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Background Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. Methods and findings The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. Conclusions Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies., Lene Wulff Krogsgaard and co-workers study temporal associations between infections and HPV vaccination., Author summary Why was this study done? In Denmark, there was a human papilloma virus (HPV) vaccination crisis in 2015, where reports of suspected adverse effects after HPV vaccination started increasing and the HPV vaccination uptake decreased dramatically. All available evidence has found the HPV vaccine to be safe and the specific cause of the reported adverse effects remains unknown. The reported symptoms were overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like. Infections are thought to be triggers of CFS, and we hypothesise that infections in temporal proximity to vaccination could also play a role for the development of suspected adverse effects following HPV vaccination. What did the researchers find? Females who had a treated infection in temporal proximity to HPV vaccination were more likely to be referred to a specialised hospital setting (HPV centre) because of suspected adverse effects after HPV vaccination compared to HPV-vaccinated females without an infection. The case-crossover and case time-control analyses made to control for potential unmeasured confounding supported this finding. What do these findings mean? Infections might be a trigger of the suspected adverse effects in a subset of females referred to an HPV centre. More research is needed in order to confirm these findings and to clarify whether infections alone or in combination with HPV vaccine could have caused the reported symptoms.

Background Treatment of cervical intraepithelial neoplasia (CIN) is associated with an increased risk of preterm delivery (PTD) although the exact pathomechanism is not yet understood. Women with untreated CIN also seem to have an increased risk of PTD. It is unclear whether this is attributable to human papillomavirus (HPV) infection or other factors. We aimed to investigate whether HPV infection shortly before or during pregnancy, as well as previous treatment for CIN, is associated with an increased risk of PTD and other adverse obstetric and neonatal outcomes. Methods and findings This was a retrospective population-based register study of women with singleton deliveries registered in the Swedish Medical Birth Register 1999–2016 (n = 1,044,023). The study population had a mean age of 30.2 years (SD 5.2) and a mean body mass index of 25.4 kg/m2 (SD 3.0), and 44% of the women were nulliparous before delivery. Study groups were defined based on cervical HPV tests, cytology, and histology, as registered in the Swedish National Cervical Screening Registry. Women with a history of exclusively normal cytology (n = 338,109) were compared to women with positive HPV tests (n = 2,550) or abnormal cytology (n = 11,727) within 6 months prior to conception or during the pregnancy, women treated for CIN3 before delivery (n = 23,185), and women with CIN2+ diagnosed after delivery (n = 33,760). Study groups were compared concerning obstetric and neonatal outcomes by logistic regression, and comparisons were adjusted for socioeconomic and health-related confounders. HPV infection was associated with PTD (adjusted odds ratio [aOR] 1.19, 95% CI 1.01–1.42, p = 0.042), preterm prelabor rupture of membranes (pPROM) (aOR 1.52, 95% CI 1.18–1.96, p < 0.001), prelabor rupture of membranes (PROM) (aOR 1.24, 95% CI 1.08–1.42, p = 0.002), and neonatal mortality (aOR 2.69, 95% CI 1.25–5.78, p = 0.011). Treatment for CIN was associated with PTD (aOR 1.85, 95% CI 1.76–1.95, p < 0.001), spontaneous PTD (aOR 2.06, 95% CI 1.95–2.17, p < 0.001), pPROM (aOR 2.36, 95% CI 2.19–2.54, p < 0.001), PROM (aOR 1.11, 95% CI 1.05–1.17, p < 0.001), intrauterine fetal death (aOR 1.35, 95% CI 1.05–1.72, p = 0.019), chorioamnionitis (aOR 2.75, 95% CI 2.33–3.23, p < 0.001), intrapartum fever (aOR 1.24, 95% CI 1.07–1.44, p = 0.003), neonatal sepsis (aOR 1.55, 95% CI 1.37–1.75, p < 0.001), and neonatal mortality (aOR 1.79, 95% CI 1.30–2.45, p < 0.001). Women with CIN2+ diagnosed within 3 years after delivery had increased PTD risk (aOR 1.18, 95% CI 1.10–1.27, p < 0.001). Limitations of the study include the retrospective design and the fact that because HPV test results only became available in 2007, abnormal cytology was used as a proxy for HPV infection. Conclusions In this study, we found that HPV infection shortly before or during pregnancy was associated with PTD, pPROM, PROM, and neonatal mortality. Previous treatment for CIN was associated with even greater risks for PTD and pPROM and was also associated with PROM, neonatal mortality, and maternal and neonatal infectious complications., In a retrospective analysis of population-based registry data, Johanna Wiik and colleagues investigate relationships between HPV infection, treatment for cervical intraepithelial neoplasia, and pregnancy and birth outcomes., Author summary Why was this study done? Treatment of cervical intraepithelial neoplasia (CIN) is associated with an increased risk of preterm delivery (PTD), preterm prelabor rupture of the membranes (pPROM), and neonatal mortality. However, the exact biological mechanism is still unknown. Women with untreated CIN also seem to have an increased risk of PTD. It is unknown whether HPV infection can cause PTD or other adverse obstetric outcomes. Although ascending bacterial infection is an established leading cause of PTD, there is limited knowledge concerning whether PTD after excisional treatment for CIN is associated with infectious complications. What did the researchers do and find? This retrospective population-based register study (1999–2016) found that HPV infection shortly before or during pregnancy is associated with an increased risk of PTD, pPROM, prelabor rupture of the membranes, and neonatal mortality. Treatment for CIN was also associated with these adverse outcomes and with an even higher risk for PTD and pPROM. This study presents new evidence that previous treatment for CIN is associated with an increased risk of maternal and neonatal infectious complications. What do these findings mean? Although we cannot claim causality due to the register-based study design, our results suggest that pregnancies after treatment for CIN should be regarded as high-risk pregnancies and counseled accordingly. These results support the idea that strategies to mitigate HPV infection, such as vaccination programs, may be beneficial for maternal and neonatal pregnancy outcomes.

Background Research has questioned the safety of delaying or withholding antibiotics for suspected urinary tract infection (UTI) in older patients. We evaluated the association between antibiotic treatment for lower UTI and risk of bloodstream infection (BSI) in adults aged ≥65 years in primary care. Methods and findings We analyzed primary care records from patients aged ≥65 years in England with community-onset UTI using the Clinical Practice Research Datalink (2007–2015) linked to Hospital Episode Statistics and census data. The primary outcome was BSI within 60 days, comparing patients treated immediately with antibiotics and those not treated immediately. Crude and adjusted associations between exposure and outcome were estimated using generalized estimating equations. A total of 147,334 patients were included representing 280,462 episodes of lower UTI. BSI occurred in 0.4% (1,025/244,963) of UTI episodes with immediate antibiotics versus 0.6% (228/35,499) of episodes without immediate antibiotics. After adjusting for patient demographics, year of consultation, comorbidities, smoking status, recent hospitalizations, recent accident and emergency (A&E) attendances, recent antibiotic prescribing, and home visits, the odds of BSI were equivalent in patients who were not treated with antibiotics immediately and those who were treated on the date of their UTI consultation (adjusted odds ratio [aOR] 1.13, 95% CI 0.97–1.32, p-value = 0.105). Delaying or withholding antibiotics was associated with increased odds of death in the subsequent 60 days (aOR 1.17, 95% CI 1.09–1.26, p-value < 0.001), but there was limited evidence that increased deaths were attributable to urinary-source BSI. Limitations include overlap between the categories of immediate and delayed antibiotic prescribing, residual confounding underlying differences between patients who were/were not treated with antibiotics, and lack of microbiological diagnosis for BSI. Conclusions In this study, we observed that delaying or withholding antibiotics in older adults with suspected UTI did not increase patients’ risk of BSI, in contrast with a previous study that analyzed the same dataset, but mortality was increased. Our findings highlight uncertainty around the risks of delaying or withholding antibiotic treatment, which is exacerbated by systematic differences between patients who were and were not treated immediately with antibiotics. Overall, our findings emphasize the need for improved diagnostic/risk prediction strategies to guide antibiotic prescribing for suspected UTI in older adults., In a study of electronic health record data, Laura Shallcross, Patrick Rockenschaub and colleagues investigate the associations between initiation of antibiotic treatment for UTI and blood stream infection and mortality among older adults in England., Author summary Why was this study done? Urinary tract infections (UTI) are common in older adults and, alongside respiratory infections, account for the majority of antibiotics prescribed in primary care Antibiotics are often prescribed inappropriately for UTI in the elderly, but the need to reduce prescribing must be balanced against the risk of increasing rare but severe outcomes, such as bloodstream infection, if antibiotic treatment is delayed A recent study in patients aged >65 years found that those who did not receive immediate antibiotic treatment for UTI were more likely to develop bloodstream infection What did the researchers do and find? We reanalyzed the relationship between the timing of antibiotic prescribing for UTI and subsequent risk of bloodstream infection (BSI) using the same dataset We did not find evidence to suggest that not immediately prescribing antibiotics for UTI increased a patient’s risk of bloodstream infection, but we did find some evidence of increased mortality. Women were less likely to develop BSI compared with men (adjusted odds ratio [aOR] 0.49, 95% confidence interval [CI] 0.43–0.55, p-value < 0.001). Increasing age (aOR 1.22, 95% CI 1.18–1.27 per 5 years, p-value < 0.001) and social deprivation (Q5 versus Q1: aOR 1.45; 95% CI 1.19–1.76, p-value < 0.001) were also independently associated with BSI. Systematic differences between patients who were/were not treated immediately with antibiotics (residual confounding) remains a potential explanation for our findings in relation to mortality. What do these findings mean? This population-based study highlights uncertainty around whether delaying antibiotics in older adults with suspected UTI increases their risk of adverse outcomes. The reasons for the systematic differences identified between patients who were and were not treated immediately with antibiotics warrants further study. Adverse consequences of antibiotic treatment in this population and the public health need to tackle antibiotic resistance highlight the need for novel diagnostic and/or risk prediction strategies to guide antibiotic prescribing decisions for suspected UTI.

Background The rise of gonococcal antimicrobial resistance highlights the need for strategies that extend the clinically useful life span of antibiotics. Because there is limited evidence to support the current practice of switching empiric first-line antibiotic when resistance exceeds 5% in the population, our objective was to compare the impact of alternative strategies on the effective life spans of antibiotics and the overall burden of gonorrhea. Methods and findings We developed and calibrated a mathematical model of gonorrhea transmission among men who have sex with men (MSM) in the United States. We calibrated the model to the estimated prevalence of gonorrhea, the rate of gonorrhea cases, and the proportion of cases presenting symptoms among MSM in the US. We used this model to project the effective life span of antibiotics and the number of gonorrhea cases expected under current and alternative surveillance strategies over a 50-year simulation period. We demonstrate that compared to the current practice, a strategy that uses quarterly (as opposed to yearly) surveillance estimates and incorporates both the estimated prevalence of resistance and the trend in the prevalence of resistance to determine treatment guidelines could extend the effective life span of antibiotics by 0.83 years. This is equivalent to successfully treating an additional 80.1 (95% uncertainty interval: [47.7, 111.9]) gonorrhea cases per 100,000 MSM population each year with the first-line antibiotics without worsening the burden of gonorrhea. If the annual number of isolates tested for drug susceptibility is doubled, this strategy could increase the effective life span of antibiotics by 0.94 years, which is equivalent to successfully treating an additional 91.1 (54.3, 127.3) gonorrhea cases per 100,000 MSM population each year without increasing the incidence of gonorrhea. Study limitations include that our conclusions might not be generalizable to other settings because our model describes the transmission of gonorrhea among the US MSM population, and, to better capture uncertainty in the characteristics of current and future antibiotics, we chose to model hypothetical drugs with characteristics similar to the antibiotics commonly used in gonorrhea treatment. Conclusions Our results suggest that use of data from surveillance programs could be expanded to prolong the clinical effectiveness of antibiotics without increasing the burden of the disease. This highlights the importance of maintaining effective surveillance systems and the engagement of policy makers to turn surveillance findings into timely and effective decisions., Reza Yaesoubi and colleagues study possible approaches to delaying the appearance of antimicrobial resistance in treatment of gonorrhea., Author summary Why was this study done? Gonorrhea is the second most common notifiable disease in the United States and has developed resistance to all first-line antibiotics. The selection of antibiotics used for gonorrhea treatment is almost always empiric and based on guideline recommendations. There is limited evidence to support the current practice of switching the first-line antibiotic after resistance to it exceeds 5% in annual surveillance estimates. Our objective was to project how alternative strategies to inform the first-line treatment recommendations impact the life span of antibiotics and the overall burden of gonorrhea. What did the researchers do and find? We developed a mathematical model that describes the key characteristics of gonorrhea transmission among men who have sex with men (MSM) in the United States. Our model estimates the life span of antibiotics and the incidence of gonorrhea under current and alternative strategies for changing first-line empiric antibiotic treatment. We found that compared to the current practice, a strategy that 1) uses quarterly surveillance estimates and 2) incorporates both the estimated prevalence of resistance and the trend in the prevalence of resistance to determine treatment guidelines could extend the effective life span of antibiotics without worsening the burden of gonorrhea. What do these findings mean? This work suggests an opportunity to optimize the use of surveillance systems to slow the spread of antibiotic-resistant strains and control the burden of gonorrhea. This requires enhancing the surveillance systems (e.g., by allowing for more frequent reporting of estimates and a larger number of observations) and the engagement of policy makers to turn surveillance findings into timely decisions. Further studies are needed to investigate the generalizability of these conclusions.

Background Protecting the health of refugees and other migrant populations in the United States is key to ensuring successful resettlement. Therefore, to identify and address health concerns early, the US Centers for Disease Control and Prevention (CDC) recommends a domestic medical examination (screening for infectious and noninfectious diseases/conditions) shortly after arrival in the US. However, because refugee/migrant populations often have differing health patterns from one another and the US population, the collection and analysis of health information is key to developing population-specific clinical guidelines to guide the care of resettled individuals. Yet little is known regarding the health status of Cubans resettling in the US. Among the tens of thousands of Cuban migrants who have resettled in the US, some applied as refugees in Cuba, some applied for parole (a term used to indicate temporary US admission status for urgent humanitarian reasons or reasons of public benefit under US immigration law) in Cuba, and others applied for parole status after crossing the border. These groups were eligible for US government benefits to help them resettle, including a domestic medical examination. We reviewed health differences found in these examinations of those who were determined to be refugees or parolees in Cuba and those who were given parole status after arrival. Methods and findings We conducted a retrospective cross-sectional analysis of the Texas Department of State Health Services database. Cubans who arrived from 2010 to 2015 and received a domestic medical examination in Texas were included. Those granted refugee/parolee status in Cuba were listed in federal databases for US-bound refugees/parolees; those who were paroled after arrival were not listed. Overall, 2,189 (20%) obtained either refugee or parolee status in Cuba, and 8,709 (80%) received parolee status after arrival. Approximately 62% of those who received parolee status after arrival at the border were male, compared with 49% of those who obtained prior refugee/parolee status in Cuba. Approximately one-half (45%) of those paroled after arrival were 19–34 years old (versus 26% among those who obtained refugee/parolee status in Cuba). Separate models were created for each screening indicator as the outcome, with entry route as the main exposure variable. Crude and adjusted prevalence ratios were estimated using PROC GENMOD procedures in SAS 9.4. Individuals paroled after arrival were less likely to screen positive for parasitic infections (9.6% versus 12.2%; adjusted prevalence ratio: 0.79, 0.71–0.88) and elevated blood lead levels (children ≤16 years old, 5.2% versus 12.3%; adjusted prevalence ratio: 0.42, 0.28–0.63). Limitations include potential disease misclassification, missing clinical information, and cross-sectional nature. Conclusions Within-country variations in health status are often not examined in refugee populations, yet they are critical to understand granular health trends. Results suggests that the health profiles of Cuban Americans in Texas differed by entry route. This information could assist in developing targeted screenings and health interventions., Emily Jentes and colleagues discuss the health of recently arrived Cuban refugees in the US., Author summary Why was this study done? Protecting the health of the tens of thousands of refugees and other migrants, including Cubans, resettling in the US is key to ensuring successful resettlement. Between 2010 and 2015, Cubans comprised a large portion of migrants resettling in the US arriving by one of two routes: (1) some received either refugee or parole status to enter the US while still in Cuba, and (2) some applied for parole status after arrival in the US. Yet little is known regarding the health status of Cubans entering the US (and, more specifically, whether the health status differed by these two routes of entry), and therefore more information is needed to inform screening procedures and health interventions for this population. What did the researchers do and find? We developed mathematical models using data collected from clinic visits shortly after arrival to the US that describe differences in health patterns between these two routes of entry among Cubans who arrived in the US from 2010 to 2015. Overall, the health patterns between the two routes of entry may differ with respect to certain health outcomes; specifically, those with parole status after arrival were less likely to screen positive for parasitic infections. Additionally, the results indicated that the Cuban migrant health profile is more similar to that of those born in the US compared with other migrant and refugee populations resettling in the US. What do these findings mean? US clinicians can use these findings to understand potential health concerns of the tens of thousands of Cubans living in the US. The findings can also be used to strengthen health screening guidance and can assist in developing health interventions specific to Cubans living in the US.

With major advances in understanding the infectious etiology of cervical cancer, preventive medicine has obtained highly promising new tools. Human papillomavirus (HPV) vaccines, together with a growing arsenal of HPV-based screening tests, have the potential to radically change public health but require diligent, large-scale implementation to reach the final goal: the elimination of cervical cancer. We reflect here upon the state of cervical cancer prevention globally as there have been several recent developments that will inform this implementation process., Karin Sundström and Miriam Elfström discuss prospects for and progress towards cervical cancer elimination.

Background Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. Methods and findings In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%–19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%–2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. Conclusions To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China., In an observational study using data from the China Gonococcal Resistance Surveillance Programme, Yueping Yin estimate rates of reduced susceptibility to WHO-recommended antibiotics for Neisseria gonorrhoeae., Author summary Why was this study done? Antimicrobial resistance in Neisseria gonorrhoeae (N. gonorrhoeae) is a global threat in the control of this infection. China has one of the biggest antimicrobial consumption rates globally. However, China has limited data on antimicrobial resistance in gonorrhea. Systematic and timely collection and analysis of data on antimicrobial susceptibility of N. gonorrhoeae will inform the development of Chinese treatment guidelines and clinical practice standards. What did the researchers do and find? Minimum inhibitory concentrations (MICs) of azithromycin and ceftriaxone were determined for 3,849 clinical isolates from patients with gonorrhea who provided samples during the time period 2013 to 2016 in 7 provinces in China. Following the Clinical and Laboratory Standards Institute criteria, MIC values were used to define isolates as resistant to azithromycin and/or with decreased susceptibility to ceftriaxone. High prevalence of resistance to azithromycin (18.6%) and decreased susceptibility to ceftriaxone (10.8%) were found in our study population. The prevalence of concomitant resistance to azithromycin and decreased susceptibility to ceftriaxone increased from 1.9% in 2013 to 3.3% in 2016. What do these findings mean? N. gonorrhoeae strains resistant to azithromycin and/or with decreased susceptibility to ceftriaxone are prevalent in China, posing a challenge for gonorrhea control. The results can be used to inform national recommendations for N. gonorrhoeae treatment in China.

In an Editorial, Guest Editors Nicola Low and Nathalie Broutet discuss the Collection on sexually transmitted infections in the context of research priorities in the field.

Background Sexually transmitted infections (STIs) and bacterial vaginosis (BV) are associated with increased transmission of HIV, and poor reproductive and sexual health. The burden of STIs/BV among young people is unknown in many high HIV prevalence settings. We conducted an acceptability, feasibility, and prevalence study of home-based sampling for STIs/BV among young men and women aged 15–24 years old in a health and demographic surveillance site (HDSS) in rural KwaZulu-Natal, South Africa. Methods and findings A total of 1,342 young people, stratified by age (15–19 and 20–24 years) and sex were selected from the HDSS sampling frame; 1,171/1,342 (87%) individuals had ≥1 attempted home visit between 4 October 2016 and 31 January 2017, of whom 790 (67%) were successfully contacted. Among the 645 who were contacted and eligible, 447 (69%) enrolled. Consenting/assenting participants were interviewed, and blood, self-collected urine (men), and vaginal swabs (women) were tested for herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis, trichomoniasis, and BV. Both men and women reported that sample collection was easy. Participants disagreed that sampling was painful; more than half of the participants disagreed that they felt anxious or embarrassed. The weighted prevalence of STIs/BV among men and women, respectively, was 5.3% and 11.2% for chlamydia, 1.5% and 1.8% for gonorrhoea, 0% and 0.4% for active syphilis, 0.6% and 4.6% for trichomoniasis, 16.8% and 28.7% for HSV-2, and 42.1% for BV (women only). Of the women with ≥1 curable STI, 75% reported no symptoms. Factors associated with STIs/BV included having older age, being female, and not being in school or working. Among those who participated in the 2016 HIV serosurvey, the prevalence of HIV was 5.6% among men and 19% among women. Feasibility was impacted by the short study duration and the difficulty finding men at home. Conclusions A high prevalence of STIs/BV was found in this rural setting with high HIV prevalence in South Africa. Most STIs and HIV infections were asymptomatic and would not have been identified or treated under national syndromic management guidelines. A nested STI/BV survey within a HDSS proved acceptable and feasible. This is a proof of concept for population-based STI surveillance in low- and middle-income countries that could be utilised in the evaluation of STI/HIV prevention and control programmes., Suzanna C Francis and colleagues report on acceptability, feasibility and prevalence results from home-based STI sampling among young men and women in rural KwaZulu-Natal, South Africa., Author summary Why was this study done? Adolescents and young adults are particularly vulnerable to sexually transmitted infections (STIs). The first strategic direction of the WHO Global Health Sector Strategy on Sexually Transmitted Infections 2016–2021 is to collect information on STI prevalence and incidence across representative populations. There is evidence that bacterial vaginosis (BV) is a risk factor for poor birth outcomes and STIs including HIV. The collection of BV prevalence may therefore also be important. Developing new cohorts for dedicated STI/BV prevalence studies may not be realistic, particularly in sub-Saharan Africa, where the impact of STIs/BV and their consequences may be greatest. Nesting STI/BV surveys within networks of health and demographic surveillance sites (HDSSs) would be an efficient way of providing data to better understand STI epidemiology among adolescents and young people in high HIV prevalence settings. What did the researchers do and find? We carried out a nested STI/BV survey among 1,342 adolescent and young people in an HDSS in KwaZulu-Natal, South Africa, between October 2016 and January 2017. Potential participants were contacted at home and invited to participate. Participants were interviewed, and samples were collected for STI/BV testing. We showed that this study was feasible within the 3.5-month time period: 1,171/1,342 (87%) individuals had ≥1 attempted home visit, of whom 790 (67%) were successfully contacted. The study was acceptable: among those contacted and eligible, 447/645 (69%) enrolled. Both men and women reported few problems with sample collection. We report a high burden of STIs/BV in this population, particularly of chlamydia (5% in men and 11% in women), herpes simplex virus type 2 (17% in men and 29% in women), and BV (42% in women). What do these findings mean? Nested STI/BV surveys in HDSSs can be feasible and acceptable; however, more survey time is needed to ensure that all potential participants are visited and contacted. These studies should be carried out in conjunction with studies to measure STI/BV prevalence in high-risk populations (e.g., female sex workers) to provide robust prevalence estimates. These data are essential to advocate, fund, plan, implement, and evaluate interventions for STI prevention and control among adolescents and young people. Strategies for the prevention and control of chlamydia, herpes simplex virus type 2, and BV are needed in this population.

Background Benzathine penicillin G (BPG) is the only recommended treatment to prevent mother-to-child transmission of syphilis. Due to recent reports of country-level shortages of BPG, an evaluation was undertaken to quantify countries that have experienced shortages in the past 2 years and to describe factors contributing to these shortages. Methods and findings Country-level data about BPG shortages were collected using 3 survey approaches. First, a survey designed by the WHO Department of Reproductive Health and Research was distributed to 41 countries and territories in the Americas and 41 more in Africa. Second, WHO conducted an email survey of 28 US Centers for Disease Control and Prevention country directors. An additional 13 countries were in contact with WHO for related congenital syphilis prevention activities and also reported on BPG shortages. Third, the Clinton Health Access Initiative (CHAI) collected data from 14 countries (where it has active operations) to understand the extent of stock-outs, in-country purchasing, usage behavior, and breadth of available purchasing options to identify stock-outs worldwide. CHAI also conducted in-person interviews in the same 14 countries to understand the extent of stock-outs, in-country purchasing and usage behavior, and available purchasing options. CHAI also completed a desk review of 10 additional high-income countries, which were also included. BPG shortages were attributable to shortfalls in supply, demand, and procurement in the countries assessed. This assessment should not be considered globally representative as countries not surveyed may also have experienced BPG shortages. Country contacts may not have been aware of BPG shortages when surveyed or may have underreported medication substitutions due to desirability bias. Funding for the purchase of BPG by countries was not evaluated. In all, 114 countries and territories were approached to provide information on BPG shortages occurring during 2014–2016. Of unique countries and territories, 95 (83%) responded or had information evaluable from public records. Of these 95 countries and territories, 39 (41%) reported a BPG shortage, and 56 (59%) reported no BPG shortage; 10 (12%) countries with and without BPG shortages reported use of antibiotic alternatives to BPG for treatment of maternal syphilis. Market exits, inflexible production cycles, and minimum order quantities affect BPG supply. On the demand side, inaccurate forecasts and sole sourcing lead to under-procurement. Clinicians may also incorrectly prescribe BPG substitutes due to misperceptions of quality or of the likelihood of adverse outcomes. Conclusions Targets for improvement include drug forecasting and procurement, and addressing provider reluctance to use BPG. Opportunities to improve global supply, demand, and use of BPG should be prioritized alongside congenital syphilis elimination efforts., Using country-level surveys and stakeholder interviews, Stephen Nurse-Findlay and colleagues investigate the global frequency of benzathine penicillin shortages and uncover commonly noted causes., Author summary Why was this study done? A single dose of low-cost benzathine penicillin G (BPG) ends syphilis infectivity in adults with no documented risk of antibiotic resistance. In spite of this, syphilis continues to infect millions globally. Pregnant women with syphilis are particularly vulnerable, as fetal transmission of the infection can cause stillbirth. The only recommended treatment for syphilis in pregnant women is BPG. Congenital syphilis remains a significant contributor to early infant mortality, particularly in low- and middle-income countries. There are several reasons for this, but one of the most important is a global shortage of BPG. In 2015, WHO began to receive anecdotal country reports of BPG stock-outs. WHO decided to assess these shortages, describe global supply and demand drivers, and propose viable policy solutions. What did the researchers do and find? The team completed 3 surveys to assess global BPG shortages occurring during 2014–2016. The first was distributed to 41 countries and territories in the Americas and 41 African countries. The second was emailed to 28 US Centers for Disease Control and Prevention country directors. The third was used in in-person interviews in 14 countries by the Clinton Health Access Initiative. In all, 95 of 114 unique countries and territories responded to the surveys. Of these, 39 reported a BPG shortage and 56 reported no BPG shortage. The team discovered 3 major issues. First, countries often obtain their product from a single wholesaler, which often obtains its products from a single final dose formulator, which often obtains its active ingredient from a single manufacturer. This “sole sourcing,” combined with a highly consolidated market, makes alternative supply difficult if there are production, quality, regulatory, or specification changes within a country’s supply chain. Second, as an off-patent medication, BPG commands a market price of pennies per dose. However, as a sterile injectable, it is also expensive to manufacture. These economics have led manufacturers to either abandon BPG production or implement stringent ordering protocols that compromise supply for low- and middle-income countries. Third, inaccurate country forecasts, weak procurement systems, and clinical knowledge gaps about syphilis treatment have compromised demand for and procurement of BPG. What do these findings mean? Widespread BPG shortages compromise treatment of adult syphilis, prevention of congenital syphilis, and treatment of other BPG-indicated conditions (including rheumatic heart disease). An uninterrupted supply of quality-assured active pharmaceutical ingredient and final formulated product will simplify BPG procurement for high-burden countries. Countries must strengthen their supply chain, purchasing, forecasting, and procurement infrastructure to mitigate shortage risk and reduce demand-side stock-outs. Countries must also strengthen testing for and treatment of maternal syphilis (and prevention of congenital syphilis) with BPG.

In a Policy Forum, Teodora Wi and colleagues discuss the challenges of antimicrobial resistance in gonococci.

Melanie Taylor and colleagues discuss progress towards eliminating vertical transmission of HIV and syphilis.

In an essay, Paul Bloem and Ikechukwu Ogbuanu discuss the public health implications of HPV vaccination.

Background Using primary human papillomavirus (HPV) testing for cervical screening increases detection of high-grade cervical intraepithelial neoplastic lesions and invasive cancer (cervical intraepithelial neoplasia grade 2+ [CIN2+]) compared to cytology, but no evaluation has been conducted in a population previously offered HPV vaccination. We aimed to assess colposcopy referral and CIN2+ detection rates for HPV-screened versus cytology-screened women in Australia’s HPV-vaccinated population (by 2014, resident women ≤33 years had been age-eligible for HPV vaccination, with 3-dose uptake across age cohorts being about 50%–77%). Methods and findings Compass is an open-label randomised trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening. In the first phase, consenting women aged 25–64 years presenting for routine screening at 47 primary practices in Victoria, Australia, provided a cervical sample and were randomised at a central laboratory at a 1:2:2 allocation to (i) image-read LBC screening with HPV triage of low-grade cytology (‘LBC screening’), (ii) HPV screening with those HPV16/18 positive referred to colposcopy and with LBC triage for other oncogenic (OHR) types (‘HPV+LBC triage’), or (iii) HPV screening with those HPV16/18 positive referred to colposcopy and with dual-stained cytology triage for OHR types (‘HPV+DS triage’). A total of 5,006 eligible women were recruited from 29 October 2013 to 7 November 2014 (recruitment rate 58%); of these, 22% were in the group age-eligible for vaccination. Data on 4,995 participants were analysed after 11 withdrawals; 998 were assigned to, and 995 analysed (99.7%) in, the LBC-screened group; 1,996 assigned to and 1,992 analysed (99.8%) in the HPV+LBC triage group; and 2,012 assigned to and 2,008 analysed (99.8%) in the HPV+DS triage group. No serious trial-related adverse events were reported. The main outcomes were colposcopy referral and detected CIN2+ rates at baseline screening, assessed on an intention-to-treat basis after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes (dataset closed 31 August 2016). Analysis was adjusted for whether women had been age-eligible for HPV vaccination or not. For the LBC-screened group, the overall referral and detected CIN2+ rates were 27/995 (2.7% [95% CI 1.8%–3.9%]) and 1/995 (0.1% [95% CI 0.0%–0.6%]), respectively; for HPV+LBC triage, these were 75/1,992 (3.8% [95% CI 3.0%–4.7%]) and 20/1,992 (1.0% [95% CI 0.6%–1.5%]); and for HPV+DS triage, these were 79/2,008 (3.9% [95% CI 3.1%–4.9%]) and 24/2,008 (1.2% [95% CI 0.8%–1.6%]) (p = 0.09 for difference in referral rate in LBC versus all HPV-screened women; p = 0.003 for difference in CIN2+ detection rate in LBC versus all HPV-screened women, with p = 0.62 between HPV screening groups). Limitations include that the study population involved a relatively low risk group in a previously well-screened and treated population, that individual women’s vaccination status was unknown, and that long-term follow-up data on disease detection in screen-negative women are not yet available. Conclusions In this study, primary HPV screening was associated with significantly increased detection of high-grade precancerous cervical lesions compared to cytology, in a population where high vaccine uptake was reported in women aged 33 years or younger who were offered vaccination. It had been predicted that increased disease detection might be associated with a transient increase in colposcopy referral rates in the first round of HPV screening, possibly dampened by HPV vaccine effect; in this study, although the point estimates for referral rates in women in each HPV-screened group were 41%–44% higher than in cytology-screened women, the difference in referral rate between cytology- and HPV-screened women was not significant. These findings provide initial support for the implementation of primary HPV screening in vaccinated populations. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001207707, Karen Canfell and colleagues report results of the Compass trial; in a large Australian cohort, HPV screening is superior to pap smears for pre-cancerous lesion identification., Author summary Why was this study done? A number of countries are currently considering a transition from cytology (Pap) testing to primary HPV testing for cervical screening. This is underpinned by evidence from a number of large-scale randomised trials showing improved early detection of high-grade precancerous disease and subsequent improved long term protection against cervical intraepithelial neoplasia grade 3 (CIN3) and invasive cervical cancer in HPV-screened women compared to those screened with cytology. However, no prior trials of these cervical screening approaches have been conducted in a population with substantial uptake of HPV vaccination, which has now been available for a decade. What did the researchers do and find? Australia has a high uptake of HPV vaccination, with all women aged ≤33 years at the time of recruitment in 2014 having previously been offered vaccination. We conducted a randomised trial of 5-yearly HPV screening versus 2.5-yearly cytology screening in women aged 25–64 years presenting for routine screening in Victoria, Australia. We examined detected rates of high-grade precancer (CIN2+) in the baseline screening round, assessed on an intention-to-treat basis after follow-up of a subgroup of women in each arm who were referred to 12 months of surveillance based on their screening results, and after a further 6 months of follow-up for histological outcomes. We found that there was a significantly higher detection rate for CIN2+ in HPV-screened women (about 1.0% for HPV-screened women versus 0.1% for cytology-screened women). What do these findings mean? These findings provide initial confirmation of an improved performance of primary HPV screening compared to cytology screening in settings with HPV-vaccinated populations. These findings from Australia, the first country to adopt a national, publicly funded HPV vaccination program, are relevant to other countries considering the implications of HPV vaccination implementation on future cervical screening approaches.

Jeanne M. Marrazzo and colleagues join PLOS Medicine's Collection on the prevention, diagnosis, and treatment of STIs with a Perspective on HIV research imperatives in our time of effective viral suppression and pre-exposure prophylaxis.

Nicola Low and colleagues announce a call for research papers on sexually transmitted infections, to accompany a Collection on the topic.

Melanie Taylor and colleagues discuss global initiatives for surveillance of sexually transmitted diseases.

Background Little is known about the relative risk of common bacterial, viral, fungal, and parasitic infections in the general population of individuals exposed to systemic glucocorticoids, or about the impact of glucocorticoid exposure duration and predisposing factors on this risk. Methods and Findings The hazard ratios of various common infections were assessed in 275,072 adults prescribed glucocorticoids orally for ≥15 d (women: 57.8%, median age: 63 [interquartile range 48–73] y) in comparison to those not prescribed glucocorticoids. For each infection, incidence rate ratios were calculated for five durations of exposure (ranging from 15–30 d to >12 mo), and risk factors were assessed. Data were extracted from The Health Improvement Network (THIN) primary care database. When compared to those with the same underlying disease but not exposed to glucocorticoids, the adjusted hazard ratios for infections with significantly higher risk in the glucocorticoid-exposed population ranged from 2.01 (95% CI 1.83–2.19; p < 0.001) for cutaneous cellulitis to 5.84 (95% CI 5.61–6.08; p < 0.001) for lower respiratory tract infection (LRTI). There was no difference in the risk of scabies, dermatophytosis and varicella. The relative increase in risk was stable over the durations of exposure, except for LRTI and local candidiasis, for which it was much higher during the first weeks of exposure. The risks of infection increased with age and were higher in those with diabetes, in those prescribed higher glucocorticoid doses, and in those with lower plasma albumin level. Most associations were also dependent on the underlying disease. A sensitivity analysis conducted on all individuals except those with asthma or chronic obstructive pulmonary disease produced similar results. Another sensitivity analysis assessing the impact of potential unmeasured confounders such as disease severity or concomitant prescription of chemotherapy suggested that it was unlikely that adjusting for these potential confounders would have radically changed the findings. Limitations of our study include the use of electronic medical records, which could have resulted in some degree of misclassification of the infectious outcomes; a possible reporting bias, as general practitioners could be more prone to record an infection in those exposed to glucocorticoids; and a low number of events for some outcomes such as scabies or varicella, which may have led to limited statistical power. Conclusions The relative risk of LRTI and local candidiasis is very high during the first weeks of glucocorticoid exposure. Further studies are needed to assess whether low albumin level is a risk factor for infection by itself (e.g., by being associated with a higher free glucocorticoid fraction) or whether it reflects other underlying causes of general debilitation., Fardet and colleagues present a large population study assessing the risks of developing infections following glucocorticoid treatment. They describe the impact of age and other conditions such as diabetes on developing infections., Editors’ Summary Background Throughout life, our immune system protects us from attack by disease-causing organisms. When a virus, bacterium, fungus, or parasite enters the human body, the immune system detects the invader and triggers a response that kills or neutralizes it. Normally, the immune system discriminates perfectly between foreign invaders and the body’s own cells and tissues, but sometimes it goes awry and begins to attack “self,” resulting in the development of an autoimmune disease such as rheumatoid arthritis (in which the immune system attacks the joints) or lupus erythematosus (in which the immune system attacks numerous tissues and organs). Immune system dysfunction is also involved in chronic inflammatory conditions. Tissue inflammation (pain, heat, redness, and swelling) is part of the normal immune response, but uncontrolled inflammation underlies sepsis (a systemic inflammatory condition that sometimes develops after a localized infection) and lung conditions such as asthma and chronic obstructive pulmonary disease. Why Was This Study Done? Inflammatory diseases and autoimmune diseases are often treated with glucocorticoids—drugs with immunosuppressive and anti-inflammatory properties. At any one time, more than 1% of the US and UK population is receiving systemic glucocorticoid therapy (whole-body therapy often given as a pill) to treat an autoimmune or inflammatory condition or to treat cancer or prevent organ rejection after transplantation. But, although prednisolone, dexamethasone, and other glucocorticoids are effective treatments for these conditions, long-term use of oral glucocorticoids is associated with serious side effects, including an increased infection risk. Several studies have investigated the overall risk of infection in specific populations receiving glucocorticoids, but little is known about the risk of individual common infections among people in the general population taking glucocorticoids. Here, the researchers undertake a population-based cohort study—an observational investigation that compares specific outcomes in groups (cohorts) of people from the general population with different baseline characteristics—to discover more about common infections in patients prescribed systemic glucocorticoids in primary care. What Did the Researchers Do and Find? Using The Health Improvement Network (THIN) primary care database, the researchers identified 275,072 adults prescribed oral glucocorticoids in the UK between 2000 and 2012, a random sample of people not prescribed glucocorticoids but with a diagnosis of the same underlying disease as the exposed individuals, and cases of infection in both cohorts. Compared to the unexposed group, the glucocorticoid-exposed group had an increased risk of three bacterial infections (septicemia, lower respiratory tract infection [LRTI], and cutaneous cellulitis), one viral infection (herpes zoster), and one fungal infection (local candidiasis) but no increased risk of varicella virus infection, dermatophytosis (a fungal infection), or scabies (a parasitic infection). The increased risk was highest for LRTI—the risk of LRTI was nearly six-fold higher in the glucocorticoid-exposed group than in the unexposed group. The relative increase in infection risk was similar whatever the duration of glucocorticoid therapy except for LRTI and local candidiasis, for which it was higher in the first few weeks of treatment. The risk of infection increased with age and was higher in people with diabetes, in people given high glucocorticoid doses, and in people with low blood albumin levels. Finally, the risks of different infections depended on the disease for which glucocorticoids were prescribed. What Do These Findings Mean? These findings show that the risk of several (but not all) common bacterial, viral, and fungal infections was higher among people prescribed glucocorticoids for a range of underlying diseases than among people matched for age, gender, and underlying disease who were not prescribed glucocorticoids. Notably, the relative risk of LRTI and local candidiasis was particularly high during the first weeks of glucocorticoid exposure. Several aspects of the study design may affect the accuracy of these findings. For example, the use of medical records may have resulted in some misclassification of infectious outcomes. However, the finding of a high risk of LRTI in patients prescribed systemic glucocorticoids should be considered before prescribing these drugs, particularly in patients with asthma or chronic obstructive pulmonary disease. The finding of an association between low blood albumin level and increased infection risk needs further investigation to determine whether a low albumin level is a direct risk factor for infection or a marker for other underlying causes of debilitation that increase the risk of infection, but it may be worth considering monitoring albumin level before and during glucocorticoid treatment. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1002024. This study is further discussed in a PLOS Medicine Perspective by Lionel Rostaing and Paolo Malvezzi The UK National Health Service Choices website provides information about corticosteroids (glucocorticoids are a specific type of corticosteroids) The Mayo Clinic has an article about the benefits and risks of corticosteroids Wikipedia has information on autoimmune disease, inflammatory disorders, and glucocorticoids (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) MedlinePlus provides links to further information about autoimmune diseases and about corticosteroids More information about The Health Improvement Network database of anonymized electronic medical records is available