Cryptic community structure and metabolic interactions among the heritable facultative symbionts of the pea aphid.

Most insects harbour influential, yet non-essential heritable microbes in their hemocoel. Communities of these symbionts exhibit low diversity. But their frequent multi-species nature raises intriguing questions on roles for symbiont-symbiont synergies in host adaptation, and on the stability of the symbiont communities, themselves. In this study, we build on knowledge of species-defined symbiont community structure across US populations of the pea aphid, Acyrthosiphon pisum. Through extensive symbiont genotyping, we show that pea aphids' microbiomes can be more precisely defined at the symbiont strain level, with strain variability shaping five out of nine previously reported co-infection trends. Field data provide a mixture of evidence for synergistic fitness effects and symbiont hitchhiking, revealing causes and consequences of these co-infection trends. To test whether within-host metabolic interactions predict common versus rare strain-defined communities, we leveraged the high relatedness of our dominant, community-defined symbiont strains vs. 12 pea aphid-derived Gammaproteobacteria with sequenced genomes. Genomic inference, using metabolic complementarity indices, revealed high potential for cooperation among one pair of symbionts-Serratia symbiotica and Rickettsiella viridis. Applying the expansion network algorithm, through additional use of pea aphid and obligate Buchnera symbiont genomes, Serratia and Rickettsiella emerged as the only symbiont community requiring both parties to expand holobiont metabolism. Through their joint expansion of the biotin biosynthesis pathway, these symbionts may span missing gaps, creating a multi-party mutualism within their nutrient-limited, phloem-feeding hosts. Recent, complementary gene inactivation, within the biotin pathways of Serratia and Rickettsiella, raises further questions on the origins of mutualisms and host-symbiont interdependencies.

Akinetopsia: A Systematic Review.

ABSTRACT: Selective motion blindness, also known as akinetopsia, is infrequently reported in the literature. Hence, little is known about the condition including its causes, time course, pathophysiology, and current diagnostic methods. In this investigation, we comprehensively surveyed the literature using a systematic review to identify each reported case of the condition. The purpose of this study was to provide an exhaustive catalog of every published occurrence to date to identify and discuss trends, commonalities, and differences among them. Our results revealed distinct characteristics for the various etiologies of this phenomenon in addition to a shared pathophysiologic pathway among them.

Does getting defensive get you anywhere?-Seasonal balancing selection, temperature, and parasitoids shape real-world, protective endosymbiont dynamics in the pea aphid.

Facultative, heritable endosymbionts are found at intermediate prevalence within most insect species, playing frequent roles in their hosts' defence against environmental pressures. Focusing on Hamiltonella defensa, a common bacterial endosymbiont of aphids, we tested the hypothesis that such pressures impose seasonal balancing selection, shaping a widespread infection polymorphism. In our studied pea aphid (Acyrthosiphon pisum) population, Hamiltonella frequencies ranged from 23.2% to 68.1% across a six-month longitudinal survey. Rapid spikes and declines were often consistent across fields, and we estimated that selection coefficients for Hamiltonella-infected aphids changed sign within this field season. Prior laboratory research suggested antiparasitoid defence as the major Hamiltonella benefit, and costs under parasitoid absence. While a prior field study suggested these forces can sometimes act as counter-weights in a regime of seasonal balancing selection, our present survey showed no significant relationship between parasitoid wasps and Hamiltonella prevalence. Field cage experiments provided some explanation: parasitoids drove modest ~10% boosts to Hamiltonella frequencies that would be hard to detect under less controlled conditions. They also showed that Hamiltonella was not always costly under parasitoid exclusion, contradicting another prediction. Instead, our longitudinal survey - and two overwintering studies - showed temperature to be the strongest predictor of Hamiltonella prevalence. Matching some prior lab discoveries, this suggested that thermally sensitive costs and benefits, unrelated to parasitism, can shape Hamiltonella dynamics. These results add to a growing body of evidence for rapid, seasonal adaptation in multivoltine organisms, suggesting that such adaptation can be mediated through the diverse impacts of heritable bacterial endosymbionts.

Context-dependent vertical transmission shapes strong endosymbiont community structure in the pea aphid, Acyrthosiphon pisum.

Animal-associated microbiomes are often comprised of structured, multispecies communities, with particular microbes showing trends of co-occurrence or exclusion. Such structure suggests variable community stability, or variable costs and benefits-possibilities with implications for symbiont-driven host adaptation. In this study, we performed systematic screening for maternally transmitted, facultative endosymbionts of the pea aphid, Acyrthosiphon pisum. Sampling across six locales, with up to 5 years of collection in each, netted significant and consistent trends of community structure. Co-infections between Serratia symbiotica and Rickettsiella viridis were more common than expected, while Rickettsia and X-type symbionts colonized aphids with Hamiltonella defensa more often than expected. Spiroplasma co-infected with other endosymbionts quite rarely, showing tendencies to colonize as a single species monoculture. Field estimates of maternal transmission rates help to explain our findings: while Serratia and Rickettsiella improved each other's transmission, Spiroplasma reduced transmission rates of co-infecting endosymbionts. In summary, our findings show that North American pea aphids harbour recurring combinations of facultative endosymbionts. Common symbiont partners play distinct roles in pea aphid biology, suggesting the creation of "generalist" aphids receiving symbiont-based defence against multiple ecological stressors. Multimodal selection, at the host level, may thus partially explain our results. But more conclusively, our findings show that within-host microbe interactions, and their resulting impacts on transmission rates, are an important determinant of community structure. Widespread distributions of heritable symbionts across plants and invertebrates hint at the far-reaching implications for these findings, and our work further shows the benefits of symbiosis research within a natural context.

Preoperative predictors of successful tumour localization by intraoperative molecular imaging with pafolacianine in lung cancer to create predictive nomogram.

OBJECTIVES: Intraoperative molecular imaging (IMI) uses cancer-targeted fluorescent probe to locate nodules. Pafolacianine is a Food and Drug Administration-approved fluorescent probe for lung cancer. However, it has a 8-12% false negative rate for localization. Our goal is to define preoperative predictors of tumour localization by IMI. METHODS: We performed a retrospective review of patients who underwent IMI using pafolacianine for lung lesions from June 2015 to August 2019. Candidate predictors including sex, age, body mass index, smoking history, tumour size, distance of tumour from surface, use of neoadjuvant therapy and positron emission tomography avidity were included. The outcome was fluorescence in vivo and comprehensively included those who were true or false positives negatives. Multiple imputation was used to handle the missing data. The final model was evaluated using the area under the receiver operating characteristic curve. RESULTS: Three hundred nine patients were included in our study. The mean age was 64 (standard deviation 13) and 68% had a smoking history. The mean distance of the tumours from the pleural surface was 0.4 cm (standard deviation 0.6). Smoking in pack-years and distance from pleura had an odds ratio of 0.99 [95% confidence interval: 0.98-0.99; P = 0.03] and 0.46 [95% confidence interval: 0.27-0.78; P = 0.004], respectively. The final model had an area under the receiver operating characteristic curve of 0.68 and was used to create a nomogram that gives a probability of fluorescence in vivo. CONCLUSIONS: Primary tumours that are deeper from the pleural surface, especially in patients with a higher pack-years, are associated with a decreased likelihood of intraoperative localization. We identified a nomogram to predict the likelihood of tumour localization with IMI with pafolacianine.

Cost-effectiveness of interventions for HIV/AIDS, malaria, syphilis, and tuberculosis in 128 countries: a meta-regression analysis.

BACKGROUND: Cost-effectiveness analyses have been conducted for many interventions for HIV/AIDS, malaria, syphilis, and tuberculosis, but they have not been conducted for all interventions that are currently recommended in all countries. To support national decision makers in the effective allocation of resources, we conducted a meta-regression analysis of published incremental cost-effectiveness ratios (ICERs) for interventions for these causes, and predicted ICERs for 14 recommended interventions for Global Fund-eligible countries. METHODS: In the meta-regression analysis, we used data from the Tufts University Center for the Evaluation of Value and Risk in Health (Boston, MA, USA) Cost-Effectiveness Registries (the CEA Registry beginning in 1976 and the Global Health CEA registry beginning in 1995) up to Jan 1, 2018. To create analysis files, we standardised and mapped the data, extracted additional data from published articles, and added variables from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Then we selected ratios for interventions with a minimum of two published articles and three published ICERs that mapped to one of five GBD causes (HIV/AIDS, malaria, syphilis, drug-susceptible tuberculosis, or multi-drug resistant tuberculosis), and to a GBD country; reported a currency year during or after 1990; and for which the comparator intervention was defined as no intervention, standard of care, or placebo. Our meta-regression analysis used all available data on 25 eligible interventions, and quantified the association between ICERs and factors at country level and intervention level. We used a five-stage statistical model that was developed to synthesise evidence on cost-effectiveness analyses, and we adapted it for smaller sample sizes by grouping interventions by cause and type (ie, prevention, diagnostics, and treatment). Using the meta-regression parameters we predicted country-specific median ICERs, IQRs, and 95% uncertainty intervals in 2019 US$ per disability-adjusted life-year (DALY) for 14 currently recommended interventions. We report ICERs in league tables with gross domestic product (GDP) per capita and country-specific thresholds. FINDINGS: The sample for the analysis was 1273 ratios from 144 articles, of which we included 612 ICERs from 106 articles in our meta-regression analysis. We predicted ICERs for antiretroviral therapy for prevention for two age groups and pregnant women, pre-exposure prophylaxis against HIV for two risk groups, four malaria prevention interventions, antenatal syphilis screening, two tuberculosis prevention interventions, the Xpert tuberculosis test, and chemotherapy for drug-sensitive tuberculosis. At the country level, ranking of interventions and number of interventions with a predicted median ICER below the country-specific threshold varied greatly. For instance, median ICERs for six of 14 interventions were below the country-specific threshold in Sudan, whereas 12 of 14 were below the country-specific threshold in Peru. Antenatal syphilis screening had the lowest median ICER among all 14 interventions in 81 (63%) of 128 countries, ranging from $3 (IQR 2-4) per DALY averted in Equatorial Guinea to $3473 (2244-5222) in Ukraine. Pre-exposure prophylaxis for HIV/AIDS for men who have sex with men had the highest median ICER among all interventions in 116 (91%) countries, ranging from $2326 (1077-4567) per DALY averted in Lesotho to $53 559 (23 841-108 534) in Maldives. INTERPRETATION: Country-specific league tables highlight the interventions that offer better value per DALY averted, and can support decision making at a country level that is more tailored to available resources than GDP per capita and country-specific thresholds. Meta-regression is a promising method to synthesise cost-effectiveness analysis results and transfer them across settings. FUNDING: Bill & Melinda Gates Foundation.

Chemotherapy-Induced Retinopathy in a Diabetic and Hypertensive Patient With Stage 4 Metastatic Pancreatic Adenocarcinoma.

Purpose: To describe a case of presumed Purtscher-like retinopathy in association with 2 chemotherapies. Methods: A retrospective chart review was performed. Results: A 40-year-old Black woman was diagnosed with pancreatic adenocarcinoma with metastasis to the liver. Cotton-wool spots and microaneurysms (dot/blot hemorrhages) were found on a routine examination 1 month after the patient started gemcitabine/paclitaxel. An increase in cotton-wool spots was noticed after she stopped gemcitabine/cisplatin therapy and started 5-fluorouracil/irinotecan/leucovorin therapy. These retinal changes were observed until the time of death. Conclusions: We believe that the Purtscher-like retinopathy began with gemcitabine toxicity but that the irreversible damage was the result of cisplatin chemotherapy. The patient's uncontrolled hypertension and type II diabetes likely put her at greater risk for developing this retinopathy.

Intraocular Lens Formula Comparison of Flanged Intrascleral Intraocular Lens Fixation with Double Needle Technique.

Purpose: To analyze visual outcomes and accuracy of intraocular lens (IOL) calculation formulas in predicting postoperative outcomes in patients undergoing flanged intrascleral IOL fixation. Design: Case Series. Subjects: Twenty-three patients who had undergone secondary IOL placement using flanged intrascleral fixation technique. Methods: Retrospective chart review. Main Outcome Measures: Corrected distance visual acuity (CDVA) and postoperative spherical equivalent based on manifest refraction. Results: Visual acuity improved from 20/577 to 20/58. Overall, the actual refraction was 0.06 D more myopic than predicted. Holladay 2, Sanders Retzlaff Kraff/Theoretical (SRK/T) and Barrett Universal II resulted in mild myopic surprise (-0.55, -0.18 and -0.20 D). Haigis and Hill-RBF (Radial Basis Function) resulted in mild hyperopic surprise (+0.28 and +0.28 D). Hoffer Q and Holladay 1 were the most accurate (-0.02D and -0.08 D). Conclusion: Flanged intrascleral IOL fixation improved vision even in patients with other posterior segment pathologies. The effective lens positioning is likely similar to in-the-bag positioning. Hoffer Q and Holladay 1 formulas with in-the-bag calculations were the most accurate.

Analysis of severity in ischemic stroke patients with coronary artery disease in the telestroke network.

Aim: This study investigated demographic and clinical risk factors associated with severity in acute ischemic stroke (AIS) patients with a history of coronary artery disease (CAD). Materials & methods: Multivariate logistic regression models were used to determine specific factors associated with worsening or improving neurologic functions among AIS patients with CAD treated in the telestroke. Results: AIS patients with CAD, peripheral vascular disease (OR: 3.995; 95% CI: 1.035-15.413; p = 0.044) and hypertension (OR: 6.056; 95% CI: 1.207-30.374; p = 0.029) were associated with worsening neurologic functions. Conclusion: Our findings suggest the need to develop strategic management to improve the care of AIS patients with a history of CAD that present with hypertension and peripheral vascular disease in the telestroke network.

This study investigated risk factors that contribute to poor outcomes in stroke patients with a history of coronary artery disease. We used advanced statistical approach to identify risk that contribute to poor neurologic functions. We observed that peripheral vascular disease and hypertension were associated with worsening neurologic functions. Our findings suggest the need to develop management plans to improve the care of acute ischemic stroke patients with a history of coronary artery disease that present with hypertension and peripheral vascular disease in the telestroke network.

Health Care Spending Effectiveness: Estimates Suggest That Spending Improved US Health From 1996 To 2016.

Health care spending effectiveness is the ratio of an increase in spending per case of illness or injury to an increase in disability-adjusted life-years (DALYs) averted per case. We report US spending-effectiveness ratios, using comprehensive estimates of health care spending from the Disease Expenditure Project and DALYs from the Global Burden of Disease Study 2017. We decomposed changes over time to estimate spending per case and DALYs averted per case, controlling for changes in population size, age-sex structure, and incidence or prevalence of cases. Across all causes of health care spending and disease burden, median spending was US$114,339 per DALY averted between 1996 and 2016. Twelve of thirty-four causes with the highest spending or highest burden had median spending that was less than $100,000 per DALY averted. Using decomposition results, we calculated an outcome-adjusted health care price index by assigning a dollar value to DALYs averted per case. When we used $100,000 as the dollar value per DALY averted, prices increased by 4 percent more than the broader economy; when we used $150,000 per DALY averted, relative prices fell by 13 percent, meaning that much of the growth in health care spending over time has purchased health improvements.

Stroke Severity among Men and Women Acute Ischemic Stroke Patients in the Telestroke Network.

INTRODUCTION: This study investigates gender differences among stroke patients treated in the telestroke network using specific risk factors that contribute to stroke severity. METHODS: We examined gender differences in stroke severity among 454 patients hospitalized with acute ischemic stroke (AIS). The logistic regression model was used to predict clinical risk factors associated with stroke severity in men and women AIS patients. RESULTS: In the adjusted analysis among women patients, increasing age (odds ratio [OR] = 1.05, 95% CI: 1.017-1.085, p = 0.003) and higher heart rate (OR = 1.031, 95% CI: 1.005-1.058, p = 0.021) were associated with worsening neurological functions, while direct admission (OR = 0.191, 95% CI: 0.079-0.465, p < 0.001) was associated with improving neurologic functions. Among men, hypertension (OR = 3.077, 95% CI: 1.060-8.931, p = 0.039) and higher international normalized ratio (INR) (OR = 21.959, 95% CI: 1.489-323.912, p = 0.024) were associated with worsening neurologic functions, while Caucasian (OR = 0.181, 95% CI: 0.062-0.526, p = 0.002) and obesity (OR = 0.449, 95% CI: 0.203-0.99, p = 0.047) were associated with neurologic improvement. CONCLUSION: Increasing age and heart rate in women, hypertension and greater INR in men contribute to worsening neurologic functions. There is a need to develop strategies to improve the care of both men and women in the telestroke network.

Cost-effectiveness of rotavirus vaccination in children under five years of age in 195 countries: A meta-regression analysis.

BACKGROUND: Rotavirus caused an estimated 151,714 deaths from diarrhea among children under 5 in 2019. To reduce mortality, countries are considering adding rotavirus vaccination to their routine immunization program. Cost-effectiveness analyses (CEAs) to inform these decisions are not available in every setting, and where they are, results are sensitive to modeling assumptions, especially about vaccine efficacy. We used advances in meta-regression methods and estimates of vaccine efficacy by location to estimate incremental cost-effectiveness ratios (ICERs) for rotavirus vaccination in 195 countries. METHODS: Beginning with Tufts University CEA and Global Health CEA registries we used 515 ICERs from 68 articles published through 2017, extracted 938 additional one-way sensitivity analyses, and excluded 33 ICERs for a sample of 1,418. We used a five-stage, mixed-effects, Bayesian metaregression framework to predict ICERs, and logistic regression model to predict the probability that the vaccine was cost-saving. For both models, covariates were vaccine characteristics including efficacy, study methods, and country-specific rotavirus disability-adjusted life-years (DALYs) and gross domestic product (GDP) per capita. All results are reported in 2017 United States dollars. RESULTS: Vaccine efficacy, vaccine cost, GDP per capita and rotavirus DALYs were important drivers of variability in ICERs. Globally, the median ICER was $2,289 (95% uncertainty interval (UI): $147-$38,993) and ranged from $85 per DALY averted (95% UI: $13-$302) in Central African Republic to $70,599 per DALY averted (95% UI: $11,030-$263,858) in the United States. Among countries eligible for support from Gavi, The Vaccine Alliance, the mean ICER was $255 per DALY averted (95% UI: $39-$918), and among countries eligible for the PAHO revolving fund, the mean ICER was $2,464 per DALY averted (95% UI: $382-$3,118). CONCLUSION: Our findings incorporate recent evidence that vaccine efficacy differs across locations, and support expansion of rotavirus vaccination programs, particularly in countries eligible for support from Gavi, The Vaccine Alliance.

Frequent Drivers, Occasional Passengers: Signals of Symbiont-Driven Seasonal Adaptation and Hitchhiking in the Pea Aphid, Acyrthosiphon pisum.

Insects harbor a variety of maternally inherited bacterial symbionts. As such, variation in symbiont presence/absence, in the combinations of harbored symbionts, and in the genotypes of harbored symbiont species provide heritable genetic variation of potential use in the insects' adaptive repertoires. Understanding the natural importance of symbionts is challenging but studying their dynamics over time can help to elucidate the potential for such symbiont-driven insect adaptation. Toward this end, we studied the seasonal dynamics of six maternally transferred bacterial symbiont species in the multivoltine pea aphid (Acyrthosiphon pisum). Our sampling focused on six alfalfa fields in southeastern Pennsylvania, and spanned 14 timepoints within the 2012 growing season, in addition to two overwintering periods. To test and generate hypotheses on the natural relevance of these non-essential symbionts, we examined whether symbiont dynamics correlated with any of ten measured environmental variables from the 2012 growing season, including some of known importance in the lab. We found that five symbionts changed prevalence across one or both overwintering periods, and that the same five species underwent such frequency shifts across the 2012 growing season. Intriguingly, the frequencies of these dynamic symbionts showed robust correlations with a subset of our measured environmental variables. Several of these trends supported the natural relevance of lab-discovered symbiont roles, including anti-pathogen defense. For a seventh symbiont-Hamiltonella defensa-studied previously across the same study periods, we tested whether a reported correlation between prevalence and temperature stemmed not from thermally varying host-level fitness effects, but from selection on co-infecting symbionts or on aphid-encoded alleles associated with this bacterium. In general, such "hitchhiking" effects were not evident during times with strongly correlated Hamiltonella and temperature shifts. However, we did identify at least one time period in which Hamiltonella spread was likely driven by selection on a co-infecting symbiont-Rickettsiella viridis. Recognizing the broader potential for such hitchhiking, we explored selection on co-infecting symbionts as a possible driver behind the dynamics of the remaining six species. Out of twelve examined instances of symbiont dynamics unfolding across 2-week periods or overwintering spans, we found eight in which the focal symbiont underwent parallel frequency shifts under single infection and one or more co-infection contexts. This supported the idea that phenotypic variation created by the presence/absence of individual symbionts is a direct target for selection, and that symbiont effects can be robust under co-habitation with other symbionts. Contrastingly, in two cases, we found that selection may target phenotypes emerging from symbiont co-infections, with specific species combinations driving overall trends for the focal dynamic symbionts, without correlated change under single infection. Finally, in three cases-including the one described above for Hamiltonella-our data suggested that incidental co-infection with a (dis)favored symbiont could lead to large frequency shifts for "passenger" symbionts, conferring no apparent cost or benefit. Such hitchhiking has rarely been studied in heritable symbiont systems. We propose that it is more common than appreciated, given the widespread nature of maternally inherited bacteria, and the frequency of multi-species symbiotic communities across insects.

Variation in Health Care Access and Quality Among US States and High-Income Countries With Universal Health Insurance Coverage.

Importance: Based on mortality estimates for 32 causes of death that are amenable to health care, the US health care system did not perform as well as other high-income countries, scoring 88.7 out of 100 on the 2016 age-standardized Healthcare Access and Quality (HAQ) index. Objective: To compare US age-specific HAQ scores with those of high-income countries with universal health insurance coverage and compare scores among US states with varying insurance coverage. Design, Setting, and Participants: This cross-sectional study used 2016 Global Burden of Diseases, Injuries, and Risk Factor study results for cause-specific mortality with adjustments for behavioral and environmental risks to estimate the age-specific HAQ indices. The US national age-specific HAQ scores were compared with high-income peers (Canada, western Europe, high-income Asia Pacific countries, and Australasia) in 1990, 2000, 2010, and 2016, and the 2016 scores among US states were also analyzed. The Public Use Microdata Sample of the American Community Survey was used to estimate insurance coverage and the median income per person by age and state. Age-specific HAQ scores for each state in 2010 and 2016 were regressed based on models with age fixed effects and age interaction with insurance coverage, median income, and year. Data were analyzed from April to July 2018 and July to September 2020. Main Outcomes and Measures: The age-specific HAQ indices were the outcome measures. Results: In 1990, US age-specific HAQ scores were similar to peers but increased less from 1990 to 2016 than peer locations for ages 15 years or older. For example, for ages 50 to 54 years, US scores increased from 77.1 to 82.1 while high-income Asia Pacific scores increased from 71.6 to 88.2. In 2016, several states had scores comparable with peers, with large differences in performance across states. For ages 15 years or older, the age-specific HAQ scores were 85 or greater for all ages in 3 states (Connecticut, Massachusetts, and Minnesota) and 75 or less for at least 1 age category in 6 states. In regression analysis estimates with state-fixed effects, insurance coverage coefficients for ages 20 to 24 years were 0.059 (99% CI, 0.006-0.111); 45 to 49 years, 0.088 (99% CI, 0.009-0.167); and 50 to 54 years, 0.101 (99% CI, 0.013-0.189). A 10% increase in insurance coverage was associated with point increases in HAQ scores among the ages of 20 to 24 years (0.59 [99% CI, 0.06-1.11]), 45 to 49 years (0.88 [99% CI, 0.09-1.67]), and 50 to 54 years (1.01 [99% CI, 0.13-1.89]). Conclusions and Relevance: In this cross-sectional study, the US age-specific HAQ scores for ages 15 to 64 years were low relative to high-income peer locations with universal health insurance coverage. Among US states, insurance coverage was associated with higher HAQ scores for some ages. Further research with causal models and additional explanations is warranted.

Cost-effectiveness of HPV vaccination in 195 countries: A meta-regression analysis.

Cost-effectiveness analysis (CEA) is a well-known, but resource intensive, method for comparing the costs and health outcomes of health interventions. To build on available evidence, researchers are developing methods to transfer CEA across settings; previous methods do not use all available results nor quantify differences across settings. We conducted a meta-regression analysis of published CEAs of human papillomavirus (HPV) vaccination to quantify the effects of factors at the country, intervention, and method-level, and predict incremental cost-effectiveness ratios (ICERs) for HPV vaccination in 195 countries. We used 613 ICERs reported in 75 studies from the Tufts University's Cost-Effectiveness Analysis (CEA) Registry and the Global Health CEA Registry, and extracted an additional 1,215 one-way sensitivity analyses. A five-stage, mixed-effects meta-regression framework was used to predict country-specific ICERs. The probability that HPV vaccination is cost-saving in each country was predicted using a logistic regression model. Covariates for both models included methods and intervention characteristics, and each country's cervical cancer burden and gross domestic product per capita. ICERs are positively related to vaccine cost, and negatively related to cervical cancer burden. The mean predicted ICER for HPV vaccination is 2017 US$4,217 per DALY averted (95% uncertainty interval (UI): US$773-13,448) globally, and below US$800 per DALY averted in 64 countries. Predicted ICERs are lowest in Sub-Saharan Africa and South Asia, with a population-weighted mean ICER across 46 countries of US$706 per DALY averted (95% UI: $130-2,245), and across five countries of US$489 per DALY averted (95% UI: $90-1,557), respectively. Meta-regression analyses can be conducted on CEA, where one-way sensitivity analyses are used to quantify the effects of factors at the intervention and method-level. Building on all published results, our predictions support introducing and expanding HPV vaccination, especially in countries that are eligible for subsidized vaccines from GAVI, the Vaccine Alliance, and Pan American Health Organization.