estimates. Whatever the case, it should be noted that the potential effect of this bias would only affect the estimates obtained from the catch data, but not those derived from the sighting rates of the catcher boats or from the scientific surveys because the efficiency at which the two species are sighted is indistinguishable. Thus, their sightability by observers, that is, the combination of the perception bias  and the availability bias  are very similar for blue and fin whales30, and this gives grounds to rely on the representativeness of the sightings ratio between the two species. Considering this, a blue whale-fin whale catch ratio was estimated as the number of blue whales for every 100 fin whales caught for the different periods and areas in the SEAS ecoregion.Because no direct abundance estimates for blue whales are available for the region, we produced a rough indication of abundance to assess the potential impact of catches on the population as well as its demographic time-trends. To do so, we compared the number of catches and sightings of blue whales obtained from the catcher boat logbooks and scientific surveys with those of fin whales, a species whose abundance is relatively well known thanks to specifically-designed line-transect boat surveys conducted in the region (see below in the “Discussion” section). In doing so, we made the following assumptions: (1) that the two species were equally attractive to whalers; (2) that the two species presented similar difficulty of capture; and (3) that the two species had a similar sightabilty rate. Until 1980, first year when blue whale protection effectively came into force in Spain, the first assumption seems valid and substantiated by the personal experience of AA, who conducted abundant fieldwork during 1977–1985 onboard the catcher boats. Being the products of both species commercially indistinguishable, the only potential bias would have been caused by the larger maximum body size of adult northern hemisphere blue whales  as compared to that of northern hemisphere fin whales 31. Table Table Table p > 0.5) between the two groups of samples neither in median (18 m) nor in distribution, but females from the official IBSA database had a significantly (p < 0.05) higher median body length (19.1 m) than those from the UB database (18.9 m).Figure Figure 32 was recorded as a fin whale, with no indication of its blue-fin whale mixed origin.The statistics available for the 1920s only record a few catches of blue whales, which probably reflects the scarcity of the species, although it is also likely that a few blue whales may have been caught and reported as fin whales (see “Discussion” section). Afterwards, the catch statistics compiled here register the capture of blue whales apparently reliably. In the case of the period 1953–1985 for NW Spain, the catch and sightings information contained in the catcher boat logbooks and in the gunner’s notebooks matched the landing records from the managing company, Industria Ballenera SA (IBSA) with only minor discrepancies, mostly in the date of capture, and are thus considered accurate. A fin whale-hybrid caught in 1984Temerario, 1953; Lobeiro, 1960; Carrumeiro, 1978 and 1980; Lobeiro, 1980; IBSA TRES, 1982, 1983 and 1985), and the rates calculated against the sperm and baleen whale catches recorded for the boats and periods involved. The resulting loss rate estimate was 3.2 for sperm whales (4 out of 126 catches) and 2.3% for baleen whales (15 out of 654 catches). Although none of the loss cases was identified as involving a blue whale, the rates from other baleen whales  can be reasonably applied also to blue whales. After correcting for losses, the resulting total number of whales actually killed was estimated at 61.4 blue whales along a period of 55 years, that is, 1.12 individuals/year.The landing records did not register the whales caught but lost after capture. The loss rates were calculated from the logbooks that contained specific details on losses  there are not detailed whaling statistics but only aggregated numbers of catches per company and factory. These records include one blue whale taken by the Rey Alfonso floating factory in the Gulf of Cadiz in 1924, one by the Professor Gruvel (A/S Congo) floating factory off Setúbal in 1925, and two by the Compañía Ballenera Española off NW Spain and brought to the Caneliñas land factory in 192514. However, when listing the bonuses that this last company payed to the crew, on June 11 1926 Carl Herlofson, the manager of the company in Spain, stated to the Norwegian direction in Tønsberg that gunner Aksel Johansen had to receive a bonus for the capture of a blue whale34. This blue whale capture was not included in the statistics, or was mislabelled as a fin whale and, although this was the only case of this nature that we could identify, it may suggest that a few additional blue whales were also caught and not reported. However, the above mentioned case is the only mention of a blue whale catch in the very abundant available correspondence and documentation from these operations, which consistently reported catches of only sperm, fin and sei whales . Apparently confirming this, the rich photographic material that has survived from these operations14 never shows a blue whale among the catch. Given that in the 1920s and 1930s the blue whale was not protected but, on the contrary, was a much sought-after species, there is no reason why its catch would have been hidden, particularly in the internal documents and correspondence of the company. Therefore, the actual occurrence of such unreported catches, if they exist at all, is considered to be very small. Conversely, the comparison of the official datasets with the internal records of the Spanish whaling companies that operated during 1944–1985 permitted to identify 31 blue whales that had been not reported, thus doubling the official catch numbers (n = 29). In many cases, the catch of these whales was declared, but they were incorrectly reported as fin whales. It is unclear why in some cases the companies correctly reported the blue whale catches while in others they produced an incorrect identification. Until 1979, when most of these unreported catches occurred, Spain was not part of the IWC so it was not bound by any catch limit or whaling regulation; indeed, some misled records are included in yearly reports that do include correctly declared blue whale catches .Despite there perhaps having been some exceptional catches of blue whales by open-boat whalers, such as the one made by the American whaling bark 13. Owing to the poor quality of lines, the company reported the loss of 32 out of 79 harpooned and secured whales in the first year of operation, that is, 40% of catches. The rate barely improved in the following season, with 22 whales lost out of 152, that is, 14,5% of catches35. However, loss rates of such magnitude were certainly not the rule, and at least in the more modern operations they were generally low. Thus, the logbooks here examined for the period 1953–1985 indicate a loss rate for baleen whales of 2.3%, a value that, although it is mostly derived from the fin whale catch, should also apply to the blue whale because of its similar body mass, shape and buoyancy. Given that the statistics only reflect the whales that were landed, the blue whale catch numbers here reported should be multiplied by a correction factor of 1.023 to estimate the actual number of whales killed, thus resulting in a take of 61.38 blue whales along a period of 55 years, that is, approximately one individual/year.Loss of killed whales appeared to be highly variable between operations. Unskilled crews, the employment of defective equipment or the use of vessels that were not proper catcher boats undoubtedly increased the probability of losing a whale after its harpooning. Even within a given operation, the success in recovering a harpooned whale probably increased with time, as long as crews gained experience and equipment was improved. For example, when the company Marcelino dos Reis Ltda initiated operations in Portugal in 1945, it employed three trawlers equipped with a harpoon gun, excessively large to be fin whales. This may be taken as an indication that these individuals were indeed misreported blue whales. However, the shape of the right tails of these distributions depart from what would be an expectable distribution of body lengths, that would end with a progressive decline in extreme values, so they are considered to be unreliable measurements. For example, for Getares (1950–1959) 4 out of 8 whales taken would have purportedly been blue whales (body length larger than 23 m), a proportion unreasonable for the fin whale/blue whale abundance ratio in the area. Unfortunately, clarification and retrospective correction of databases is unfeasible with the current level of information. However, the existence of these oversized whales must be borne in mind and it cannot be ruled out that the number of blue whales actually taken from the population was indeed somewhat higher than the above estimate.The comparison between the IBSA body length distributions of the fin whales caught during 1974–1985 and those reported of the UB database, distributions and median body length are similar for males, but for females the median was 20 cm longer in the first database than in the second. This small difference can be explained by the fact that, while IBSA workers measured the whale’s body length from tip of the snout to the tip of tail flukes, UB scientists did that from the tip of the snout to the notch of flukes . The fin whale body length data from the other operations, although often limited in sample size, showed distributions and medians that reasonably matched the IBSA much larger and verified dataset. However, the fin whale body length distributions from Getares (1950–1959), Benzú (1947–1954), and Setúbal (1950–1951) contained a number of individuals longer than 23 m, that is36 for higher latitudes of the North Atlantic . The difference may be due to a lower selectivity of whalers when catching whales in the SEAS but the statistics do not contain any specimen larger than 24 m, which in other North Atlantic regions were frequent, despite the fact that whalers would certainly have tried by all means to capture a specimen of this size. The apparent lack of large individuals may be due to a certain population stratification with latitude, with juveniles tending not to penetrate such high latitudes as adults, as it has been observed in the South Atlantic, where a gradient in sizes and a greater presence of juveniles in southern latitudes apparently occurs37. Moreover, the statistics regularly recorded the presence and length of foetuses4, but none of the recorded blue whales caught was apparently pregnant, again supporting the absence of fully adult individuals. One caught whale, however, was only 9.1 m long, which indicates that this was a calf.The mean body length of individuals reported as blue whales was somewhat lower for both sexes than corresponding values given by Risting40. Consistent with this low abundance, the catches of this species in the SEAS only represented a very small fraction of the total catches of the species conducted in the North Atlantic4. Because a line-transect model requires a minimum number of sightings to be fitted, a consequence of such low abundance of blue whales is that the various line-transect surveys carried out in the region that have served to produce population numbers for other cetacean species, mostly the fin whale44, have been unable to collect enough data for blue whales to produce an approximate estimate of abundance or even density, as it would have been ideal. However, an insight into the relative abundance of this species can be obtained through the ratio between the catches or sightings of blue whales as related to those of fin whales. It should be noted that the resulting numbers of such exercise cannot be considered population estimates for blue whales, but just rough approximations to the relative abundance of the species.The blue whale does not appear to have ever been abundant in the temperate waters of the eastern North Atlantic. Strandings of blue whales along the shorelines of northwestern Africa, western Spain, continental Portugal and southwestern France are unusual in both historical and more recent times33. In the twentieth century there is no information available on sighting rates until the 1980s, but in the 1920s the catch ratio of blue whales for every 100 fin whales was only 0.02–0.18% depending on the area, that is, an order of magnitude lower than the already low pre-exploitation sighting rates observed in the open-boat vessels’ logbooks. This undoubtedly reflects the severe effects of the massive blue whale catches that occurred in the North Atlantic during the last decades of the nineteenth century and the early decades of the twentieth century6. From the 1940s and up to the 1970s, the catch ratio between the two species increased to 0.47–1.6%, probably as a consequence of the opposing trends in their abundance: while the blue whale benefited from the ban in its exploitation approved by the IWC8, the fin whale replaced the blue whale as a main target and whaling pressure on that species suddenly increased1. It is interesting to note that the ratio was not uniform between areas, and during the second half of the twentieth century it was 3–4 times higher in the southern whaling grounds than off NW Spain. It is very likely that this does not reflect a higher abundance of blue whales in the southern grounds but rather a much reduced density of fin whales there as a consequence of the collapse of the Gibraltar Straits subpopulation due to the unsustainable level of catches that had been made in the 1920s45.Previous to the onset of blue whale exploitation by modern whalers, the American open boat vessels operating during 1862–1889 in the Gibraltar Straits ground had a sighting ratio of 5,9 blue whales for every 100 fin whales, as shown by the data recorded in the whaling vessels’ logbooks14, the blue whale/fin whale ratio showed a progressive increase with time. In 1979 Spain joined IWC and stopped taking blue whales. No catch ratios can thus be calculated, but the sightings ratios from both the IWC-type logbooks and the UB-surveys shows a continued rise in the proportion of blue whales sighted as related to that of fin whales. Although the rate appears somewhat higher in the UB-surveys (2.86%) than in the sightings performed by whalers (1.94%), this apparent difference should be taken with caution because sample size was much lower in the first database than in the second (n = 248 vs n = 1336) and thus would be expected to be less accurate.In NW Spain, where the fin whale population was relatively abundant despite 6 decades of almost continuous exploitation46 because the cruise covered the whaling grounds and adjacent waters, and the sighting rates obtained were consistent with those found in surveys from the 1980–1990s47 covering smaller or partially overlapping areas. A comparable survey conducted in 2016 in a somewhat different and larger area43 resulted in a fin whale abundance estimate of 18,142 individuals . This latter survey was conducted during 4–28 July, that is, about 2 months earlier than the period when blue whales visit the area, and concentrated its effort in shelf waters with relatively sparse coverage of offshore waters, all which combined to produce insufficient data to assess blue whale abundance and is considered suboptimal for comparative purposes43. If the blue whale/fin whale sighting rate obtained in the catcher boat and survey observations of the 1980s is applied to the 1989 Bucklands’s et al.46 estimate, the resulting abundance of blue whales in the SEAS ecoregion is 337 individuals (95% CI 202–561) when applying the 1.94% value, and 497 individuals (CI 298–828) when applying the 2.86% value. These figures are much higher than the abundance of only a few tens suggested for the area by Cooke5. Taking into account the above abundance numbers, the catches conducted during the period 1921–1979 by the Iberian whaling operations  are not expected to have had a significant effect on the trajectory of the population.A line transect survey conducted in 1989 resulted in a fin whale abundance estimate of 17,335 individuals , a figure that is considered robust48, and 9.75% off Iceland49. Iceland, which appears to be a main feeding ground for the eastern subpopulation19, is where the blue whale appears to reach its highest density. In this area, the sightings from both the whaling boats and line transect cruises indicate that the population has been increasing during the last decades at a mean annual rate of 4–5.2%50, values that are somewhat lower than the 7.3% estimated for Antarctic blue whales51. As a result of this raise in abundance, the population off Iceland was estimated in 2015 to be at about 3000 individuals (95% CI 1377–6534), that is, about six times higher than the estimate for 198952. If these annual rates of increase are applied to the gross estimates of abundance in the SEAS estimated for 1989, it can be derived that the number of blue whales in the region must be currently over a thousand individuals. Such an increase would be consistent with the progressive penetration of the species in the shelf waters and the rise in strandings and sightings that has been reported in the last decade in NW Spain55. However, despite the apparent increase in abundance the school size has remained very low, with most sightings being of mixed schools with fin whales or of single individuals, as it is the case in other depleted blue whale populations56.During summer, blue whale relative abundance in the NE Atlantic tends to increase northwards. Thus, the blue whale/fin whale ratio was found to be 1.94–2.86% off NW Spain, 7.7% in the Irish Porcupine Seabight5, although they are still much lower than those which the species once enjoyed in the North Atlantic. The total number of blue whales killed in this ocean during the first decades of exploitation was likely in the range 15–20,0005. As a consequence, its initial population size was over such threshold and the current levels of abundance would still be below one third of pre-exploitation numbers. Whatever the case, these are proximate calculations that should not be regarded as robust estimates of population size but can be used as a guidance to infer rough levels of abundance of the species until especially dedicated line-transect surveys or photoidentification studies provide more accurate numbers.Because the population estimates conducted in the various regions of the North Atlantic derive from line transect surveys conducted in all cases during the July–September period, it is reasonable to assume that the figures resulting from them correspond to exclusive aggregations of blue whales and thus can be added; if this is correct, and the annual rates of increase observed in Iceland are applied to the above numbers, the current (2021) size of the overall eastern North Atlantic blue whale subpopulation would presumably be in the order of 4000–5000 individuals. Such abundance levels are higher than those commonly proposed for the basinSupplementary Information.


The epidemiology on the human papillomavirus (HPV) among females in Southern China is not well-established. Baseline data on the prevalence of HPV infection in China prior to mass prophylactic HPV vaccination would be useful. Thus, this study aims to determine the type-specific HPV prevalence and distribution among females from Southern China prior to mass HPV vaccination.A retrospective cross-sectional study employing 214,715 women attending ChenZhou NO.1 People’s Hospital for cervical screening during 2012–2018 was conducted prior to widespread HPV vaccination. HPV genotype was detected using nucleic acid molecular diversion hybridization tests. The overall prevalence, age-specific prevalence, type distribution, and annual trend were analyzed.The overall HPV prevalence was 18.71%  among Southern China females. During 2012–2018, the prevalence of HPV infection showed a downward tendency, from 21.63%  in 2012 to 18.75%  in 2018. Age-specific HPV distribution displayed a peak at young women aged less than 21 years , 20.07%  among women aged 21–30 years, 17.29%  among women aged 31–40 years, 17.23%  among women aged 41–50 years, 21.65%  among women aged 51–60 years, and 25.95%  among women aged over 60 years. Of the 21 subtypes identified, the top three prevalent high-risk HPV (HR-HPV) genotypes were HPV52 , − 16 , and − 58 ; the predominant low-risk HPV (LR-HPV) genotypes were HPV81  and − 6  respectively. Incidence of HR-HPV only, LR-HPV only and mixed LR- and HR-HPV were 15.17, 2.07 and 1.47% respectively. Besides, single HPV infection accounted for 77.30% of all positive cases in this study.This study highlights 1) a high prevalence of HPV infection among females with a decreasing tendency towards 2012–2018, especially for young women under the age of 21 prior to mass HPV vaccination; 2) HPV52, − 16 and − 58 were the predominant HPV genotypes, suggesting potential use of HPV vaccine covering these HPV genotypes in Southern China. Human papillomavirus (HPV) is the leading cause of cervical cancer and responsible for about 91% of anal cancers, 75% of vaginal cancers and 70% oropharynx cancer . In ChinHPV genotypes are linked to the degree of cervical lesions . InfectiThe prevalence of HPV varies geographically widely, ranging from 6% in southeastern Asia to 32% in eastern Africa, and from 6.7 to 44.5% in China . HPV scrFrom January 2012 to December 2018, 214,715 females (age range from 19 to 83 years) were enrolled in this study. All participants were from gynecology department and physical examination center of Chenzhou NO.1 People’s Hospital. They have got HPV tests for various reasons, including physical examination, vaginitis, urethritis, irregular vaginal bleeding, cervicitis, undiagnosed abdominal pain and genital warts. In addition, repeated samples from the same women were excluded.All of the cervical samples were taken by the physician, but not self-sampling, using a 200 mm polyethylene Cervix brush device  following the regular procedures for speculum examination. The samples were transferred to a sampling tube containing a transport medium  and stored at 2–8 °C until HPV DNA extraction within a week. Cervical samples can be kept in a transport medium for 2 weeks at 4 °C according to the manufacturer’s manual.DNA was extracted by Cell Lysis Kit  accompanying with the negative and positive quality control products throughout the whole process. HPV genotyping have been performed using HPV assay kit  since 2012 with no modifications. This kit detected 21 HPV genotype via gene amplification technology and diversion hybridization. The low limit of detection (LOD) for HPV DNA is 500 copies/ml according to manufacturer’s protocol. This assay uses HPV L1 consensus PCR primers (MY09/11) for the amplification and a human housekeeping gene β-globin as an endogenous internal control to ensure appropriate DNA purification, PCR reaction and specimen quality. PCR was carried out in 25 μl reaction mixture in a thermal cycler, the cycling parameters of which were as follows: 20 °C for 10 min, 95 °C for 9 min, followed by 40 cycles , with a final extension at 72 °C for 5 min. HPV types were then classified via a nylon membrane immobilized with 21 different type-specific probes. Quality controls of HPV genotyping including External Quality Assessment and Internal Quality Control were implemented throughout the study.Analyses were conducted with SPSS version 19.0. Descriptive statistical analysis was performed on the distribution of HPV genotypes using indicators such as frequency and prevalence. The Chi-square test was used to test the differences between prevalence, genotypes and number of co-infections of HPV in different age groups and time groups.The study was approved by the ethics Committee of Chenzhou NO.1 People’s Hospital and conducted strictly in accordance with the Declaration of Helsinki, including the confidentiality and anonymity. No informed consent or other action on the part of the patients was required due to anonymous analyses of the data. All experiments were carried out in the lab certified by the National Center for Clinical Laboratories following the laboratory biosafety guidelines.From 2010 to 2018, 214,715 eligible female participants were enrolled for final statistical analysis in this study. Among them, 40,168 cases  were positive for at least one HPV genotype  was the most common genotype, followed by HPV16  and − 58 , accounting for 76.36% of all detected HPV types (Table P < 0.001), and a similar result was also observed for LR- HPV infection  and 3.67% (95% Cl 3.59–3.75%) respectively. HR-HPV infection was significantly higher among women with single infection (12.46%) than those with multiple HPV infections , 2.07% , 1.47% , respectively, and a significant difference was observed in the distribution of HR-HPV only, LR-HPV only, and mixed LR- and HR-HPV infections among the six age groups  accounting for 77.30% of the 40,168 HPV-positive cases, whereas multiple infections  were rare. For those infected with multiple HPV genotypes, the prevalence decreased significantly as the number of infected HPV genotypes increased . Both LR- and HR-HPV only infection had the highest prevalence in single HPV infection (2.00% vs. 12.46%), which declined gradually as the number of co-infections increased. Particularly, HR-HPV only infection took up the majority in women with double and triple HPV infection, and mixed LR- and HR-HPV infections correlated with those infected with more than three HPV genotypes, while none of the infections with three or more genotypes were detected in those with LR-HPV only infections , showing a downward trend from 2012 to 2018, and women aged less than 21 years old showed the highest HPV prevalence. Importantly, HPV52, − 16, and − 58 were the major genotypes at all times, regardless of the fact that their ranks varied with respect to the ages and years. Our study enables the estimations of HPV vaccine impact among women spanning a broad age range, provide guidance for clinical care and public health policy including cervical screening and vaccination, and would also be useful for the other low- and middle-income areas with a heavy HPV infection burden to fight against cervical cancer.


Neuropeptide Y (NPY), a 36-amino acid neuromodulator, is mainly secreted by neurons in the central and peripheral nervous systems, which participate in the regulation of a series of physiological processes. However, there are few studies on its correlation with intracranial hemorrhage (ICH). The purpose of this study is to determine whether the serum NPY level is related to the prognosis of ICH.  364 patients diagnosed with ICH were included in the current study. The demographics, anthropometrics, medical history, clinical severity, and laboratory data are collected. Enzyme-linked immunoassay (ELISA) was used to detect the serum NPY level of each patient upon admission. Three months after the occurrence of ICH, we used the modified Rankin scale (mRS) to evaluate the prognosis of patients, and mRS > 2 was defined as a poor prognosis. p = 0.036) and smaller hematoma volume (p = 0.039). The results of ELISA showed that compared with patients with a poor prognosis, ICH patients with a good prognosis had lower serum NPY levels . Linear correlation analysis showed that the serum NPY level of ICH patients was significantly positively correlated with the baseline NIHSS score  and hematoma volume . Receiver operating characteristic (ROC) curve analysis showed that the sensitivity of the serum NPY level to predict the prognosis of ICH was 70.9%, the specificity was 72.6%, and the cut-off value was 24.2 ng/ml.  A total of 364 patients with ICH were included in the study, including 140 patients with a good prognosis and 224 patients with a poor prognosis. Compared with patients with a poor prognosis, ICH patients with a good prognosis have a lower baseline National Institutes of Health Stroke Scale (NIHSS) score ( The serum NPY level may be used as a predictor of ICH prognosis. Intracranial hemorrhage (ICH) refers to any bleeding within the skull, which destroys neurons or compresses the surrounding brain tissue and causes neurological dysfunction . The gloA neuropeptide is a small protein substance produced by neurons, which can exert a variety of physiological and behavioral processes by acting on different substrates . NeuropeStudies have shown that NPY plays an important role in stress response and antianxiety properties . NeuropeWe included 364 ICH patients in the First Affiliated Hospital of Jinzhou Medical College from April 1, 2018, to March 31, 2020. The selection criteria for ICH patients are within 24 hours of the onset of ICH and confirmation by computed tomography (CT) as ICH. The exclusion criteria for ICH patients are as follows: mRS > 2 before admission; combination with trauma, aneurysm, and arteriovenous malformations; a history of tumor; ICH patients requiring surgical treatment; and multiple organ dysfunction such as the heart, liver, and kidney. Our research was approved by the Jinzhou Medical Ethics Committee, and all participants or family members authorized us to use these data for clinical research.Baseline data of ICH patients were collected after enrollment. These data include demographics or anthropometrics, medical history, and clinical severity. Among them, demographics or anthropometrics include age, gender, and BMI. Medical history mainly includes whether there is a history of hypertension, diabetes, hyperlipidemia, and coronary heart disease. Evaluation indicators of clinical severity include NIHSS scores and hematoma volume. All baseline data are collected, recorded, and analyzed by dedicated personnel.The National Institutes of Health Stroke Scale (NIHSS) is designed to assess the neurological outcome and recovery of stroke patients. The main assessment content of NIHSS includes the level of consciousness, facial muscle function, limb strength, sensory function, ataxia, lateral neglect, extraocular movement, visual field, aphasia, and dysarthria. The NIHSS score ranges from 0 to 42, and the higher the score, the more serious the neurological deficit .CT is a quick and effective detection tool to confirm the diagnosis of ICH. After admission, all patients underwent head CT examination to confirm the diagnosis. Commercial Analyze Direct 11.0 software  was used to determine hematoma volume in CT images. The image analysis is performed by experienced imaging doctors, who are blind to the research object and research plan.The venous blood of all ICH patients was collected by nurses within 24 hours of admission. The collected venous blood was allowed to stand at room temperature for 20 minutes and then centrifuged at high speed to obtain serum. Purchased ELISA reagents were used to detect serum NPY levels. A purchased ELISA reagent  was used to detect serum NPY levels. The operation of ELISA refers to the product specification and previous research reports . Other lAfter 3 months of ICH, the modified Rankin scale (mRS) was used to evaluate the prognosis for all patients. mRS was created by Scottish doctors in 1957 and now is a globally used tool to evaluate the degree of neurological disability. mRS is a 6-point neuroevaluation scale, with a score ranging from 0 to 5 . It is gt-test. Categorical variables are expressed by the number (%), and the comparison between the variables uses the chi-squared test. In order to clarify the correlation between serum NPY levels in ICH patients and baseline data, Pearson correlation was used for analysis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the accuracy of serum NPY levels in predicting the prognosis of ICH. A p value of less than 0.05 is considered statistically significant. In this study, SPSS 20.0  was used for statistical analysis.Continuous variables are represented by the mean ± standard deviation, and the comparison between variables is performed by a During the participant recruitment period, a total of 364 ICH patients were enrolled. According to the evaluation results of the mRS score after 3 months, we divided the participants into a good prognosis group (mRS ≤ 2) and a poor prognosis group (mRS > 2). p > 0.05).We collected demographics or anthropometrics , medical history , and laboratory data  of the two groups. The results showed that the difference between the above indicators between the poor prognosis group and the good prognosis group was not statistically significant .The clinical severity was evaluated by NIHSS scores and hematoma volume, which reflected the degree of neurological impairment in patients with ICH. The NIHSS scores of ICH patients in the good prognosis group and poor prognosis group were 10.5 ± 3.4 points and 11.3 ± 3.6 points, respectively. The hematoma volume of ICH patients in the good prognosis group and the poor prognosis group was 11.9 ± 2.3 ml and 12.5 ± 2.9 ml, respectively. As shown in p < 0.001).Peripheral blood NPY concentration results showed that the NPY levels in the good prognosis group and the poor prognosis group of ICH patients were 19.4 ± 3.7 ng/ml and 27.6 ± 3.3 ng/ml, respectively. As shown in p > 0.05). However, serum NPY levels in ICH patients were positively correlated with NIHSS scores . This positive correlation also appeared between the serum NPY level and hematoma volume .The results of the correlation analysis are summarized in In order to determine the diagnostic accuracy of serum NPY concentration on the prognosis of ICH, we adopted the method of ROC analysis. ROC analysis showed that the sensitivity of serum NPY concentration in diagnosing the prognosis of ICH was 70.9%, the specificity was 72.6%, and the cut-off value of NPY as a predictor was 24.2 ng/ml. The results of ROC analysis are shown in Our study compared the difference in serum NPY concentration between ICH patients with good prognosis and poor prognosis. Our study found that the serum NPY concentration of patients in the ICH prognosis group was significantly higher than that in the poor prognosis group. Through further research, we also found that serum NPY concentration was positively correlated with the NIHSS score and hematoma volume. These results suggest that serum NPY concentration may have potential value in predicting the prognosis of ICH. Therefore, we used ROC analysis to verify the accuracy of serum NPY in predicting the prognosis of ICH. Finally, we found that serum NPY can be used to predict the prognosis of ICH with high sensitivity and specificity, which can be used as a target for predicting the prognosis of ICH.NPY is a neurotransmitter synthesized and released by neurons first identified from a pig brain. NPY is the most abundant peptide in the mammalian brain and is highly conserved throughout the evolutionary process . NPY is NPY has been shown to be involved in the regulation of a variety of neurological diseases. Japanese scholars found in Osaka that the plasma NPY concentration of patients with Alzheimer's disease (AD) decreased, suggesting that NPY is involved in the pathogenesis of AD . French In recent years, the relationship between NPY and stroke has also been widely reported. The study by Yu et al. found that gene polymorphism in the NPY promoter region is an independent risk factor for ischemic stroke, indicating that NPY may be involved in the disease process of stroke . Korean Our research has some limitations. First of all, we are a single-center study; secondly, we did not do dynamic detection of serum NPY levels; finally, we did not do long-term follow-up for the prognosis of ICH. Nevertheless, our study revealed for the first time the potential correlation between NPY and the prognosis of ICH.Increased serum NPY levels may be a predictive target for the poor prognosis of ICH. The correlation between NPY and ICH is worthy of further study, which may provide a new path for the prevention and treatment of ICH.


Randomized controlled trials have shown a higher sensitivity and longer negative predictive value of high-risk human papillomavirus (HPV) testing than cytology for cervical cancer screening; however, little is known about the effectiveness of HPV testing in middle-income countries. Understanding the characteristics of HPV testing may increase the priority of HPV testing in health policies. The study aims to evaluate the effectiveness of HPV testing in the national cervical cancer screening programme in China.We performed a nationwide, population-based study using individual data from the national cervical cancer screening programme in rural China between 2015 and 2017. The analyses included 1,160,981 women aged 35–64 years who underwent cytology alone or high-risk HPV testing with cytology or genotyping triage. The main outcome was cervical intraepithelial neoplasia 2 or worse (CIN2+). We used multivariate logistic regressions and performed sensitivity analyses with propensity score matching to compare the screening positive, colposcopy referral, detection rate, and positive predictive value (PPV).The screening positive rates for HPV testing and cytology were 10.1% and 4.0%, respectively. The per protocol colposcopy referral rate of HPV testing was significantly lower than that of cytology (3.5% vs 4.0%), and this difference was mostly due to the low referral threshold of cytology (≥ASC-US). Overall, HPV testing detected more CIN2+  and had a higher PPV  than cytology. The colposcopy referrals of HPV testing in comparison to cytology differed by income status; it significantly increased in lower-middle-income areas  and significantly decreased in upper-middle-income areas . Sensitivity analyses demonstrated the reliability and robustness of the results.The introduction of HPV testing could improve both the CIN2+ detection rate and efficiency of cervical cancer screening programme, supporting the introduction of primary screening with high-risk HPV testing in China. Further study is needed to investigate the long-term effect of this change.The online version contains supplementary material available at 10.1186/s12916-021-02026-0. The World Health Organization (WHO) launched the global elimination plan for cervical cancer through vaccination, high-performance tests, and treatment for precancerous lesions . RandomiSome high-income countries have fully or partially switched from cytology-based screening to HPV-based screening , and theAn Argentina study yielded similar results as in high-income countries , but theThis study aimed to assess the effectiveness of HPV testing in the national cervical cancer screening programme and to provide real-world evidence about the introduction of primary screening with HPV testing in China and other similar middle-income countries.The NACCSPRA was implemented in more than 1000 counties across China and was used to screen approximately 10 million rural women aged 35–64 years per year . The proThis study extracted individual screening data from the programme between January 2015 and December 2017 for a population-based, contemporaneous comparison. We included 131 HPV pilot counties based on the following criteria: (1) had at least 1000 women screened, (2) had more than 70% of colposcopy attendance, and (3) had complete records from one round of screening. Simultaneously, cytological monitoring counties were included as the comparison . Different HPV assays were used depending on the local conditions and we showed the main five types of polymerase chain reaction-based HPV assays  and 95% confidence interval [CI] with multivariable logistic regression for comparisons, adjusting for age, ever screening, and income classification. To balance the confounding factors between the two groups, we conducted sensitivity analyses with propensity score matching. Briefly, we conducted 1:1:1 matching among cytology, HPV testing with cytology triage, and HPV testing with genotyping triage using propensity scores and the calliper matching algorithm with a calliper value of 0.1 standard deviations [P value less than 0.05 was considered statistically significant. All analyses were conducted with SAS version 9.4 software. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .The study included 1,160,981 women, of whom 833,469 underwent HPV testing and 327,512 underwent cytology (Table P<.001). There was no difference in the proportion of HPV positivity between the two HPV subgroups. The women who underwent HPV testing with triage had a lower per protocol colposcopy referral rate than women who underwent cytology alone . There was no significant difference in the adherence to colposcopy referral between HPV testing and cytology . Additionally, 1039 women with normal cytology, 3283 women with HPV negativity, and 5180 women with HPV positivity and negative cytology attended immediate colposcopy.Figure P<.001). The colposcopy referral rates of HPV testing with cytology triage or genotyping triage were 2.2% and 4.0%, respectively. HPV testing with cytology triage had comparable CIN2+ detection with cytology (4.4 vs 4.4 per 1000), but HPV genotyping triage had significantly higher CIN2+ detection than cytology . The PPV for CIN2+ for both HPV-testing with cytology triage and genotyping triage  was significantly higher than for cytology (P<.001 for both).Table P<.05 for all). In upper-middle-income areas, the CIN2+ detection for HPV testing was higher than that for cytology without statistical significance . Nonetheless, the per protocol colposcopy referral rate was significantly lower for HPV testing than cytology , and thus the PPV for CIN2+ was higher for HPV testing .Table P<.001) but lower for HPV testing with cytology triage . CIN2+ detection for HPV testing with either cytology triage or genotyping triage was significantly higher than for cytology. Finally, an approximately 2.7 times higher PPV for CIN2+ was found for HPV testing with cytology triage compared with cytology, whereas the increase in PPV for HPV testing with genotyping triage was not statistically significant. In upper-middle-income areas, colposcopy referral rates for HPV testing with cytology triage and genotyping triage were 2.2% and 4.0%, respectively, significantly lower than for cytology (P<.001 for both). The CIN2+ detection for HPV testing with cytology triage was lower than cytology , but for HPV testing with genotyping triage, it was higher than cytology . The PPV for CIN2+ was significantly higher than cytology for both HPV testing with cytology triage and genotyping triage .Figure P<.001). In immediate referrals for women who needed intensified screening, CIN2+ detection rate in women who were any HPV positive with negative cytology was 5.0%, significantly higher than that for women who were positive for non-HPV-16/18 with negative cytology .Table First, the results were consistent between analyses using the weighted and unweighted data  –8, 11, bOur comparisons of HPV testing with cytology triage or genotyping triage to cytology were discordant in different income settings. This is likely explained by the variations in the quality of cytology-based screening. In lower-middle-income areas, the quality of cytology is generally poor due to insufficient cytologists and inadequate quality assurance, which led to high benefits of HPV testing. However, HPV genotyping triage that needed more referrals may dramatically increase the workload of colposcopy and exacerbated the diagnostic accuracy , which pThe introduction of HPV testing has to reconsider the follow-up of women with HPV positivity with negative cytology. Multiple visits to complete a full screening would be difficult to implement in low-resource settings and decrease the effectiveness . Our stuThis study, to our knowledge, was the largest study thus far that conducted a comprehensive assessment of primary screening with HPV testing in a middle-income country. Its large sample size enabled robust comparisons of HPV-based and cytology-based screening strategies by income classifications. Particularly, the participants in this study were all unvaccinated, and the conclusions would be applicable for countries where expanded vaccination programme have not yet been carried out.Several limitations should be discussed. First, the study did not randomly allocate the screening methods. However, the risk of precancerous or cancerous lesions would be comparable between the two groups because of the similar geographic distribution, an assumption supported by the sensitivity analyses. Second, the absolute difference between the two groups should be interpreted prudently. CIN2+ detection and colposcopy referral would be underestimated for HPV testing due to no follow-up for HPV positivity with negative cytology, and the loss-to-follow-up in the immediate referral also affects the estimation. Although the extent of the impact was unknown, we believe this would attenuate the benefits of HPV testing but not reverse the conclusions, apart from colposcopy referrals. Third, CIN3+ is a preferable endpoint but this programme did not require the separation of CIN2/3 because of the immediate treatment for CIN2+. Finally, there were different HPV assays and devices in the study; however, all assays have been well verified clinically and had high agreement.Our study has substantial implications for the prevention of cervical cancer in middle-income countries, particularly for countries that currently use cytology with a low referral threshold. Although the cost of HPV testing may delay full accessibility in low-resource setting, a modelling study showed that early introducing HPV testing would have the opportunity to prevent more cases of cervical cancer and save more quality-adjusted life years . ChanginOur study found that primary screening with HPV testing improved the effectiveness of the national cervical cancer screening programme. Our results support the introduction of HPV testing in China and similar middle-income countries and has implications for the global elimination of cervical cancer. Long-term follow-up data are needed to further investigate the protective efficacy of HPV testing in reducing the incidence of cervical cancer.Additional file 1: Table S1. The distribution of eligible women screened by HPV testing or cytology. Table S2. Overview of the HPV assays specifications and related parameters in the programme. Table S3. ORs of HPV testing with different triages versus cytology alone by income classifications. Table S4. Sensitivity analyses for relative effectiveness of HPV testing and cytology based on unweighted data. Table S5. Demographic characteristics of women in pre-propensity score matching and post-propensity score matching. Table S6. Sensitivity analysis with propensity score matching for comparisons of HPV testing and cytology alone. Fig. S1 Flow diagram of primary cytology screening. Fig. S2 Flow diagram of primary HPV testing with cytology triage. Fig. S3 Flow diagram of primary HPV testing with partially genotyping triage. Fig. S4 Screened women by geographic areas and calendar, China 2015-17.)Additional File 2. STROBE checklist for the reports of observational studies.


Human papillomavirus (HPV) vaccination rates among adolescents are increasing in Minnesota (MN) but remain below the Healthy People 2020 goal of 80% completion of the series. The goal of this study was to identify messaging and interventions impacting HPV vaccine uptake in MN through interviews with clinicians and key stakeholders.We conducted semi-structured key participant interviews with providers and stakeholders involved in HPV vaccination efforts in MN between 2018 and 2019. Provider interview questions focused on messaging around the HPV vaccine and clinic-based strategies to impact HPV vaccine uptake. Stakeholder interview questions focused on barriers and facilitators at the organizational or state level, as well as initiatives and collaborations to increase HPV vaccination. Responses to interviews were recorded and transcribed. Thematic content analysis was used to identify themes from interviews.14 clinicians and 13 stakeholders were interviewed. Identified themes were grouped into 2 major categories that dealt with messaging around the HPV vaccine, direct patient–clinician interactions and external messaging, and a third thematic category involving healthcare system-related factors and interventions. The messaging strategy identified as most useful was promoting the HPV vaccine for cancer prevention. The need for stakeholders to prioritize HPV vaccination uptake was identified as a key factor to increasing HPV vaccination rates. Multiple providers and stakeholders identified misinformation spread through social media as a barrier to HPV vaccine uptake.Emphasizing the HPV vaccine’s cancer prevention benefits and prioritizing it among healthcare stakeholders were the most consistently cited strategies for promoting HPV vaccine uptake. Methods to combat the negative influence of misinformation about HPV vaccines in social media are an urgent priority. The HPV vaccine is recommended for administration to all adolescents in the USA for the prevention of HPV-related cancers and anogenital warts . Uptake Clinician recommendations influence parents’ opinion of their adolescents’ receipt of the HPV vaccine , 5. MultIn order to better understand what methods to employ to improve HPV vaccine uptake, we aimed to first understand what messages were perceived by clinicians and healthcare stakeholders that were thought to impact uptake of the HPV vaccine. Additionally, we aimed to gather further knowledge of best practices and innovative strategies being used to promote HPV vaccine uptake that would provide information to design future interventions. We performed a thematic content analysis of interviews conducted with practicing clinicians and HPV-focused stakeholders in Minnesota to address these aims.We conducted semi-structured key participant interviews with 14 clinicians and 13 key stakeholders in Minnesota regarding HPV vaccination. The interviews took place from July 2018 to August 2019. Clinicians were interviewed by an infectious disease fellow physician and PhD student in epidemiology. Stakeholder interviews were conducted by an Epidemiology PhD and the project’s principal investigator as well as a PhD student in epidemiology. We asked about effective messaging strategies, quality improvement initiatives, and support for HPV vaccine-related legislation in Minnesota. This research was considered exempt by the University of Minnesota Institutional Review Board (IRB).Key informant interviews were structured according to a guide comprised of questions asked of each clinician or stakeholder. Clinician and stakeholder interview questions were developed by a team consisting of an epidemiologist with experience involving development of HPV screening guidelines, other epidemiologists with experience conducting content analysis, and a practicing infectious disease fellow physician. All interviews were audio recorded and transcribed verbatim by study personnel.Thematic content analysis was used to analyze the data. The framework for content analysis was to identify key phrases involving messaging around the HPV vaccine and strategies to improve uptake among clinicians and healthcare-related stakeholders. Prior to conducting interviews, the coding scheme for clinician interviews was developed by an infectious disease fellow physician and MPH student based around pre-determined interview questions. The coding scheme for stakeholder interviews was developed by the project’s principal investigator.The content of the transcribed interviews was independently reviewed by two researchers. Each reviewer first independently read through the entire text of each transcribed interview once and identified key words or phrases associated with barriers or facilitators to HPV vaccination. Subsequently, the key words and phrases that were identified were compared between the two researchers via a second read-through of each interview with patterns among the coded words used to identify specific themes. Identified themes were reviewed in research team sessions to further refine them and lessen the risk of individual reader bias.A target sample size of fifteen individuals was set prior to clinician recruitment. Clinicians were included if they were physicians or nurse practitioners currently working in an ambulatory clinic in Minnesota and were involved in discussions about the HPV vaccine with their patients. Additionally, only clinicians who were able to order and prescribe the HPV vaccine were eligible to participate. Retired clinicians and those not actively engaged in an ambulatory primary care practice were excluded. Affiliates at the Minnesota chapter of the American Cancer Society and the Minnesota Department of Health aided in identifying clinicians for this study through purposive sampling. Outreach to clinicians occurred via e-mail contact by a research assistant. Potential participants were e-mailed the interview questions and a consent form prior to the interview. Consent to participate was confirmed via an e-mail reply message or verbally prior to the start of the interview.Participants were asked a series of open-ended questions related to their communication about the HPV vaccine as shown in Table We also interviewed thirteen key healthcare stakeholders operating in Minnesota who were identified via purposive sampling. Identification of stakeholders was achieved with the assistance of the Minnesota Health Department and the Minnesota Chapter of the American Cancer Society. Outreach to stakeholders occurred in the same manner as was done with clinicians.Participants were asked a series of open-ended questions adapted from a previously published survey Table  8]. Que. Que8]. A total of 27 semi-structured interviews were completed with 14 clinicians and 13 stakeholders. Upon completion of content analysis, we identified three larger thematic categories addressing messaging and interventions impacting HPV vaccine uptake. These three thematic categories included messaging pertaining to patient–clinician interactions around the HPV vaccine Table .Table 3Pn = 11, for stakeholders n = 6). Interviewees often cited how parents would raise concerns that receipt of the HPV vaccine could result in early initiation of sexual activity and more frequent sexual encounters among adolescents. As one clinician expressed, “the parents have to [give] written consent in order to administer [the] HPV vaccine. And I would say the most common concern is about sexually transmitted virus [sic]. That’s why parents refuse it…” (Clinician 7). One stakeholder noted that “in my opinion, some of it is perception about, you know, you only need the vaccine if you are sexually active, and you are going to encourage sexually active behavior if you give your kid the HPV vaccine” (Stakeholder 2). Concerns that the age at which the vaccine was recommended was too young were noted by some clinicians and were related to concerns about addressing adolescent sexual activity— “Addressing the fact that you are offering a vaccine prior to sexual activity to young people starting at the age of eleven. That often takes parents aback quite a bit” (Clinician 9).Concerns regarding parental perceptions about the connection between the HPV vaccine and sexual activity featured commonly in both clinician and stakeholder interviews. Messaging around the impact of the HPV vaccine on sexual activity was the most frequently identified theme .n = 11) and a primary health outcome of HPV vaccination programs identified by stakeholders (n = 13).Discussing vaccines in the context of cancer prevention was commonly cited as a messaging tool for promotion of the HPV vaccine Table . CliniciConcerns surrounding misinformation being spread on social media were also very common. Clinicians described encounters with parents who found misinformation online and how challenging they found addressing misinformation about the vaccine could be. One clinician noted that misinformation derived from the internet could raise “emotional kinds of concerns that are really hyped up … It’s pretty intense. If you bought into it, you’d but into it hook, line, and sinker. It’s got a lot of fear-based drive to it” (Clinician 10). Stakeholders shared in this frustration but highlighted that some media campaigns to raise awareness have had positive results. As one stakeholder noted, “one way to engage in this information sharing is through social media usage, with newspaper articles, mainstream media, and credible news sources to leverage this information and make vaccination the norm” (Stakeholder 9).Bringing in outside experiences during clinician–patient interactions was frequently noted as a method to help normalize the HPV vaccine and its benefits and counter misinformation derived from other sources. Some providers shared their positive personal experiences with the vaccine as one clinician noted that “I typically share that my children have gotten or will get it and that it’s our only vaccine that prevents cancer” (Clinician 10). Most clinicians noted the impact of making a strong recommendation to get the HPV vaccine as a priority to increase its uptake. As one clinician stated, “I think having a conversation with the families to make sure they understand why we’re doing it and the importance of it—the clinician-to-family conversation. We also present it as part of the recommended immunization series, but to use, it’s the same … It’s an important vaccine that we highly recommend” (Clinician 8).Stakeholders were asked about HPV vaccination at the organizational level. For most organizations, HPV vaccination had become more of a priority recently. However, it was often in competition with other organizational commitments: “Well, if I could say on a scale of 1 to 10, it’s not a 0 and it’s not a 10 … maybe an 8 because it is publicly reported” (Stakeholder 2).Less than half of the clinicians we interviewed knew of ongoing quality improvement initiatives to increase HPV vaccine uptake within their organizations. Clinicians who noted quality improvement initiatives frequently cited local access expansion and clinic workflow measures as targets for increasing HPV vaccine uptake. Expanding access to the vaccine by offering it at venues outside the clinic was one commonly cited measure with a clinician noting “We also have started offering the HPV vaccine in our express clinics. We have two express clinics in the community where … they’re located at supermarkets” (Clinician 5). Changes addressing vaccines during the check-in process and leveraging the electronic medical record (EMR) system were also commonly employed to try to increase HPV vaccine uptake. One example of this was a clinician who noted that checking for vaccine receipt occurred at the time of any visit even outside of usual annual physicals—“If they’re in for any other visit outside of a yearly physical, then the rooming process includes checking the vaccine status for anybody even if it’s not for their annual visit …” (Clinician 10).Partnerships precipitated by stakeholder groups with clinicians were felt to be crucial at improving HPV vaccine uptake. One stakeholder noted that “we have completed two rounds of a quality improvement initiative working with physicians not only in Minnesota but also in a five-state area to improve administration of first-dose HPV before age 13 for both boys and girls in their practice. We’ve seen those rates increase from 30 up to 70% as part of the second round of the quality improvement that we have done” (Stakeholder 6). For organizations in which stakeholders described an ongoing quality improvement initiative, the use of financial incentives for patients who have received the HPV vaccine was considered to result in high rates of success. One stakeholder noted that “we have member incentives in the form of [gift cards] that we are giving out to members when they get their full series of HPV vaccination” (Stakeholder 8).Our study identified themes around messaging and interventions involving HPV vaccine uptake commonly encountered by clinicians and healthcare-related stakeholders practicing in Minnesota. The most commonly encountered concern raised by adolescents’ parents about the HPV vaccine during clinic visits involved its impact on sexual activity. The messaging strategy most consistently recommended among interviewees was the promotion of the HPV vaccine as a cancer prevention vaccine. Several clinicians in our study described the benefit of framing the vaccine solely in terms of its cancer prevention benefit. This insight is prescient given that efforts in other states to evaluate barriers to HPV vaccine uptake have shown that a lack of understanding about the link between cancer and the HPV vaccine is common among parents of adolescents , 10. TheAdditionally, concerns about misinformation related to the impact of social media were common among both clinician and stakeholder interviewees. Also mentioned were quality improvement initiatives and media campaigns that utilize electronic media to counter misinformation and promote the benefits of the HPV vaccine. There is an emerging literature around the possibility of utilizing social media to better understand concerns related to the HPV vaccine . Some stOur sampling strategy for identifying interviewees is a potential limitation of this study given that many of our interviewees were drawn from Minnesota’s largest metropolitan areas, potentially decreasing the viewpoints of residents of more rural parts of the state. However, we worked in conjunction with the Minnesota Department of Health to identify areas of lower vaccine uptake within Minnesota and did specific outreach in those counties of the state found to have HPV vaccine uptake rates that were below the statewide average. An additional limitation of our study was its small number of interviewees, which could reduce the perceived number of factors identified in our study as being significant to a larger group of clinicians or stakeholders . However, our sampling methods allowed for outreach to interviewees over a broad geographic area within Minnesota, resulting in capture of a diverse breadth of attitudes around HPV vaccination. This can help us to build upon prior studies on this topic in Minnesota that utilized a narrower scope of recruitment , 16. TheIn conclusion, clinicians and stakeholders working within Minnesota highlighted consistent messages expressed by patients and their family members that were often grounded in a lack of knowledge about the HPV vaccine or misinformation. These factors could contribute to hesitancy to receive the HPV vaccine and account for issues with increasing HPV vaccine uptake to the Healthy People 2020 target of 80% completion of the vaccine series among adolescents.Messaging methods to counter misinformation were also described as were techniques involving quality improvement projects being implemented in some clinics as previously described. These included providing a strong provider recommendation to receive the HPV vaccine, focusing on cancer prevention benefits of the vaccine, normalizing the vaccine as part of a standard set of immunizations, leveraging clinic workflow and EMR systems, using social media campaigns to promote awareness and factual information about the vaccine, and utilizing novel strategies such as financial incentives to promote vaccine uptake. The information gleaned from this study will be informative for designing clinical interventions at a larger scale to help increase HPV vaccine uptake. While this study was conducted within Minnesota, the lessons learned can be applied more generally to other communities outside the state.


The recurrence of CIN 1+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group . A non-significant trend of reduction rate of HPV persistence was observed in the vaccinated compared with the unvaccinated cohorts . Conclusions: HPV vaccination, in adjuvant setting, is associated with a reduced risk of recurrent CIN 1+ and CIN 2+ after surgical treatment.Objective: The aim of this meta-analysis was to discuss evidence supporting the efficacy of adjuvant human papillomavirus (HPV) vaccination in reducing the risk of recurrent cervical intraepithelial neoplasia (CIN) 2 or greater after surgical treatment. Methods: A systematic literature search was performed for studies reporting the impact of HPV vaccination on reducing the risk of recurrence of CIN 2+ after surgical excision. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Results: Eleven studies met the inclusion criteria and were selected for analysis. In total, 21,310 patients were included: 4039 (19%) received peri-operational adjuvant HPV vaccination while 17,271 (81%) received surgery alone. The recurrence of CIN 2+ after treatment was significantly lower in the vaccinated compared with the unvaccinated group (OR 0.35; 95% CI 0.21–0.56;  In 20r burden . HPV typr burden . In 2017r burden .Despite the increasing introduction of HPV vaccines and screening strategies, cervical cancer still remains the first most common gynecological cancer worldwide ,5. CurreThe main goal of cervical screening programs is to detect early and treat pre-cancerous lesions  or high-grade squamous intraepithelial lesions (HSIL)). Preneoplastic cervical lesions are generally treated with excisional surgery, most commonly using loop electrosurgical excision procedure (LEEP) or conization (either with laser or cold knife) . NeverthEnormous attempts are being made to obtain the first therapeutic HPV vaccine ,16,17. Iclinicaltrials.gov were searched using a Boolean search algorithm for articles published up to February 2021. The process of evidence acquisition combined the following search terms: “cervical cancer”, “cervical disease”, “cervical intraepithelial neoplasia”, “human papillomavirus”, “vaccine”, and “vaccination”  guidelines .The study selection was done independently by two authors . The publications were evaluated dependent on predefined inclusion and exclusion criteria. The inclusion criteria were as follows: (1) randomized controlled, prospective or retrospective observational studies; (2) patients undergoing surgery for HPV-related cervical dysplasia; (3) prophylactic HPV vaccination (either shortly before or after surgery) versus no vaccination; (4) histologically confirmed CIN 2+ recurrence. The exclusion criteria were as follows: (1) case reports, case studies, editorials, review articles and conference abstracts; (2) studies testing newly developed HPV vaccines that have not received FDA approval; (3) studies in which participants had invasive disease, immunodeficiency or autoimmune conditions, received systemic corticosteroids, or were pregnant.Data extraction from each included study was done on the basis of study characteristics and predefined outcome variables. The following items were extracted from each study: journal and year of publication, study design, study endpoint, study population (age and number of patients), type of treatment , type of HPV vaccine , time of vaccination (before or after surgery), duration of follow-up, number of CIN recurrences. Discrepancies of opinion between the reviewers were resolved by consensus.The methodological quality of each study was assessed according to how patients were allocated to the arms of the study, the concealment of allocation procedures, blinding, and data loss due to attrition. The studies were then classified qualitatively according to the guidelines published in the Cochrane Handbook for Systematic Reviews of Interventions v.5.1.0 . Based oA further quality score was used to evaluate whether any studies were useful for the purpose of our analysis ,33,34,35(1)1.1CIN 2+ recurrence: recurrences of CIN 2+ (irrespective of HPV type and HPV 16/18-related) have been extrapolated from the studies.1.2CIN 1+ recurrence: recurrences of CIN 1+ (irrespective of HPV type and HPV 16/18-related) have been extrapolated from the studies.Primary outcomes(2)2.1HPV persistence: the detection of positive HPV test at the first clinical follow-up after surgical treatment.2.2CIN 3 recurrence: recurrences of CIN 3 (irrespective of HPV type and HPV 16/18-related) have been extrapolated from the studies.2.3Persistence of abnormal cervical cytology: the detection of abnormal cervical cytology at the first clinical follow-up after surgical treatment.Secondary outcomesOutcomes that are particularly concerning for patients in this context were selected:2 statistic. A “hybrid” Mantel–Haenszel random-effects model with inverse-variance weighting was used in meta-analyses if any heterogeneity was detected, whereas a fixed-effect model was used if no heterogeneity was identified [p < 0.05 was considered statistically significant. We decided to examine publication bias with Egger’s test and funnel plots if the number of studies was 10 or above, since these analyses are underpowered otherwise. Six domains were evaluated: random sequence generation, allocation concealment, blinding of outcome assessor, completeness of outcome data reporting, selective outcome reporting, and other potential sources of bias.The data were analyzed using RevMan software . Dichotomous outcomes from each study were expressed as an odds ratio (OR) with a 95% confidence interval (CI). Heterogeneity between studies was reported with the Ientified . A valueA search of the Medline (PubMed) database up to 12 February 2021 resulted in 50 relevant articles. Further search of other electronic databases yielded no additional articles .No additional eligible studies were retrieved by hand searching bibliographies. Of these studies, 39 were excluded, according to our inclusion/exclusion criteria, as they evaluated other therapies than conization/LEEP or provided no adjuvant HPV vaccination. Eleven studies fulfilled the predefined inclusion criteria and were eligible for inclusion in the final meta-analysis ,45,46,47All studies were published between 2012 and 2020. The study designs included: three prospective non-randomized studies ,44,46, o-Random sequence generation (selection bias): A total of 4 studies ,39,40,42-Allocation concealment (selection bias): A total of 4 studies ,39,40,42-Blinding of participants and personnel (performance bias): Only two studies ,44 did n-Blinding of outcome assessment (detection bias): Only two studies ,45 did n-Incomplete outcome data (attrition bias): All studies reported complete outcome data, thus we rated all them as having low risk of bias for this item.-Selective reporting (reporting bias): We assessed six studies ,45,46,47The risk of bias of included studies is reported in 2 59% (95% CI 20.2–78.9%). The pooled estimated odds ratio (OR) was 0.35   .2 4% (95% CI 0–85.3%). The pooled estimated OR in this subgroup was 0.35   .2 65% (95% CI 0–88.1%). The pooled estimated OR for this subgroup in prospective trials was 0.36   .2 65% (95% CI 21.3–84.4%). The pooled estimated OR was 0.51   .2 0% (95% CI 0–84.7%). The pooled estimated OR in this subgroup was 0.36   .2 0% (95% CI 0–90%). The pooled estimated OR for this subgroup in prospective trials was 0.20   .2 0% (95% CI 0-89.6%). The pooled estimated OR was 0.84   .p = 0.05). No data about CIN 3 recurrences correlated with HPV 16–18 were reported.One study  reportedPersistence of Abnormal Cervical Cytologyp = 0.04).One study  evaluateThe beneficial role of HPV vaccines in protecting against cervical cancer by lowering the risk of getting infected with HPV has been fairly established, especially when they are given before initiating sexual activity ,9. ConveSeveral studies suggested that HPV vaccination has a statistically significant impact in reducing post-surgical recurrent disease both in women and men exposed to previous HPV infection ,48,49. Ip < 0.0001). This clinical benefit is equally evident when restricting the analysis to the two most oncogenic HPV types (HPV 16 and 18), that are included in the vaccine. These results may have significant clinical implications considering that the risk of relapse after the surgical treatment is relatively high, ranging from 9% to 14% [The present meta-analysis demonstrates that HPV vaccination is effective as an adjunct to surgery in preventing the risk of relapse for cervical dysplasia. The overall risk reduction of having a new or persistent CIN 2+ after surgery was 65%. The pooled estimated OR was 0.35  a comprehensive evaluation of all currently available data providing a large sample size ; (b) the prospective nature of four studies, with one true randomized controlled trial investigating the utility of adjuvant HPV vaccination after surgical excision for CIN 2+ compared with placebo or surgical procedure alone; (c) the quality of the methodology used along with the strict inclusion criteria, in order to specifically answer the proposed question. There are also several limitations of this study: (a) different inclusion criteria and methodologies  were used, resulting in significant heterogeneity between studies; (b) since the published evidence on this topic is lacking, both randomized and non-randomized studies were included in the final analysis; (c) one study  accounteAll studies except one are concordant in suggesting the beneficial role of HPV vaccination ,34,35,36As a consequence of the growing attention on the role of post-LEEP vaccination, three meta-analyses focused on this specific point have been recently published. Interestingly, these manuscripts showed superimposable findings, all in accordance with our data  , Lichterclinicaltrials.gov: the NOVEL trial , the VENUS study , and the COVENANT trial . Results from these studies will probably provide new insights on this emerging topic.Besides the above-mentioned limitations, focusing on clinical practice, by pooling the currently available data on this topic, it can be made an initial and interesting association between the reduction of CIN recurrence and the administration of perioperative HPV vaccination. However, this is still not enough to allow the application of HPV vaccination in this setting as an evidence-based routine practice. Even if some physicians may already rely on these early results and recommend vaccination after surgery for cervical dysplasia, the costs of vaccination are still not covered by healthcare systems. Currently, there are three randomized controlled trials ongoing on p < 0.0001). Further large-scale, randomized controlled studies are required to confirm these findings and drive adjuvant HPV vaccine into routine clinical practice. Moreover, the optimal timing of vaccination remains to be clarified.The present meta-analysis of eleven studies demonstrates that using prophylactic HPV vaccination as an adjunct to surgical excision for CIN 2 or greater reduces the risk of recurrent disease (OR 0.36; 95% CI 0.22–0.57;


Antibodies to HPV-16 and -18 were measured using a pseudovirion-based neutralization assay. A total of 96 subjects were enrolled; 31.3% and 68.7% received the 2D and 3D schedule, respectively. Of these, 66.7% and 57.6% of the 2D and 3D participants, respectively, were male. The seroconversion rates for HPV-16 and HPV-18 were 100% in all cases, except for HPV-18 in males who received the 3D schedule (97.4%). In males, the anti-HPV-16 geometric mean titers (GMTs) were 6859.3  and 7011.1  in the 2D and 3D groups (p = 0.946), respectively, and the anti-HPV-18 GMTs were 2039.3 (1432.2–2903.8) and 2859.8 (1810.0–4518.4) in the 2D and 3D (p = 0.313) groups, respectively. In females, the anti-HPV-16 GMTs were 15,758.7  and 26,241.6  in the 2D and 3D groups (p = 0.197), respectively, and the anti-HPV-18 GMTs were 5971.4  and 9993.1  in the 2D and 3D groups (p = 0.271), respectively. In summary, a 2D schedule is as immunogenic in young adolescents with IR as a 3D schedule in older subjects and those without IR.HIV-infected patients are at increased risk of human papillomavirus (HPV) acquisition and HPV-associated diseases. This study set out to determine whether a two-dose (2D) HPV vaccination schedule was sufficient in HIV-infected adolescents with immune reconstitution (IR) following antiretroviral treatment. Participants aged 9–15 years who had CD4 cell counts > 500 cells/mm Similar to adults, adolescents living with human immunodeficiency virus (ALHIV) have a higher incidence of human papillomavirus (HPV) infection, abnormal pap smears, and persistent HPV infection, leading to an increased risk of anogenital cancers than non-ALHIV ,2,3. The®), quadrivalent  and nonavalent , have been licensed. All three vaccines exhibited excellent safety profiles and were highly efficacious in preventing HPV infections and premalignant anogenital lesions caused by the HPV types included in the vaccines [Three prophylactic HPV vaccines, bivalent  has resulted in normalized immune function and CD4 T-lymphocyte (CD4) counts. A study in ALHIV with CD4 counts more than 350 cells/mmlescents . The queWe conducted a cohort study to investigate whether young adolescents with successful ART who received a 2D HPV vaccine schedule generated a similar HPV antibody response to older adolescents or those subjects without immune reconstitution who received a 3D schedule.3 and HIV-1 RNA levels  < 40 copies/mL for at least one year, were assigned to the 2D schedule. Older adolescents (15–24 years old) or young participants who did not meet the criterion of immune reconstitution were assigned to the 3D schedule. The 2D group received HPV vaccinations scheduled at months 0 and 6, and the 3D group received vaccinations scheduled at months 0, 1–2, and 6. All the male participants received the qHPV vaccine, and the females received bHPV, according to the local guidelines and vaccine availability at the time of the study’s initiation. Participants who had previously received the HPV vaccine or received immunosuppressive agents were excluded from the study.This single-center prospective cohort study enrolled HIV-infected adolescents aged 9–24 years at the Pediatric HIV Clinic at Siriraj Hospital, a tertiary care center in Bangkok, Thailand. After the informed consent process, the participants were assigned to receive either a 2D or 3D schedule of the HPV vaccine, according to age and HIV immune status. Participants aged 9–15 years who had been receiving ART with immune reconstitution, defined as CD4 counts >500 cells/mmBlood samples (5 mL) were collected at pre-vaccination (month 0) and at 1 to 3 months after the last dose (months 7–9). Any adverse events following immunization were observed according to routine practice. This study was approved by the local Institutional Review Board.50) is defined as the highest serum dilution that reduces the secreted alkaline phosphatase activity by at least 50% in comparison to a control (pseudovirion without serum). A sample with an ED50 value ≥ 100 was considered HPV-seropositive. Seronegative titers (<100) were given a value of 50. All the laboratory staff were blinded to the vaccination status of each participant, and each sample was identified according to a unique study number.Antibodies to HPV-16 and -18 were measured using the HPV pseudovirion-based neutralization assay (PBNA), as described by Barzon et al. . The neu2 test or Fisher’s exact test for category variables. Seroconversion was defined as a change from seronegative results at pre-vaccination (month 0) to seropositive results at 1 to 3 months after the last dose (months 7–9). HPV type-specific geometric mean titers (GMTs) were calculated. We log-transformed the neutralizing antibody titers and compared the 2D and 3D schedule groups by using Student’s t-test. All the statistical analyses were performed using STATA 15.1 . A p value < 0.05 was considered statistically significant for all the analyses.Demographic data including age, CD4 counts, and VL are summarized by descriptive statistics. Continuous data are presented using medians, interquartile ranges (IQRs), and proportions, as appropriate. Differences between participants receiving 2D or 3D schedules in terms of demographic characteristics were compared using the Mann–Whitney U test for continuous variables and a χA total of 96 adolescents were enrolled, of which 93 (96.9%) were perinatally infected, and 58 (60.4%) were male. Of the 30 (31.3%) and 66 (68.7%) participants who were assigned to the 2D and 3D groups, 20 (66.7%) and 38 (57.6%) were males, respectively.According to the demographic data , there wAll 58 male participants who received the qHPV vaccine were seronegative for HPV-16 and -18 at pre-vaccination. The seroconversion rates for HPV-16 were 100% (20/20) and 100% (38/38) in the 2D and 3D groups, respectively, and the seroconversion rates for HPV-18 were 100% (20/20) and 97.4% (37/38) in the 2D and 3D groups, respectively. Of the 38 female participants who received bHPV, two were seropositive for HPV-16 and -18 at pre-vaccination (one for HPV-16 and one for HPV-18). All the female participants who were initially seronegative for an HPV serotype at baseline demonstrated 100% seroconversion for both HPV-16 and -18 in both the 2D and 3D groups .p = 0.946), respectively, and the anti-HPV-18 antibody GMTs were 2039.3 (95% CI: 1432.2–2903.8) and 2859.8 (95%CI: 1810.0–4518.4) in the 2D and3D groups (p = 0.313), respectively. In the female participants, the anti-HPV-16 antibody GMTs were 15,758.7  and 26,241.6  in the 2D and 3D groups (p = 0.197), respectively, and the anti-HPV-18 antibody GMTs were 5971.4  and 9993.1 (95% CI: 5950.8–16781.1) in the 2D and 3D groups (p = 0.271), respectively. There was no difference in GMT between the 2D and 3D groups for each of the vaccines. The GMT in males who received qHPV was about 40% lower for both HPV-16 and -18 compared to that in the females who received bHPV  were 6859.3  and 7011.1  in the 2D and 3D groups (ved bHPV . There wved bHPV .Human papillomavirus vaccination is strongly recommended for ALHIV individuals because they have a higher risk of acquiring HPV infections and lower HPV clearance rates compared to HIV-uninfected individuals, thereby leading to an increased risk of HPV-associated diseases such as anogenital cancers ,16,17,18The seroconversion rate for HIV-infected adolescents in our cohort was 97–100% for both HPV-16 and -18 in both the 2D and 3D groups, consistent with previous studies reported for ALHIV individuals who received a 3D schedule ,20,21. T3 is an appropriate marker of immune reconstitution, which may be immunogenic following a 2D HPV vaccination schedule.HIV infects and deletes CD4+ T cells that normally support adaptive T- and B-cell responses including high-quality antibody production . In prevAnother finding of this study in both the 2D and 3D groups, in line with other studies, was the superior overall immunogenic response for bHPV compared to qHPV for both HPV-16 and-18 ,24. We fThere are some limitations in this study. The relatively small number of participants in each group might have prevented us from detecting any significant differences in antibody levels. In addition, we did not include a young healthy control group, which meant that a comparison of HPV vaccine immunogenicity between ALHIV and healthy volunteers cannot be made. We are also unable to compare immunogenicity between bHPV and qHPV in the same sex, as we used a gender-specific vaccine type. Finally, the follow-up in our study was limited, and we did not examine the clinical efficacy of the vaccine. Further studies are needed with larger numbers of participants in more settings and a longer follow-up period to determine the duration of the immunity as well as the clinical efficacy in ALHIV.3 and persistent virologic suppression, can generate a similar antibody response following a 2D HPV vaccination schedule when compared with older adolescents and those without immune reconstitution who receive a 3D schedule. Further studies to formally evaluate the 2D HPV vaccination schedule in HIV-infected adolescents are warranted. Our findings are particularly relevant for countries where HIV infections and HPV diseases are prevalent and where HPV vaccine coverage is low.Adolescents aged 9–15 years with immune reconstitution, indicated by CD4 counts > 500 cells/mm